@MedicalBooksStore 2014 Contraception

Contraception and
Pregnancy in Patients with

Rheumatic Disease
Lisa R. Sammaritano
Bonnie L. Bermas
Editors
123
Contraception and Pregnancy in Patients
with Rheumatic Disease
Lisa R. Sammaritano • Bonnie L. Bermas
Editors
Contraception and Pregnancy

in Patients with
Rheumatic Disease
Editors
Lisa R. Sammaritano Bonnie L. Bermas
Division of Rheumatology Division of Rheumatology
Hospital for Special Surgery Brigham and Women’s Hospital
Weill Cornell Medical College Harvard Medical School
New York, NY, USA Boston, MA, USA
ISBN 978-1-4939-0672-7 ISBN 978-1-4939-0673-4 (eBook)

DOI 10.1007/978-1-4939-0673-4
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2014940170
© Springer Science+Business Media New York 2014

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To our patients, who make going
to work a pleasure;
To our families, who make coming
home a joy.
Lisa R. Sammaritano
Bonnie L. Bermas
Preface
Rheumatologic diseases disproportionally impact women during their reproductive

years. Rheumatologists are not trained as obstetricians and many of us lack the
experience of managing pregnant patients. Similarly, most obstetricians are not
familiar with the intricacies of treating rheumatologic disorders. Thus, clini-
cians are often faced with difficult management issues that surround family
planning including contraception, assisted reproductive technologies, preg-
nancy, and nursing.
The various rheumatologic disorders impact pregnancy outcomes differently.
Some diseases such as systemic lupus erythematosus (SLE) can increase the risk of
pregnancy complications. Others such as rheumatoid arthritis (RA) are less likely to
do so. In turn, pregnancy itself induces immunologic changes that can either cause
symptoms to improve or worsen. Competing needs of the developing fetus and the
mother may limit medications typically used in disease management, compounding
the challenge of disease management. Additionally, the type of contraception and
method of assisted reproductive technology may need to be adjusted in women with
rheumatologic disorders.
In creating this textbook, our hope was to provide information and guidance to
clinicians in the area of reproduction and rheumatic disorders. What follows sum-
marizes the current state of knowledge in this area. This textbook starts by review-
ing the immunology and obstetric management of pregnancy in general. It then
provides general guidelines for pre-pregnancy assessment of the rheumatology
patient. In Part II, pregnancy in specific rheumatologic disorders is discussed,
including SLE, Sjogren’s syndrome, mixed connective tissue disease, undifferenti-
ated connective tissue disease, antiphospholipid syndrome, RA and seronegative
spondyloarthropathy, systemic sclerosis, vasculitides, and inflammatory myositis.
In Part III, contraception and assisted reproductive technology methods are
reviewed. Finally, the topics of neonatal lupus, medication use during pregnancy
and lactation, and the long-term outcome of children of rheumatic disease patients
are covered.
vii
viii Preface
As rheumatologists who have been interested in this field for many years, we
have faced many challenges of family planning in our patients with rheumatologic
disorders. Along with these challenges have come incredibly gratifying experi-
ences in negotiating contraception and pregnancy alongside these patients. We are
grateful to them for letting us participate in these journeys. We are also indebted to
our coauthors, each of whom provided invaluable expertise in an important area in
this field.
New York, NY, USA Lisa R. Sammaritano

Boston, MA, USA Bonnie L. Bermas
Contents
Part I Basics of Pregnancy
1 Immunology of Pregnancy ..................................................................... 3

Danny J. Schust and Amanda J. Stephens
2 Normal Pregnancy, Pregnancy Complications,
and Obstetric Management.................................................................... 31
D. Ware Branch and Luchin F. Wong
3 General Approach: Pre-pregnancy Assessment
of the Rheumatic Disease Patient .......................................................... 63
Lisa R. Sammaritano and Bonnie L. Bermas
Part II Pregnancy in Specific Rheumatic Diseases
4 Systemic Lupus Erthematosus ............................................................... 79

Sara Wasserman and Megan E.B. Clowse
5 Pregnancy in Sjogren’s Syndrome, Mixed Connective Tissue
Disease, and Undifferentiated Connective Tissue Disease................... 99
Bonnie L. Bermas and Lisa R. Sammaritano
6 Antiphospholipid Syndrome .................................................................. 109
Alana B. Levine and Michael D. Lockshin
7 Rheumatoid Arthritis and Seronegative Spondyloarthropathy ......... 139
Monika Østensen and Marianne Wallenius
8 Pregnancy in Patients with Systemic Sclerosis ..................................... 159
Cecily A. Clark-Ganheart, Julia Timofeev, and Virginia D. Steen
9 Vasculitis and Pregnancy........................................................................ 171
Lindsay Lally and Robert F. Spiera
ix
x Contents
10 Myositis and Pregnancy ......................................................................... 185

Stephen J. Di Martino
Part III Additional Reproductive Issues
11 Contraception in Rheumatic Disease Patients ..................................... 201

Lisa R. Sammaritano
12 Assisted Reproductive Techniques in Rheumatic
Disease Patients ....................................................................................... 229
Carl A. Laskin, Kenneth I. Cadesky, Christine A. Clark,
and Karen A. Spitzer
13 Neonatal Lupus ....................................................................................... 251
Barbara Mendez, Amit Saxena, Jill P. Buyon, and Peter M. Izmirly
14 The Medical Management of the Rheumatology
Patient During Pregnancy ...................................................................... 273
Bonnie L. Bermas
15 Long-Term Outcome of Children of Rheumatic
Disease Patients ....................................................................................... 289
Cecilia Nalli, Alessandro Iodice, Rossella Reggia,
Laura Andreoli, Andrea Lojacono, Mario Motta, Antonella Meini,
Elisa Fazzi, and Angela Tincani
Erratum ........................................................................................................... E1
Index ................................................................................................................. 305
Contributors
Laura Andreoli Rheumatology and Clinical Immunology, Department of Clinical

and Experimental Sciences, Spedali Civili and University of Brescia, Brescia, Italy
Bonnie L. Bermas Division of Rheumatology, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
D. Ware Branch Department of Obstetrics and Gynecology, University of Utah
Health Sciences Center and Intermountain Health Care, Salt Lake City, UT, USA
Jill P. Buyon Department of Rheumatology, New York University School of
Medicine, New York, NY, USA
Kenneth I. Cadesky Department of Obstetrics and Gynecology (Reproductive
Endocrinology and Infertility), Mount Sinai Hospital; LifeQuest Centre for
Reproductive Medicine, Toronto, ON, Canada
Christine A. Clark LifeQuest Centre for Reproductive Medicine, Toronto,
ON, Canada
Cecily A. Clark-Ganheart Department of Obstetrics & Gynecology, Division of
Maternal-Fetal Medicine, Medstar Washington Hospital Center, Medstar Georgetown
University Hospital, Washington, DC, USA
Megan E.B. Clowse Division of Rheumatology and Immunology, Duke University
Hospital, Durham, NC, USA
Stephen J. Di Martino Division of Rheumatology, Hospital for Special Surgery,
New York, NY, USA
Elisa Fazzi Unit of Child and Adolescent Neuropsychiatry, Department of Clinical
Alessandro Iodice Unit of Child and Adolescent Neuropsychiatry, Department of
Clinical and Experimental Sciences, Spedali Civili and University of Brescia,
Brescia, Italy
xi
xii Contributors
Peter M. Izmirly Department of Rheumatology, New York University School of

Medicine, New York, NY, USA
Lindsay Lally Division of Rheumatology, Hospital for Special Surgery,
New York, NY, USA
Carl A. Laskin Departments of Medicine (Rheumatology) and Obstetrics &
Gynecology, (Reproductive Endocrinology and Infertility), LifeQuest Centre for
Reproductive Medicine, University of Toronto, Toronto, ON, Canada
Alana B. Levine Division of Rheumatology, Hospital for Special Surgery,
New York, NY, USA
Michael D. Lockshin Division of Rheumatology, Hospital for Special Surgery,
New York, NY, USA
Andrea Lojacono Obstetrics and Gynecology, Department of Clinical and
Experimental Sciences, Spedali Civili and University of Brescia, Brescia, Italy
Antonella Meini Unit of Pediatric Immunology and Rheumatology, Pediatric Clinic,
Spedali Civili and University of Brescia, Brescia, Italy
Barbara Mendez Albert Einstein College of Medicine, Department of
Rheumatology, Montefiore Medical Specialists, Scarsdale, NY, USA
Mario Motta Neonatology and NICU, Spedali Civili and University of Brescia,
Brescia, Italy
Cecilia Nalli Rheumatology and Clinical Immunology, Department of Clinical
Monika Østensen Department of Rheumatology, National Service for Pregnancy
and Rheumatic Disease, University Hospital of Trondheim, Trondheim, Norway
Rossella Reggia Rheumatology and Clinical Immunology, Department of Clinical
Lisa R. Sammaritano Division of Rheumatology, Hospital for Special Surgery,
Weill Cornell Medical College, New York, NY, USA
Amit Saxena NYU Langone Medical Center, Center for Musculoskeletal Care,
New York, NY, USA
Danny J. Schust Department of Obstetrics, Gynecology and Women’s Health,
University of Missouri, Columbia, MO, USA
Robert F. Spiera Division of Rheumatology, Hospital for Special Surgery,
New York, NY, USA
Karen A. Spitzer LifeQuest Centre for Reproductive Medicine, Toronto,
ON, Canada
Contributors xiii
Virginia D. Steen Department of Medicine/Rheumatology, Medstar Georgetown

Amanda J. Stephens Department of Obstetrics, Gynecology and Women’s Health,
University of Missouri, Columbia, MO, USA
Julia Timofeev Department of Obstetrics & Gynecology, Division of Maternal-
Fetal Medicine, Medstar Washington Hospital Center, Medstar Georgetown
Angela Tincani Rheumatology and Clinical Immunology, Department of Clinical
Marianne Wallenius Department of Rheumatology, National Service for Pregnancy
and Rheumatic Disease, University Hospital of Trondheim, Trondheim, Norway
Institute of Neuroscience, Norwegian University of Science and Technology,
Trondheim, Norway
Sara Wasserman Division of Rheumatology and Immunology, Duke University
Hospital, Durham, NC, USA
Luchin F. Wong Department of Obstetrics and Gynecology, University of Utah
Health Sciences Center, Salt Lake City, UT, USA
Part I
Basics of Pregnancy
Chapter 1
Immunology of Pregnancy
Danny J. Schust and Amanda J. Stephens
Abbreviations
ADCC Antibody-dependent cellular cytotoxicity

ANG2 Angiopoietin 2
CMV Cytomegalovirus
CSA Chondroitin sulfate A
CTL Cytotoxic T lymphocyte
DAF Decay-accelerating factor
DC Dendritic cell
EVT Extravillous cytotrophoblast
hCG Human chorionic gonadotropin
HLA Human leukocyte antigen
IFN Interferon
IL Interleukin
KAR Killer activation receptor
KIRS Killer immunoglobulin-like receptors
LIF Leukemia inhibitory factor
LIRS Leukocyte immunoglobulin-like receptors
MAC Membrane attack complex
MBL Mannose-binding lectin
MCP Membrane cofactor protein
MHC Major histocompatibility complex
MS Multiple sclerosis
NF-κB Nuclear factor-kappa B
D.J. Schust, M.D. (*) • A.J. Stephens, M.D.

Department of Obstetrics, Gynecology and Women’s Health, University of Missouri,
500 North Keene Street, Suite 203, Columbia, MO 65203, USA
e-mail: SchustD@health.missouri.edu
L.R. Sammaritano and B.L. Bermas (eds.), Contraception and Pregnancy 3

in Patients with Rheumatic Disease, DOI 10.1007/978-1-4939-0673-4_1,
4 D.J. Schust and A.J. Stephens
NK Natural killer
PIBF Progesterone-induced binding factor
PIGF Placental growth factor
RA Rheumatoid arthritis
SLE Systemic lupus erythematosus
SynT Syncytiotrophoblast
TCR T cell receptor
Tfh Follicular helper T lymphocyte
TGF Transforming growth factor
Th T helper
TNF Tumor necrosis factor
Treg T regulatory lymphocyte
UL Unique long
uNK Uterine natural killer lymphocyte
US Unique short
VEGFC Vascular endothelial growth factor C
VZV Varicella zoster virus
Introduction
Through numerous pathways, the immune system works to protect an individual

from exogenous pathogens and from neoplastic cellular changes. During develop-
ment, immune cells are programmed to discriminate self from non-self and to
respond appropriately at initial encounters with self and foreign antigens. When this
recognition mechanism fails, the immune system may react inappropriately against
self antigens and initiate a series of events that result in autoimmune disorders.
During pregnancy, alterations of these recognition processes by the maternal
immune system determine the success or failure of continued fetal growth and
development until birth. Pregnancy presents a particular immunologic challenge
because the tissue antigens presented to the maternal immune system are a combi-
nation of self (maternally derived) and non-self (paternally derived) constituents.
The Menstrual and Reproductive Cycle
Throughout the menstrual cycle and pregnancy, changes occur within the lining
of the uterine cavity (endometrium) in response to reproductive hormones, particularly
the reproductive steroids, estrogen and progesterone [1]. The proliferative phase of
the menstrual cycle is characterized by estrogen dominant regeneration of the endo-
metrium [2]. After initial “healing,” regrowth of the ever-changing endometrial
“functionalis” layer begins approximately 5 days after the beginning of the men-
strual cycle, which is defined clinically as day 1 of bright red vaginal bleeding.
1 Immunology of Pregnancy 5
This regrowth results from rapid proliferation of the endometrial glands and stroma,
which gives this phase of the menstrual cycle its common name—the proliferative
phase. Important to this regrowth is a revascularization of the endometrium, which
was poorly vascularized during the relatively hypoxic “sloughing” phase of men-
struation. Alterations in the length of the proliferative phase are largely responsible
for variations from the classical 28 day menstrual cycle. Near the end of the prolif-
erative phase, endocrine, autocrine, and paracrine events within the hypothalamic–
pituitary–ovarian axis cause a rapid increase or surge in luteinizing hormone (LH)
secretion and ovulation occurs soon thereafter. During this time, local and systemic
progesterone levels begin to increase while estrogen levels decrease somewhat. If
implantation follows, progesterone levels continue to rise. This progesterone domi-
nant part of the menstrual cycle is called the luteal phase and its length is fairly
consistent from cycle to cycle. The endometrium of the luteal phase responds to this
new hormonal milieu by undergoing a transformation in preparation for implanta-
tion that is called decidualization. The endometrium is now renamed the decidua.
Between cycle days 20–24, specific morphologic changes in the decidua character-
ize the “window of implantation,” including decreased microvilli and the develop-
ment of cilia with luminal protrusions on the apical glandular surface called
pinopodes [3]. The maternal uterine spiral arteries develop and continue to grow.
The dominant follicle that released the oocyte at the time of ovulation develops into
the corpus luteum which produces progesterone to maintain an early pregnancy
until the placenta is capable of sufficient progesterone production, approximately
7–9 weeks of gestation. If implantation does not occur, the corpus luteum regresses
in a predictable fashion. In response to falling levels of estrogen and progesterone,
a series of cytokine-, chemokine-, and prostaglandin-mediated events lead to endo-
metrial hypoxia, endometrial shedding, and menstruation. If implantation occurs
and the pregnancy progresses normally, estrogen, progesterone, human chorionic
gonadotropin (hCG), and a variety of other hormones continue to increase to sup-
port the developing embryo.
Implantation is one of the most complex and important events of pregnancy and
continues to be targeted in many investigations of pregnancy immunology. At least
50 % of all pregnancies fail to synchronize the necessary events of implantation and
only 25 % of all fertilized ova will generate a live birth. The majority of early preg-
nancy losses are of chromosomally abnormal human embryos [4–6]. Major histo-
compatibility antigens that have the potential to induce an alloimmune response in
the maternal host are expressed on the surfaces of human preimplantation embryos
but the role of these antigens in pregnancy has not been fully elucidated (described
in detail below) [7]. While it is generally accepted that the mother recognizes and
responds to these alloantigens, it is possible that aberrant maternal recognition of
these antigens in certain pregnancies may play a role in implantation failure [8].
Approximately 6 days after fertilization in the fallopian tube, the develop-
ing embryo becomes a blastocyst that has an inner cell mass that will develop
into the fetus and an outer trophectoderm layer, which will subsequently dif-
ferentiate to become the multilayered placenta. Once the blastocyst attaches to
the decidua, the trophectoderm differentiates into the syncytiotrophoblast and
cytotrophoblast. Initially, the syncytiotrophoblast invades into the decidua and

allows the blastocyst to be enveloped with maternal tissue. The trophoblast
quickly perforates the maternal capillaries and the spaces within the syncy-
tium are filled with maternal blood. These areas enlarge and fuse to become
the intervillous space of the human placenta, the site at which nutrient and gas
exchange occurs between the mother and her developing embryo. Two weeks
after implantation, the cytotrophoblast cell subpopulation in the placenta pro-
liferates into buds that grow through the syncytium. The trophoblast cells of
the post-implantation placenta are generally divided into two populations: (1)
villous trophoblast that covers the chorionic villi and interacts with maternal
blood in the intervillous space and (2) extravillous trophoblast ( EVT) that
migrate into the decidua and surround the maternal spiral arteries, destroying
the muscular walls and leading to endothelial cell swelling. Like syncytiotro-
phoblast, EVT come into direct contact with maternal peripheral blood
(Fig. 1.1 ) [ 9 ]. Remodeling of the maternal spiral arteries by endovascular tro-
phoblast creates low resistance vascular channels that are largely unable to
respond to maternal vasoactive stimuli; this prevents compromise of the utero-
placental blood flow during maternal stressors. The remaining extravillous
cytotrophoblast cells will be in direct contact with the immune cells of the
maternal decidua. EVT typically invade through the decidua and invasion can
extend as far as the inner third of the myometrium in healthy pregnancies.
Alterations in the depth of such invasion have been seen in pregnancy patholo-
gies such as preeclampsia and intrauterine growth restriction (poor invasion)
and placenta percreta (overly robust invasion).
Basic Principles of Immune Response
The immune system is divided into two general methods of response, the innate
immune response and the acquired immune response. Cooperation between these
two systems is often needed to provide effective responses to a foreign pathogen as
these responses differ in intensity, onset, and specificity.
Innate Immunity
When a foreign pathogen enters the body, the innate immune mediators are the first
to encounter the pathogen. The innate immune response is comprised of a variety of
cells and tissues that provide initial host defense. Epithelial tissues containing pro-
tective tight intercellular junctions, such as those in the skin and mucosal mem-
branes, are often the first location of pathogen exposure. Other components of the
innate immune response include phagocytic and cytotoxic cells and a range of
Fig. 1.1 The human maternal–fetal interface in early pregnancy. The fetal aspect of the maternal–
fetal interface is comprised of a very large number of branching placental villi that are bathed by the
maternal blood filling the intervillous space (IVS). Placental villi contain fetal vessels (FV) embed-
ded in stroma and covered by trophoblast. Floating villi (FV) and anchoring villi (AV) are covered
by a mostly continuous (in early pregnancy) layer of syncytiotrophoblast, the multinucleated syncy-
tium of cells that coats the IVS and comes into direct contact with maternal blood. Syncytiotrophoblast
is the product of fusion of the underlying cytotrophoblast progenitor cells. Unlike floating villi, which
float freely in the IVS, anchoring villi cross the IVS and attach to the maternal decidua (MD). At the
tips of the anchoring villi, some cytotrophoblast cells cease proliferating and transform into invasive
extravillous cytotrophoblast (EVT) cells. These cells leave the anchoring villi to invade through the
decidua, often reaching as far as the inner third of the uterine myometrium. A subset of extravillous
cytotrophoblast cells, called endovascular trophoblast (EnT) remodels the maternal uterine spiral
arteries (SpA), replacing cells of the maternal vascular wall and creating a vaso-inert conduit for the
maternal blood that dumps into the IVS after about 11–12 weeks of gestation. From soon after initial
implantation until about 10–11 weeks of gestation, extravillous trophoblast plugs the ends of the
SpA and the IVS is filled with nutrient rich exudates
effector molecules, including inflammatory response molecules, antimicrobial pep-

tides, and cytokines. The innate immune response is a rapid generalized response
that is not specific to the pathogen or other foreign antigen. It is unable to establish
memory toward a pathogen or other foreign antigen and therefore cannot develop
adaptations to the antigen that promote more rapid or robust immunologic responses
upon future exposure.
Acquired Immunity
The first exposure and resulting primary immune response to a foreign pathogen
induce other cells and pathways in the acquired immune system to form an adaptive
response to a subsequent exposure. When that same antigen is encountered a second
time, it will be confronted by a quantitatively and qualitatively different immune
response called a secondary response. Antigen-specific cells and molecules of the
acquired immune system often interact and cooperate with components of the innate
immune defense systems. For instance, antibodies of the acquired immune system
may bind to bacterial surface antigens leading to phagocytosis by macrophages of
the innate immune system. Macrophages can also process and present antigens to
specific T cells during a primary response.
Antigen-specific lymphocyte responses are characterized by their proliferative
capacity as well as by functional differentiation into cells with effector capacities
(i.e., the production of antibodies and cytokines) and the capacity for antigen-
specific memory.
Primary and Secondary Immune Responses
When naïve B cells recognize peptide antigens, they interact with CD4+ T cells to
produce both primary and secondary humoral immune responses. The primary
response to an antigen requires a large amount of antigenic stimulus and peaks
5–10 days after exposure. Primary responses typically secrete more IgM than IgG
and the scale of response is lower than the second exposure. Primary exposure pro-
motes the generation of memory B cells which then contributes to the secondary
immune response.
After subsequent exposures, the secondary humoral response occurs. This
response is faster acting, taking only 2–5 days to reach peak intensity and much
more robust than a primary response. A larger amount of IgG is secreted compared
to IgM. The IgG has multiple effects and can cross the placenta from mother to fetus
in increasing amounts beginning by about 15 weeks of gestation. IgG can bind anti-
gen in its variable region, causing recognition and internalization by phagocytic
cells. IgG also promotes antibody-dependent cellular cytotoxicity (ADCC) by sig-
naling lysis by cytotoxic T cells, Natural Killer (NK) cells, or NKT cells.
After antigen-induced proliferation, some of the newly developed lymphocytes
may commit to become long-term memory cells that survive and maintain their
antigen specificity for many years. Activated B cells will also undergo isotype
switching and change their antigen-specific immunoglobulin secretory product
from the IgM subtype to IgG, IgE, or IgA, each of which has distinct physiologic
and biologic functions. Through these processes, a maturing immune response
maintains antigen specificity while simultaneously establishing memory and func-
tional diversity.
Cellular Effectors of an Immune Response
Leukocytes, including lymphocytes, monocytes, macrophages, dendritic cells, neu-

trophils, basophils, and eosinophils, are the cellular effectors of the immune system
(Table 1.1). Lymphocytes are further divided based on their function and on cell
surface markers, called “cluster of differentiation” or CD markers. Lymphocytes
include T cells, B cells, and natural killer cells. B and T lymphocytes originate in
the bone marrow and play a role in antigen-specific immune responses.
T (Thymus-Derived) Cells
Prior to their entrance into the thymus, T cell precursors lack antigen receptors as
well as CD3, CD4, and CD8 surface proteins. All mature T cells have CD3 proteins
on their surface. As CD4 and CD8 negative T cells pass through the thymus, they
mature into T cells that initially express both CD4 and CD8 cell surface receptors.
Table 1.1 Cells involved in the innate and adaptive immune response
Innate immune system
Macrophages Phagocytosis
Antigen presentation
Produce IL-1, IL-8, TNF
Neutrophils Kill opsonized pathogens
NK cells Recognize cells lacking MHC class I products, viral infected cells,
and oncogenically transformed cells
Cytotoxic
γδ T cells Produce IL-10 and TGFβ
Adaptive immune system

Cytotoxic T-cell Lyse infected target cells
T-helper (Th) cells Cytokine-producing lymphocytes
Th1 Produces IL-2 and IFNγ
Activates cytotoxic T cells
Initiates delayed hypersensitivity
Th2 Produces IL-4, IL-5, and IL-13
Promotes antibody responses
Th17 Promotes inflammation
Produces IL-17
Recruits neutrophils
Treg Suppresses inflammation
Produces IL-10 and TGFβ
B-cell Produces antibodies
Presents antigen to Th cells
Dendritic cell Antigen presentation
IL interleukin, TNF tumor necrosis factor, NK natural killer, MHC major histocompatibility
complex, IFN interferon, TGF transforming growth factor
Maturation of the T cell continues as the cell migrates from the cortex of the thymus
to the medulla where the T cells will now express either CD4 or CD8. These cells
then migrate out of the thymus into the peripheral blood and tissues. CD4 positive
T cells develop into helper T cells upon reaching peripheral lymphoid tissues.
Despite its certain oversimplification, helper T cells are often subdivided into sev-
eral groups, with categorization based largely on effector function and the identity
of the helper cells’ dominant cytokine secretory products (for further detail, see
section on cytokines). For example, T helper cell type 1 (Th-1) cells activate cyto-
toxic T cells by producing interleukin (IL)-2; they aid in the initiation of delayed-
type hypersensitivity through their effects on macrophages and they produce
cytokines that help to orchestrate B cells isotype switching. Th-2 cells produce IL-4
and IL-5, which promote B cell differentiation into antibody-producing plasma
cells. In contrast to CD4 positive helper T cells, CD8 positive T cells become cyto-
lytic T cells (CTLs) or suppressor T cells (currently called regulatory T (Treg) cells)
upon leaving the thymus [10]. CTLs lyse infected or otherwise altered target cells.
B (Bone Marrow-Derived) Cells
B cells mature within the bone marrow prior to their migration into the peripheral
immune system. B cells differentiate into plasma cells that produce the antibodies of
the humoral immune response. They may also present antigen to helper T cells [11].
NK (Natural Killer) Cells
Natural killer cells are circulating lymphocytes that are classically ascribed non-
antigen-specific responses, although this concept is still being fully clarified. NK
cells recognize cells lacking major histocompatibility complex (MHC) class I prod-
ucts (see below) and attack virally infected or oncogenically transformed target cells.
They also display cell surface receptors (specifically CD16) that enable recognition
of antibody-coated target cells and allow NK cells to function as a major effector of
ADCC. The NK cell can kill target cells through the release of cytotoxic granules
containing perforin and granzymes [12]. Activated NK cells can also secrete cyto-
kines, including interferon (IFN)-γ and tumor necrosis factor-alpha (TNF-α) [12].
Monocytes, Macrophages, and Dendritic Cells
Monocytes are derived from bone marrow stem cells and circulate in the peripheral
blood and tissues. Within specific tissues, monocytes mature into macrophages.
Macrophages are capable of phagocytosis, antigen presentation, and cytokine
production [13, 14]. When tissue macrophages encounter bacteria, viruses, and
other foreign antigens, they may phagocytize some of the encountered antigens. The
macrophage phagosome can then fuse with lysosomes, resulting in the production
and/or release of reactive oxygen and nitrogen compounds and lysosomal enzymes
that can destroy the pathogen. After ingestion, class II MHC proteins on the cell
surface of macrophages can also present fragments of the antigen to CD4 positive
helper T cells. Macrophages can produce IL-1 and tumor necrosis factor which are
important for inflammation. They can also secrete IL-8 and attract neutrophils and
T cells to the site of infection. Dendritic cells, like macrophages, are antigen-presenting
cells that express class II MHC proteins and react with CD4 positive T cells [15].
They are also important in the primary antibody response of B cells.
Other Effector Cells
Neutrophils, eosinophils, and basophils are effector cells of the innate immune sys-
tem whose reactivities are most specific for certain pathogens. Each has also been
associated with specific immune-mediated diseases. Eosinophils have classically
been described as central in defense against parasites and in asthma. Basophils are
important in immediate hypersensitivity reactions.
Soluble Components of Immune Responses
Immunoglobulins and Humoral Immunity
Immunoglobulins (Ig) are composed of dimerized heavy and light chains [13]. The
N-terminal portions of each chain are highly polymorphic and are therefore termed
the variable regions. The variable region of one heavy change combines with the
variable region of a light chain to confer the antigen specificity of the immuno-
globulin. The C-terminal segments of each immunoglobulin chain have minimal
polymorphism and are called the constant regions. Constant segments are respon-
sible for the specific biologic functions of the immunoglobulin molecule, including
complement activation and binding to cell surface receptors. Ig isotypes include
IgA, IgD, IgE, IgG, and IgM. IgG, IgE, and IgD typically present as single Ig mono-
mers; IgA circulates as dimers; and IgM as pentamers.
Each Ig isotype has characteristic functions. IgA dimers are associated with
mucosal surfaces. IgE molecules are involved in immediate hypersensitivity reac-
tions by releasing mediators from mast cells and basophils upon exposure to anti-
gens. Membrane-bound IgD and IgM interact with antigen-recognizing B cell
receptors on naïve B cells. Pentavalent IgM can fix and activate the complement
cascade. Due to its small size, IgG is the only immunoglobulin that can pass through
the placenta in significant amounts.
Fig. 1.2 The complement

cascade. The complement
cascade can be activated via
several pathways. The
classical pathway is activated
by the pathogen surface itself
or by the binding of
complement component C1
(C1q) to free antibody
complexes or antibody bound
to pathogen. The lectin
pathway is activated by the
binding of mannose-binding
lectin (MBL) to components
of the pathogen surface.
In the alternative pathway,
active complement
component C3b binds
directly to the pathogen. All
pathways set in motion a
series of enzymatic cleavage
steps involving several
complement components
(C5–C9) that result in direct
or indirect attack on the
inciting pathogen. Here,
direct cell lysis occurs
through formation of a
membrane attack complex
(MAC)
Complement
The complement components represent an important effector arm of immune pro-

tection. The system is composed of an array of circulating proteins in the maternal
blood stream that can be activated by classical, alternative, and lectin pathways
(Fig. 1.2). Activation of these pathways causes a cascade of downstream effects
involving proteolysis and assembly in a manner analogous to the coagulation cas-
cade. Through the classical pathway, complement component C1q binds to antigen–
antibody complexes (IgG or IgM) or directly to the surface of a microorganism. In
the alternative pathway, spontaneously activated C3b binds directly to the pathogen.
The lectin pathway is similar to the classical pathway; however, mannose-binding

lectin (MBL) binds to the pathogen surface. After initial binding, a series of enzy-
matic cleavages ensues, creating C4b and C2a components that bind and produce
C3-convertase, which ultimately drives the production of C5a, the most potent of
the anaphylatoxins. The outcomes of activation of the complement cascade include
opsonization or phagocytosis of antigens, chemotaxis or recruitment of macro-
phages and neutrophils, and direct cell lysis. The latter can occur through the forma-
tion of a membrane attack complex (MAC) that creates an ion permeable
transmembrane pore in the target cell and promotes osmotic lysis of this target.
Cytokines
In conjunction with immunoglobulins and the components of the complement cas-

cade, cytokines (e.g., interleukins, IFNs, tumor necrosis factors, transforming
growth factors) and chemokines complete the list of soluble mediators of immune
responses. Cytokines, secreted proteins made by immune cells, are pleiotropic and
have a variety of effects on a number of different cell surface receptors. Cytokines
can activate or inhibit other cells of the immune system. Cytokines often have com-
plementary and/or redundant effects at cell surface receptors. Once produced, they
are secreted rapidly and produce autocrine, paracrine, or endocrine responses.
Cytokines are particularly integral to T helper cell differentiation. CD4+ T helper
cells travel from the thymus through the peripheral tissues as naïve Th0 cells. When
first presented with an antigen, the direction of CD4+ T helper cell differentiation is
based upon the cytokines released from other antigen-presenting cells, such as den-
dritic cells and macrophages as well as the cell surface co-receptors expressed on
the Th0 cell [16]. The differentiation of the CD4+ T helper cell into T helper cell
subtypes is termed polarization and specific cytokines appear to direct this process
(Fig. 1.3). Interleukin 12 (IL12), IL 18, and interferon gamma (IFNγ) stimulate the
Th0 cell to differentiate into a Th1 cell capable of secreting inflammatory cytokines
including IFNγ, IL1, and TNF-α. If the Th0 cell is exposed to IL4, the Th0 cell then
develops into a Th2 cell that secretes IL4, IL5, IL9, and IL13 [17]. Th2 cells partici-
pate in allergic-type responses, including mast cell and eosinophil activation and
antibody production. Although the Th1:Th2 paradigm was the first to be described
in detail, other types of T helper cells, their cytokine secretory profiles, and their
characteristic transcription factors have been and continue to be reported. Th17
cells are produced from exposure to transforming growth factor beta (TGFβ) and
IL-6. These cells secrete IL17 and IFNγ [17]. T regulatory (Treg) cells are produced
in the presence of TGFβ and the transcription factor forkhead box P3 (Foxp3)
and secrete IL10, IL35 and TGFβ [18]. Tregs have several activities, including: (1)
reducing the cytolytic activity of NK cells [19], (2) inhibiting the development of
dendritic cells [20], and (3) decreasing CD3+ T cell proliferation and cytokine
release [21]. Peripheral and endometrial Tregs may be particularly important in
pregnancy health and maintenance [22, 23]. Specific T helper cell subtype secretory
products tend to further amplify the production of identical cells through positive
Fig. 1.3 T helper cell differentiation. Differentiation of T helper cells from naïve Th0 cells to
T helper cell subpopulations characterized by distinct cytokine secretory profiles is largely depen-
dent on the cytokine microenvironment present at the site of antigen presentation to the naïve cell.
The number of described T helper cell subtypes continues to grow and one depiction of these
subtypes is shown here. The transcription factors related to a particular differentiation pathway are
included below the subtype (e.g., FoxP3 for T regulatory cell differentiation) as are several of the
characteristic secretory products of a given subtype. While T helper cell differentiation was once
thought to be unidirectional, this is now being questioned. Activity and re-differentiation of par-
ticular T helper cell subpopulations can be modulated by the secretory products of other T helper
cell subpopulations (depicted as dotted and solid curved lines). IL interleukin, IFN interferon, TGF
transforming growth factor
and negative feedback loops. Although the development of T helper cell subtypes
was once thought to be unidirectional, recent descriptions of T helper cell plasticity
show that regulation of this development is quite complex [16].
Basis of Immune Specificity and Immune Cell Education
Unlike the innate immune response, effector cells of the acquired immune response
typically cannot recognize free antigen. Rather, they must recognize antigen in the
context of an antigen-presenting cell. These antigens are typically processed and
Fig. 1.4 The MHC region of human chromosome 6. Many of the genes encoding proteins integral
to antigen presentation are located within a fairly well-characterized region of the short (p) arm of
human chromosome 6. Called the MHC, the region is further subdivided into a three general groups
of loci. The class I region contains genes encoding MHC class I molecules, such as human leuko-
cyte antigens A, B, C, E, F, and G (HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G). The
class II region contains genes encoding MHC class II molecules such as HLA-DR and HLA-DQ.
The class III region contains a varied group of genes encoding molecules important to immune
recognition and response. These include MHC-like molecules involved in innate immune recogni-
tion (MICA and MICB), several of the complement components (C2, C4A, C4B) and many others
presented on the cell surface of antigen-presenting cells in the innate immune sys-
tem to the effector cells of the acquired immune system. These specific effector
cells distinguish the cell presenting the antigen as “self” and the antigen as “for-
eign,” which the effector cell can do because it has been previously “educated” to
recognize these distinctions (see below). Antigen presentation is essential for devel-
opment of cellular and humoral immune responses [24]; the specificity of this pre-
sentation is exquisitely sensitive at the level of a particular effector cell but
remarkably broad when all “educated” effector cells are considered.
The MHC
The MHC is a large cluster of highly polymorphic genes that are found on the short
arm of human chromosome 6 (Fig. 1.4). The protein products of the MHC aid in the
distinction between self and non-self or altered-self (e.g., pathogens, foreign tis-
sues, and oncogenically transformed cells/proteins). MHC-encoded proteins include
two major types of antigen-presenting molecules called MHC class I and MHC
class II products. MHC class I molecules are further subdivided into classical, class
Ia (human leukocyte antigen (HLA)-A, -B, and -C), and nonclassical, class Ib
(HLA-E, -F, and -G) constituents.
Class Ia molecules are expressed on the surface of nearly every nucleated cell in
the human body. Class Ia molecules provide defense against intracellular pathogens
such as viruses by presenting pathogen-derived antigens to cytotoxic T cells. They
also aid in the detection of oncogenically transformed cells by presenting altered
intracellular protein antigens to immune effector cells. MHC class Ia molecules are
central to the distinction between self and non-self, which is best exemplified in
transplant rejection. MHC class Ia molecules act as ligands for the T cell receptor
(TCR) on CD8+ cytotoxic/suppressor T cells. MHC class Ia antigens can also par-
ticipate in the inhibition or activation of NK cells through inhibitory NK-cell recep-
tors and activating NK-cell receptors (killer activation receptor, KAR). Nonclassical
MHC class Ib molecules are less polymorphic and likely have less importance in
antigen presentation; however, continued research is investigating their role in
immunologic disease. These MHC class I subtypes appear to be particularly rele-
vant in the immunology of the maternal–fetal interface (see below)
MHC class II molecules (HLA-DR, -DP, and -DQ) are present on the surface of
a smaller fraction of cells than that expressing MHC class I. MHC class II expres-
sion is generally limited to antigen-presenting cells, including dendritic cells, mac-
rophages, monocytes, B cells, and a variety of tissue-specific antigen presenters
(e.g., Langerhan’s cells in the skin). MHC class II molecules are important in the
removal of extracellular pathogens such as bacteria. MHC class II molecules inter-
act with CD4+ T helper cells leading to humoral immune responses.
Lymphocyte Education
The ability to determine self from non-self is an imperative function of lympho-

cytes. Immature B cells within the bone marrow that recognize self antigens with
high avidity undergo negative section and die by apoptosis. The remaining B cells
within the bone marrow are tolerant to self antigens and this tolerance is indepen-
dent of MHC molecules [25].
T lymphocytes, however, undergo a more complex education during which MHC
molecules play a central role. Upon entering the thymus, immature T cells that lack
the TCR (the CD3 antigen is part of the TCR) and the co-receptors CD4 and CD8
come to express all three cell surface molecules and are considered “double (CD4
and CD8) positive” cells. T cells that recognize self MHC with low avidity undergo
positive selection. Among positively selected cells, those with receptors that recog-
nize self MHC class I molecules become CD8+ cytotoxic/suppressor T cells. Those
positively selected T cells with receptors that recognize self MHC class II molecules
become CD4+ helper T cells. Negative selection occurs when double positive cells
recognize self MHC with high avidity and these cells are selected for deletion. If
this process is imperfect, there is potential for autoimmunity.
The Fetal Allograft
The maintenance of a successful pregnancy requires an intricate coordination and

balance between the mother and the developing embryo and fetus. In 1953, Medawar
proposed the idea of the fetal allograft [26]. He theorized that there was anatomic
separation between the mother and the fetus, that the fetus itself must be antigeni-
cally immature, and that the mother was immunologically inert during the pregnant
state. Over the last six decades these theories have helped guide the field of repro-
ductive immunology and have been advanced upon. It is now known that there is no
anatomic separation between the mother and the fetus. The fetus, a semi-allograft
carrying maternal and paternal antigens, possesses fetal trophoblast cells that are
antigenic and carry nonclassical MHC class I antigens. Finally, although altered, the
maternal immune system is fully functional during pregnancy.
Cellular Immune Effectors in Pregnancy
Peripheral Immune Cells During Pregnancy
One of the first changes noted within the maternal immune system during preg-
nancy is an increase in overall peripheral leukocyte number (Fig. 1.5) [27]. The
distribution of leukocyte types, quantities, locations, and functions is modified dur-
ing pregnancy and results in altered immune responses. Many of these alterations
likely contribute to the relapsing and remitting nature of some autoimmune disor-
ders during pregnancy.
Peripheral T Lymphocytes
Peripheral T cells exhibit decreased mitogen responses and diminished proliferative

responses during pregnancy [28]. Women with recurrent pregnancy loss do not
dampen their proliferative responses to recall antigens to the same extent as their
counterparts with uncomplicated pregnancy histories [29]. Memory CD4+ T cell
numbers decrease, naïve CD4+ T cell numbers increase, and there is an overall
decrease in the surface expression of activation markers HLA-DR and CD25 [30].
The quantity of circulating maternal Treg cells has also been shown to increase dur-
ing the first and second trimesters of human pregnancy [31], likely secondary to
increasing levels of systemic estradiol. Failure of Treg expansion in the periphery
(and in the decidua) has been linked to adverse pregnancy outcomes, including early
pregnancy loss [32, 33], preeclampsia, and preterm delivery [34].
Maternal progesterone levels are elevated throughout pregnancy and peak in the
third trimester. Progesterone may stimulate the synthesis of an incompletely
Fig. 1.5 Interfaces between maternal immune cells and trophoblast in the human placenta. Fetally
derived trophoblast comes into direct contact with maternal blood at three distinct sites within the
maternal–fetal interface. After about 10 weeks of gestation syncytiotrophoblast contacts the mater-
nal peripheral blood filling the intervillous space. Endovascular trophoblast contacts maternal
peripheral blood flowing through the remodeled maternal spiral arteries. The immune cells popu-
lating the peripheral blood during pregnancy are composed of: 50–70 % neutrophils, 25–30 % T
cells, 5–10 % B cells, 5–10 % NK cells, and 5 % monocytes and immature dendritic cells.
Extravillous cytotrophoblast contacts the maternal immune cells populating the decidua. The
immune cell subtypes in the decidua differ dramatically from those in the peripheral blood.
Decidual immune cells are comprised of: 50–70 % NK cells, 15–20 % macrophages, 10–15 % T
cells, and 10–15 % monocytes and immature dendritic cells, but almost no B cells or neutrophils
characterized progesterone-induced binding factor (PIBF) by lymphocytes [35].

Like progesterone, circulating levels of this substance appear to increase as gesta-
tion progresses, then drop after delivery. Investigators have demonstrated that in
pregnancies resulting in preterm labor, miscarriage, or pregnancy-induced hyper-
tension, PIBF levels are abnormally low [36, 37]. Further, high concentrations of
PIBF can promote differentiation of CD4+ T cells into Th2 cells that favor anti-
inflammatory regulators [36], as further discussed below. Whether directly related
to PIBF or induced via alternative mechanisms, the overall decrease in Th1 responses
and shift toward Th2 responses that occurs during human pregnancy can be docu-
mented at the maternal–fetal interface and systemically [38].
Peripheral NK Cells
During pregnancy, NK cells undergo dramatic and important alterations in surface

receptor expression. The majority (90 %) of human peripheral NK cells express
small amounts of CD56 (CD56dim) and large amounts of CD16 on their cell surfaces
(CD56dimCD16+). The remaining (10 %) of peripheral NK cells exhibit high levels of
CD56 (CD56bright) and low levels of CD16 [39]; this latter expression pattern is simi-
lar to that of the majority of decidual NK cells (CD56brightCD16−) [40]. The overall
number of peripheral NK cells is decreased in pregnant women when compared to
their nonpregnant counterparts [27, 38, 41]. NK cells produce less IFNγ during
pregnancy [38] which decreases their cytotoxic capacities. These changes also are
responsible for a shift from cellular to humoral immune responses. When these
changes do not occur and NK cells remain highly cytotoxic and in nonpregnant
proportions, the rate of spontaneous pregnancy loss increases and the success of in
vitro fertilization (measured by per cycle live birth rates) decreases [42].
Peripheral Neutrophils
The majority of the increase in total circulating leukocyte cell numbers characteris-
tic of pregnancy is accounted for by an increase in neutrophils [43]. These neutro-
phils, however, have reduced anti-microbicidal effects, reduced chemotaxis, and
reduced phagocytic activities [44].
Decidual Immune Cells
The number, subclasses, and functional phenotypes of the immune cells populating
the uterus are transformed throughout the menstrual cycle and, even more dramati-
cally, during pregnancy. These changes are largely in response to alterations in local
and circulating levels of the reproductive steroids (Fig. 1.5) [45, 46]. During the
proliferative phase of the menstrual cycle, less than 10 % of the cells in the
endometrium are leukocytes. This number increases to 20 % in the decidua of the

late secretory phase of the menstrual cycle and to over 40 % in early pregnancy [47].
Within the pregnancy decidua, a remarkable 70 % of CD45+ leukocytes are uterine
NK (uNK) cells (CD56bright). Other cells within the decidua include macrophages,
monocytes, and a small number of T cells (Fig. 1.5). Neutrophils and B cells are rare
in the human endometrium and decidua at any time during the menstrual cycle or
pregnancy. Changes in the number and/or relative frequency of any of these immune
cell populations can lead to dramatic alterations in the immune response to the
developing pregnancy and may be related to increased rates of pregnancy loss.
Special Decidual Immune Cell Subpopulations
NK Cells
The phenotypes of the NK cells that populate the decidua during the luteal phase of
the menstrual cycle and early pregnancy are very different from those of the periph-
eral blood, with an apparent dramatic reduction in the subpopulation of
CD56dimCD16+ NK cells that dominate the periphery and a marked increase in the
CD56brightCD16− cells that are a small minority in the periphery. It is becoming
increasingly clear that this change in NK cell phenotype, while the result of a com-
bination of recruitment from the peripheral compartment and proliferation in situ, is
mainly dependent on the latter [48].
The predominant NK cell subtype in the decidua has been called by numerous
names: uNK cells, decidual NK cells, decidual granular lymphocytes, and large
granular lymphocytes. These cells make up approximately 70 % of the total endo-
metrial lymphocyte population in early pregnancy [40, 49]. This number decreases
after 20 weeks of gestation and uNK cells are nearly absent in the endometrium at
term. uNK cells are particularly prevalent at the implantation site, suggesting they
may specifically recognize extravillous cytotrophoblast cells as fetal [40]. While
their exact function within the decidua is still under investigation, it is hypothesized
that uNK cells influence maternal endometrial mucosal and arterial function and/or
placental trophoblast invasion [50]. Unlike the majority of their peripheral counter-
parts, uNK cells display fairly limited cytotoxic capabilities [51, 52]. Instead, they
are efficient and potent cytokine producers [49]. Human uNK cells produce a vari-
ety of cytokines including: macrophage inflammatory protein-1α, granulocyte-
macrophage colony-stimulating factor, interferon-γ, TGFβ, vascular endothelial
growth factor C (VEGFC), placental growth factor (PIGF), and angiopoietin 2
(ANG2) that play a role in angiogenesis and vascular stability. Through these cyto-
kines, uNK cells may help to mediate trophoblast invasion and modify maternal
spiral arteries to lead to the increase in blood flow necessary for normal pregnancy
[53]. Note that the minority of decidual NK cells that have the peripheral phenotype
will maintain nonpregnant expression of activation markers in anembryonic and
ectopic pregnancies and may play a role in early pregnancy loss [54, 55].
Macrophages, T-Cell Receptor γδ+ T Lymphocytes, and Dendritic Cells
Macrophages increase early in pregnancy, then stabilize throughout the remainder

of gestation, and make up approximately 10 % of decidual cells at the implantation
site [56]. This increase is believed to play a role in the proinflammatory environ-
ment seen very soon after conception that appears necessary to prepare the endome-
trium for implantation [1]. However, for much of normal human pregnancy, the
predominant activities of decidual macrophages are immunosuppressive [56]. Like
T helper cells, macrophages have been subcategorized by their secretory products
into several phenotypes. After early pregnancy, most decidual macrophages are of
the M2 phenotype, secreting IL-10, prostaglandin E2 (PGE2), and indoleamine 2,
3-dioxygenase (IDO). IL-10 inhibits proinflammatory cytokine production from
T cells and decreases the ability of macrophages and dendritic cells to present
antigens by inhibiting their surface expression of MHC class II and costimulatory
molecules [56]. These actions may also help with the development of T-cell anergy to
fetal cells and may contribute to the Th2 shift typical of uncomplicated pregnancies
(discussed below).
While the majority of circulating T cells in humans carry the αβ T cell receptor,
a small proportion have a different TCR subtype called the γδ TCR. γδ+ T cells are
more prevalent within the tissues of the mucosal immune system and within the
decidua in pregnant and nonpregnant women. Their numbers in the decidua are ele-
vated during the luteal phase of the menstrual cycle when compared to the follicular
phase. Their frequency is even higher during the first trimester of pregnancy and,
in fact, both circulating and decidual γδ + T cells comprise a larger proportion of
T cells in pregnant women when compared to nonpregnant women [51]. Decidual γδ+
T cells secrete IL-10 and TGF-β; they promote trophoblast invasion and inhibit tro-
phoblast apoptosis [51]. The true physiologic function of these cells has not yet been
determined and their role in pregnancy maintenance is still under investigation.
Dendritic cells (DC) within the decidua express MHC class II molecules and are
CD14−. It is thought that DCs are more specialized than macrophages at presenting
antigen to T cells [56]. Uterine DCs may play a very early and important role in the
maintenance of pregnancy since depletion of uterine DCs inhibits endometrial
decidualization and angiogenesis [57].
Soluble Immune Effectors and Pregnancy
Complement
In pregnancy, maternal complement levels are equal to or greater than in the non-
pregnant state [55]. Activation of complement against paternal antigens could
potentially be harmful to the developing fetus and result in adverse outcomes that
include those disorders that result from poor placentation (e.g., intrauterine growth
retardation, preeclampsia) or pregnancy loss. Several complement regulatory pro-

teins are expressed by the trophoblast that may be central to inhibiting such activa-
tion. These include decay-accelerating factor (DAF, CD55), membrane cofactor
protein (MCP, CD46), and CD59 [54]. DAF inhibits the alternative complement
pathway by preventing the formation and accelerating decay of C3/C5 convertase
[58]. MCP inhibits the classical complement pathway by binding C3b on the cell
surface and by functioning as an inactivating cofactor for C3b and C4b. CD59
inhibits the assembly of the MAC.
Cytokines and the Cytokine-Shift Hypothesis
Few individual cytokines appear to be absolutely necessary for pregnancy mainte-

nance. Of the cytokines that are, leukemia inhibitory factor (LIF) and IL-11 have
been shown to be imperative for blastocyst implantation but not for continued fetal
development. LIF functions at the blastocyst attachment/adhesion phase and IL-11
functions in the controlled response to the implanted blastocyst [59].
The actions of T helper cells have been shown to greatly affect the outcome of a
pregnancy. As discussed previously, Th1 cells produce IL-2 and interact with cyto-
toxic T cells; the majority of their actions are proinflammatory. Th-2 cells, on the
other hand, produce IL-4 and IL-5 which promote B cell development into antibody-
producing plasma cells. The overall effect is largely anti-inflammatory. In 1993, the
cytokine-shift hypothesis was proposed, which posited that pregnancy was an anti-
inflammatory condition [60]. It was thought that the intrauterine environment of
normal pregnancies was Th2 dominant, whereas pregnancies resulting in fetal
losses were associated with increased amounts of interferon-γ, IL-2, and tumor
necrosis factor-α which are harmful to the developing fetus [47]. Currently, it is
debated whether pregnancy is an inflammatory or anti-inflammatory condition and
to call it purely one or the other may be an oversimplification.
It may be more useful to divide human pregnancy into three distinct immuno-
logic phases: implantation/placentation, fetal growth and development, and parturi-
tion [61]. From blastocyst attachment to the early second trimester, a proinflammatory
environment is noted within the woman’s body. Decidual NK cells secrete IL-8 and
interferon-inducible protein-10 as well as other angiogenic factors that aid in suc-
cessful decidualization and in trophoblast invasion [62]. The maternal experience of
this overwhelming proinflammatory response and dramatic hormonal changes may
partly explain the symptoms of morning sickness [61]. The second trimester to near
birth is a period of rapid fetal growth and is thought to be anti-inflammatory in
nature. Although anti-inflammatory IL-10 is thought to be essential for maintenance
of a pregnancy, IL-10 levels are markedly reduced in term placentas that are not yet
in labor, when compared with first- and second-trimester placentas [63]. The down-
regulation of IL-10 near term may, in fact, contribute to the onset of labor. It has
been demonstrated that parturition is characterized by a migration of inflammatory
cells into the cervices, myometria, chorioamniotic membranes, and amniotic
cavities of women with spontaneous labor at term [63, 64]. Local accumulation of
these cells dramatically increases the local levels of inflammatory cytokines such as
IL-1β, IL-6, TNF-α and IL-8 that promote the onset of contractions and progression
through delivery of the infant and separation of the placenta.
The Implantation Site and Transplantation Antigens
The implanting human blastocyst is characterized by an inner cell mass represent-

ing the developing fetus and an outer layer of trophectoderm that will become the
placenta [65]. After several weeks of initial development and differentiation, the
human placenta is characterized by a complex collection of branching villi. Each of
these tree-like structures contains a core of fetal vessels surrounded by a loose
stroma. Some villi float freely in the intervillous space (floating villi), while others
reach across this space to attach to the maternal decidua (anchoring villi). Both
types of villi are covered by two layers of trophoblast along surfaces that face the
intervillous space (Fig. 1.1). The inner layer is comprised of cytotrophoblast cells.
These cells are covered by a multinucleated syncytium of the cytotrophoblast cells
called the syncytiotrophoblast. The syncytiotrophoblast layer is generally continu-
ous during early pregnancy and this layer is the source of human placental lactogen
and hCG [66]. Later in pregnancy the syncytiotrophoblast is characterized by scat-
tered “knots” of syncytialized cells.
At sites where anchoring villi meet the maternal decidua, a subset of cytotropho-
blast cells further differentiates into invasive extravillous cytotrophoblast (EVT)
cells. These cells move through and populate the maternal decidua and can even be
found in the inner third of the uterine myometrium in normal pregnancies. EVT also
surround and remodel the maternal spiral arteries, replacing vasoactive vascular
cells with vaso-inert endovascular trophoblast cells. This ensures continuous and
robust blood supply to the developing fetus even in the face of fairly significant
maternal stressors. The human placenta is unique in its level of trophoblast invasion
into the maternal tissues and is one of the few placentas in nature that permit direct
access of fetally derived trophoblast cells to maternal immune cells [67]. Three
subsets of human trophoblast display this level of intimate association with mater-
nal tissues: (1) the syncytiotrophoblast (SynT) layer that coats the placental villi
and is directly exposed to the maternal peripheral blood in the intervillous space,
(2) extravillous cytotrophoblast (EVT) cells that directly interact with maternal
decidual immune cells, and (3) endovascular cytotrophoblast cells of the remodeled
uterine spiral arteries carrying maternal peripheral blood to the fetus (Fig. 1.1). All
of these trophoblast subtypes are initially derived from villous cytotrophoblast cells.
Consistent with Medawar’s allotransplantation paradigm, syncytiotrophoblast lacks
both MHC class I and class II molecules [68], making it antigenically “invisible” to
maternal T cells. This is not true for the other trophoblast subtypes making contact
with the maternal immune system and the lack of MHC class I on syncytiotropho-
blast is problematic from the standpoint of NK cell recognition anyway (see below).
EVT [69] and endovascular trophoblast cells [70] display at least three potentially
allogenic MHC class I subtypes on their cell surfaces: the classical MHC class Ia
molecule, HLA-C, and the nonclassical class Ib molecules, HLA-E and HLA-G
[45, 46]. The MHC class Ib molecules have a limited degree of polymorphism and
are therefore less effective in antigen presentation. This alteration in antigen presen-
tation may actually be protective for the EVT and endovascular trophoblast cells as
it would be unlikely that the paternal HLA-G would be recognized as foreign [71].
Further, the presence of an MHC class I molecule of any type on their cell surface
protects these trophoblast cell subsets from NK cell-mediated cytolysis, since such
recognition is based not on self vs. non-self, but rather on the absence of any MHC
class I or class I-like products [72]. While often described as fairly non-polymorphic,
the trophoblast expressed MHC class Ia molecule, HLA-C, has actually been shown
to display a fairly high degree of polymorphism [73, 74]. Still, for uncertain rea-
sons, HLA-C molecules do not appear to stimulate robust antipaternal adaptive
immune responses [75].
HLA-C’s major role at the maternal–fetal interface may be to modulate the activ-
ities of the voluminous NK cells in the decidua. Since natural killer cells recognize
and destroy cells that lack MHC class I antigens, the expression of HLA-G, -E, and
-C on EVT and endovascular trophoblast cells may protect these cells from uNK-
mediated attack [69, 75]. For example, although all NK cells express a variety of
activating and inhibitory receptors on their cell surfaces, HLA-E molecules bind to
an inhibitory receptor that is expressed on all uNK cells (but not all peripheral NK
cells) [76]. HLA-C molecules are the preferential ligands for NK killer inhibitory
receptor subtype, KIR2D, and interactions between particular genotypes of this
polymorphic MHC molecule and of the polymorphic KIR2Ds have been associated
with adverse pregnancy outcomes [67]. Overall, interactions between trophoblast
MHC molecules and activating and inhibitory receptors on decidual NK cells and
macrophages are poor inducers of cytotoxicity [52], but important to maintenance
of pregnancy [77, 78]. These interactions have also been shown to be necessary for
decidual and vascular trophoblast invasion, spiral artery remodeling, and angiogen-
esis [79, 80]. Trophoblast MHC class I molecules have also been associated with the
cytokine shifts that occur in normal pregnancy. For example, EVT-expressed
HLA-G suppresses Th1 cytokine secretion and induces anti-inflammatory Th2
cytokine production by decidual cells [71].
Interestingly, despite studies showing support for an important role for HLA-G
in the immune modulation that occurs during pregnancy, homozygosity for a null
allele of the HLA-G gene does not appear to affect human fertility and pregnancy
outcomes [81]. When approached from an evolutionary viewpoint, this should not
be overly surprising. The success of human pregnancy may be too central to the
survival of the species to expect anything other than redundancy and overlap in
protective mechanisms. Similar findings were also mentioned in the section on
cytokines and the cytokine shift. Here too, these molecules are deemed to be impor-
tant to pregnancy maintenance, yet few play absolutely essential roles.
Pregnancy as a State of Immune Modulation
It is now widely accepted that during pregnancy, the implanting fetus is recognized
by the maternal immune system and robust immune responses at the maternal–fetal
interface, including proinflammatory and proangiogenic responses, have been dem-
onstrated in developmentally normal pregnancies [80, 82]. These immune responses,
however, occur in an environment consisting of dramatic hormonal and metabolic
changes. As a result of the dynamic background upon which the immunologic
changes of pregnancy occur, it is often unclear which particular alterations are nec-
essary for pregnancy success.
Hormonal Regulation
As previously discussed, circulating levels of estrogen and progesterone rapidly

increase after ovulation, and if conception occurs, continue to rise until after deliv-
ery of the placenta. Among the many immunomodulatory roles ascribed to it, pro-
gesterone inhibits mitogen-induced proliferation of CD8+ T cells and cytokine
secretion by these cells; it also promotes Th2 responses and increased secretion of
LIF [83–85]. All of these progesterone-induced changes aid pregnancy mainte-
nance. Progesterone also inhibits TNF-α, a cytokine that can have deleterious effects
on a developing fetus. The role of estrogen in immune modulations of pregnancy is
less well accepted than that of progesterone. Estrogen favors pregnancy mainte-
nance by down regulating delayed-type hypersensitivity reactions, promoting Th2
type immune responses, and protecting against chronic allograft rejection [85].
Estrogen is largely responsible for the increases in the circulating and decidual Treg
populations characteristic of normal pregnancy [86, 87]. Other, nonsteroidal hor-
mones also increase dramatically during pregnancy and several have been linked to
the immune modulation seen in the pregnant female. For example, hCG has been
shown to increase IL-27 and IL-10 (anti-inflammatory), to decrease IL-17 (pro-
inflammatory) expression, and to increase the number of circulating Tregs when
administered exogenously to women [88]. hCG can decrease HLA-DR expression
on dendritic cells in culture [89] and will attract Treg cells toward trophoblast cells
in models of the human maternal–fetal interface [90]. Interestingly, prolactin, which
reaches fairly high levels in the circulation of pregnant women, exerts fairly pro-
inflammatory effects on the adaptive and innate arms of the maternal immune sys-
tem [91]. The fact that many of the maternal immune changes vary throughout
pregnancy despite continually increasing levels of anti-inflammatory (progesterone,
hCG, estrogen) and pro-inflammatory (prolactin, estrogen) reproductive hormones
speaks to the complexity of this system.
Autoimmune Diseases and Pregnancy
Many observed alterations in immune function and autoimmune disorders have

been demonstrated in pregnancy. Th1-mediated autoimmune diseases, such as rheu-
matoid arthritis (RA) and multiple sclerosis (MS), have been noted to be improved
with fewer flares during pregnancy. In contrast, the severity and number of flares in
Th2-mediated disorders, such as systemic lupus erythematosus (SLE), characteristi-
cally increased during pregnancy [92]. Overall, pregnant women with underlying
autoimmune disorders may experience varying, albeit somewhat predictable,
changes in their disease status and symptomology. Although certainly oversimpli-
fied, rheumatologic diseases whose pathophysiology involves inflammatory changes
may improve during pregnancy while those with more allergic or antibody-mediated
underpinnings may worsen. Autoimmune diseases and their alteration and manage-
ment during the pregnant state will be discussed in much greater detail throughout
this textbook.
Conclusion
Maternal immune system changes begin prior to conception as the cellular milieu
within the endometrium and developing decidua varies with the menstrual cycle.
These changes, including increasing numbers of uNK cells and a shift toward Th2
immune responses, are imperative for the proper implantation and continuance of a
successful pregnancy, but may place the mother at risk for exacerbation of select
autoimmune disorders. Inadequate development of these altered immune responses
has been linked to increased risk of pregnancy wastage and pregnancy complications,
including preeclampsia and intrauterine growth restriction.
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Chapter 2
Normal Pregnancy, Pregnancy Complications,
and Obstetric Management
D. Ware Branch and Luchin F. Wong
Introduction
Profound changes in maternal physiology occur during pregnancy to accommodate

the growing fetus. Understanding these changes is fundamental to proper manage-
ment of the obstetric patient and identification of pathologic changes. This is of
great importance as reproductive-aged women are disproportionately affected by
rheumatic diseases, and in some cases an initial diagnosis is made in the course of
an evaluation for adverse obstetric outcomes. In this chapter we first address normal
fetal development followed by the various physiologic changes that occur in major
organ systems. Next we address antenatal care and fetal surveillance. Finally we
discuss common complications of pregnancy. As some of these complications occur
with greater frequency in the obstetric patient with underlying rheumatic disease or
may be confused with relapse or exacerbation of rheumatic disease(s), understand-
ing the nuances in management will serve as a basis for understanding modifica-
tions that may be required in the management of the woman with underlying
rheumatic disease.
D.W. Branch, M.D. (*)

Department of Obstetrics and Gynecology, University of Utah Health Sciences Center and
Intermountain Health Care, 30 North 1900 East, Room 2B200 SOM,
Salt Lake City, UT 84132, USA
e-mail: ware.branch@hsc.utah.edu
L.F. Wong, M.P.H., M.D.
Department of Obstetrics and Gynecology, University of Utah Health Sciences Center,
Salt Lake City, UT, USA

32 D.W. Branch and L.F. Wong
Embryonic Development and Fetal Physiology
The ovum is fertilized in the Fallopian tube and makes its way to the uterus over the
course of 5–6 days. During this time, the rapidly dividing cells of the fertilized
ovum undergo blastulation, a process by which the cells of the zygote take the shape
of a fluid-filled structure with distinct external and internal cellular components.
The resulting blastocyst is composed of external cells destined to interact with the
uterine endometrium and form the placenta, while a separate group of cells form the
inner cell mass, destined to form the embryo and enclosing membrane structure.
The blastocyst reaches the uterine cavity about 1 week after fertilization and
implants in the endometrial lining (endometrium) of the uterus on average 9 days
after fertilization, though it may occur as early as 6 days and as late as 12 days.
Human chorionic gonadotropin (hCG), produced by trophoblast (placenta) tissue, is
secreted at the blastocyst stage and is first detectable in the urine and blood of preg-
nant women 8–10 days after conception (day 22–24 of a 28-day menstrual cycle).
The most external of the trophoblastic cells of the blastocyst in contact with the
endometrium form an invasive, mutlinucleated syncytium, the syncytiotrophoblast.
The syncytiotrophoblast is to be distinguished from more proximal, single-cell
cytotrophoblast. After implantation, the synctyiotrophoblast just under the forming
embryo and amniotic cavity thickens and then forms vacuolar spaces. The resulting
matrix of cellular trabeculae and vacuolar spaces are the precursors of the placental
villi and intervillus spaces. In the third week after conception, the fetal villus vascu-
lature begins to form.
For most of the first 10 weeks of pregnancy, the lacunae of the forming placenta
are filled with clear fluid, without the presence of a genuine relationship between
maternal and embryonic circulations. During this period gas and nutrient exchange
with the embryonic structures is of a passive nature, with intervillus space oxygen
concentrations being <20 mm Hg. In the meantime, the terminal portions of the
uterine arteries that penetrate into the decidualized endometrium, known as spiral
arterioles, have undergone remarkable transformation, with replacement of vascular
wall smooth muscle and elastic fibers with fibrinoid. The initial result is a dilated
and nonmuscular terminal arteriolar structure.
Within the first few weeks of pregnancy, cytotrophoblastic cells that have
migrated peripherally, known as extravillius cytotrophoblasts, associate with the
altered terminal spiral arterioles. Other important changes in the maternal vascula-
ture have been in play. The more distal segments of the spiral arteries also dilate
under the influence of pregnancy-related hormones, and the overall maternal blood
flow to the uterus begins to increase considerably.
Around 10–12 weeks gestation the cellular occlusion of terminal spiral arterioles
begins to clear, allowing maternal blood to enter the intervillus space and bathe the
fetal villi. With this the oxygen tension in the intervillus space rises. Concomitant
maturation of the fetal villi and fetal production of capable (non-nucleated) erythro-
cytes complete the requirements for a true placental circulation. The key
2 Normal Pregnancy, Pregnancy Complications, and Obstetric Management 33
components of this circulation are that it is of relatively high volume and low
velocity such that the pressure within the intervillus space is also relatively low,
lower than that in the fetal villous vasculature. The net result is that oxygenated
maternal blood can enter the intervillus space and bathe the delicate fetal villi with-
out damaging or collapsing them.
At the time of implantation, the blastocyst contains about 200 cells. The inner
cell mass, or embryonic disc, is distinguishable from the trophoblastic cells of the
blastocyst. Within a few days, the embryonic disc forms into two cell layers, the
primitive ectoderm and the underlying endoderm. The “embryonic period” of devel-
opment begins at the beginning of the third week after fertilization, or the fourth
menstrual week. In the ensuing 8 weeks, all major organs of the embryo are formed,
though further development of organs occurs in the subsequent fetal period (tenth
menstrual week).
The events that take the embryonic disc to that of a fully formed embryo with all
major organs in place are quite obviously complex and occur in a well-delineated
sequence. Cardiac formation can serve as an example. In the fifth menstrual week,
the appearance of a splanchnic mesodermal layer of cells allows the development of
the embryonic vasculature. One element, the primitive heart tube, appears in the
fifth menstrual week when two adjacent midline endothelial tubes fuse. Surrounding
splanchnopleuric mesoderm condenses to form a mantle of myoepicardium.
Subendocardial tissue forms from connective tissue between the endocardium of
the primitive heart tube and the myoepicardial mantle. This primitive structure
begins to contract in the early fifth menstrual week and is visible pulsatile by high-
resolution ultrasound by the end of the fifth menstrual week. The tubular structure
bulges in five regions along its length, each destined to form an adult cardiac struc-
ture, but with the future atrial and sinus venosus tissues lying caudal to the future
tissues that form the ventricles and major artery outflows. The tubular heart struc-
ture undergoes rightward looping, pushing the future ventricular and atrial regions
into their adult relationships with the atrial tissues lying cranial to the ventricular
tissues. Subsequently, complex partitioning of the tissues occurs in sequence result-
ing in a 4-chambered heart by the eighth menstrual week. Recognizable neonatal
cardiac defects may result when this process goes awry. Failure of the formation of
a septum between the aorta and pulmonary trunk produces persistent truncus arte-
riosus, while partial or aberrant division yields such defects as transposition of the
great arteries or tetralogy of Fallot. Failure of the septal division of the primitive
atrium leads to atrial septal defects.
It is during the period of organogenesis that the embryo is susceptible to the tera-
togenic effects of certain drugs or other substances, though it is estimated that only
10 % of all birth defects are due to a teratogenic agent per se. One example is the
vitamin K antagonist warfarin, used widely as an anticoagulant. Maternal use of
warfarin between the sixth and ninth menstrual weeks of gestation results in the
warfarin embryopathy in an estimated 5–10 % of exposed embryos. This syndrome
may include facial anomalies, skeletal anomalies, microcephaly, and mental retar-
dation. Evidence is mounting that warfarin inhibition of arylsulfatase E activity is
involved in the teratogenesis of the drug. Use of warfarin later in pregnancy may
also result in additional adverse fetal effects.
Critical organ developments occur in the fetal period. The fetal period begins at
the end of the ninth or beginning of the tenth menstrual week. The embryo-fetus is
about 4 cm long, all major organs are formed (though many are immature), and the
skeletal structures are easily recognized. By the fourteenth week the sex of the fetus
can be discerned by visual inspection of the genital region. Fetal lungs, formed by
the seventh gestational week, undergo important branching and vascularization
thereafter. The development of the gas-exchanging segments of the respiratory tree
begins in the 22nd to 24th week and alveolar development continues into childhood.
Survival outside the uterus is impossible before this time due to an inability to
exchange oxygen and carbon dioxide. Rudimentary brain structures are in place by
the end of the embryonic period, but the brain remains a smooth-surfaced structure
for at least half of pregnancy, with gradual development of the mature pattern of
gyral and sulcal folding occurring in an orderly sequence after 20 weeks gestation
and into childhood. Cortical neurogenesis is not completed in the fetus until nearly
20 weeks gestation.
By 20 weeks, the fetus weighs about 300 g and some scalp hair may be found.
A period of linear fetal growth begins, with glucose being the major fetal nutrient
for oxidative metabolism and acquired via facilitated transport across the placenta.
Amino acids and lactate are also used in aerobic metabolism by the fetus. Human
placental lactogen in the mother’s circulation impairs maternal tissue uptake of glu-
cose, leaving it the circulation and available to the placenta (as well as predisposing
to maternal glucose intolerance in genetically susceptible individuals). Free fatty
acids, glycerol, and free amino acids also cross the placenta for use by the fetus.
Fetal fat tissue deposition occurs primarily over the final third of pregnancy, increas-
ing somewhat gradually from about 26 to 32 weeks and more rapidly thereafter.
There is considerable interest today in environmental influences of fetal growth,
especially by way of gene imprinting.
One of the most remarkable features of the fetal physiology is the fetal circula-
tion. Fetal blood does not require oxygenation by the fetal lungs, and little fetal
blood circulates through the pulmonary vascular circuit. Well-oxygenated fetal
blood returns from the placenta via the umbilical vein, which divides into the ductus
venosus and the portal sinus, with the ductus venosus being the major branch. These
venous structures access the inferior vena cava high in the abdominal cavity in a
way that favors the course of well-oxygenated blood flow along the medial aspect
of the inferior vena cava in its return to the heart. When it reaches the right atrium,
the configuration of the fetal upper atrial septum shunts the well-oxygenated blood
through the patent fetal foramen ovale into the left ventricle from which it is
directed to the systemic arterial circulation. Less well-oxygenated blood returning
to the right atrium via the inferior and superior vena cava is deflected through the
tricuspid valve to the right ventricle. Most blood ejected from the right ventricle
courses through the ductus arteriosus, a fetal vessel connecting to the descending
aorta. Only a small proportion of the right ventricular outflow is directed to the
relatively high-resistance pulmonary circulation. Right ventricular blood entering

the descending aorta via the ductus arteriosus is carried back to the placenta via the
fetal hypogastric arteries leading to the umbilical arteries.
Dramatic alterations to these uniquely fetal circulatory elements occur at birth:
the umbilical vessels, ductus arteriosus, ductus venosus, and foramen ovale close or
constrict. Expansion of the lungs at birth is associated with a dramatic decrease in
pulmonary circulatory resistance. Right ventricular outflow preferentially follows
the pulmonary circuit, to be oxygenated before its return to the left atrium. The adult
circulation is established.
Maternal Physiologic Changes in Pregnancy
Cardiovascular System
Unique changes in maternal physiology occur in pregnancy to support the growing

fetus and placenta and to protect the mother from blood loss at delivery. These
changes are seen very early in pregnancy and normalize rapidly after delivery.
Maternal plasma volume increases as early as 6 weeks, increasing 45 % and reach-
ing a maximum of about 5,000 mL at 32 weeks. Red blood cell mass also increases
roughly 20–30 % during pregnancy and is believed to be stimulated by progester-
one, placental chorionic somatomammotropin, and possibly prolactin. Due to this
disproportionate increase in plasma as compared to red blood cells, a physiologic
anemia can be observed in the third trimester.
Anatomic changes to the entire cardiovascular system also occur. There is a soft-
ening of the smooth muscle and collagen as early as 5 weeks, likely mediated by
vasodilatory effects of progesterone and nitric oxide. This results in mildly decreased
blood pressure, which nadirs at 24–32 weeks and increases closer to term. These
changes also result in a physiologic dilation of the heart, which along with an
enlarging gravid uterus works to shift the cardiac axis anteriorly and to the left. This
results in the appearance of an enlarged cardiac silhouette on chest X-ray. Although
there is an increase in cardiac compliance, there is no change in ejection fraction.
Cardiac output increases by 30–50 % in pregnancy, half of which occurs by
8 weeks. The increase in cardiac output plateaus at 26–28 weeks [1]. This increase
reflects an increase in both heart rate (by 15–20 beats per minute) and stroke volume
(by 40 %) [2, 3]. Roughly 500–800 mL/min of blood is preferentially shunted to the
uterus, ten times the requirement in a nonpregnant woman. Cardiac output can
decrease up to 25–30 % when turning from a lateral recumbent to supine position
due to gravid compression of vena cava. The most dramatic changes to cardiac
output occur peripartum. Cardiac output increases 15 % in during 2nd stage with
maternal expulsive efforts early labor, 25 % in active labor, and 50 % with maternal
expulsive forces during the second stage of labor. Immediately after delivery, car-
diac output can be expected to increase 80 % secondary to autotransfusion of the
blood previously sequestered in the uterus, but returns to pre-labor values by an

hour after delivery [4].
Respiratory System
Maternal oxygen requirements increase 20–40 % to support the increase oxygen

requirements of the fetus, placenta, and other maternal organs [5]. Elevated estrogen
levels in pregnancy cause relaxation of the ligaments between the ribs and sternum,
resulting in an increase in the subcostal angle and chest diameter. These changes
along with the enlarging uterus contribute to an overall decrease in maternal oxygen
reserve: 5 % decrease in total lung capacity and 20 % decrease in functional residual
capacity. For this reason, women with pulmonary disease are more susceptible to
early decompensation. However, there is 40 % increase in tidal volume. As respira-
tory rate does not change, there is a parallel increase in minute ventilation. Pregnancy
is also a state of mild hyperventilation, mediated by progesterone to create a state of
chronic mild respiratory alkalosis, which facilitates transfer of carbon dioxide from
the fetus to the mother. The mean arterial pH is 7.43, and mean serum bicarbonate
is 21.5 mEq/L [6–9]. The alkaline environment increases 2,3-diphosphoglycerate,
which serves to favor oxygen transfer to the fetus. Normal blood gas values in preg-
nancy can be found in Table 2.1.
Hormonal changes of pregnancy also stimulate increased upper respiratory vas-
cularity, mucosal edema, and mucosal secretion, which can predispose the woman
to epistaxis, nasal congestion, upper airway obstruction, and even obstructive sleep
apnea.
Renal System
Significant changes to renal anatomy and function occur during pregnancy. There
is increased renal plasma flow during pregnancy, up to 75 % at 16 weeks and
maintained until the third trimester after which there is a 25 % decline [10].
Table 2.1 Normal pregnancy Arterial pH 7.44 (7.39–7.45)

blood gas PO2 90–107 mmHg
PCO2 25–33 mmHg
HCO3− 16–22 mEq/L
Modified from the 23rd edition of
Williams Obstetrics (2010)
Likewise, there is a 50 % increase in glomerular filtration rate during the first

trimester and maintained until the end of pregnancy; this results in decreased
serum creatinine (average of 0.5 mg/dL) and urea (average of 9 mg/dL) [11].
There are also changes in renal tubular function and excretion of nutrients.
Glycosuria is common in pregnancy, but typically intermittent and not necessarily
reflective of serum glucose levels or gestational age. One study found that 90 % of
pregnant women with normal serum glucose excreted 1–10 g of glucose per day
in their urine [12]. However, repetitive findings of glycosuria should prompt
screening for diabetes. Urinary excretion of protein and albumin is also increased
in pregnancy, particularly in the second half of pregnancy but does not typically
exceed 300 mg per 24 h.
Increased renal vasculature and interstitial volume result in an increase in renal
size, up to 1 cm in length. There is also dilation of the collecting system, typically
more pronounced on the right side (average of 15 mm) than the left (average of
5 mm) due to the dextrorotation of the gravid uterus and location of the sigmoid
colon [13]. Dilation of the collecting system can be partially attributed to progester-
one, which causes smooth muscle relaxation. These changes typically reverse by
6 weeks postpartum.
Gastrointestinal System
Elevated progesterone levels in pregnancy decrease gastrointestinal motility and

gastroesophageal sphincter tone. These changes, along with uterine compression of
the stomach, result in increased gastric reflux. Up to 80 % of pregnant women will
have gastroesophageal reflux, and the prevalence and severity increases with
increasing gestational age and resolves with delivery. Progesterone’s relaxing effect
on smooth muscle also decreases small intestinal peristalsis. Similar changes in
colonic transit time are thought to occur and supported by animal studies. This
increase in intestinal transit time may serve to increase nutritional absorption, but
also contributes to constipation and bloating.
Little anatomic changes to the liver occur during pregnancy, with the exception
of an upward shift, which corresponds to the upward shift of the diaphragm and
growing uterus. There is a small decrease in the upper limit of aspartate transami-
nase and alanine transaminase [14]. Serum alkaline phosphatase increases two to
fourfold during pregnancy, most of which occurs during the third trimester.
Isoenzyme testing may be performed to distinguish placental production from liver
or bone production of alkaline phosphatase. The increased alkaline phosphatase is
mostly attributable to placental production of alkaline phosphatase, not hepatic pro-
duction. Serum albumin and protein decrease throughout pregnancy, although this
is largely due to hemodilution. Thus, any changes in liver enzymes, with the excep-
tion of alkaline phosphatase, should prompt further evaluation.
Other proteins produced by the liver are also increased during pregnancy. The
concentrations of specific binding proteins such as corticosteroid-binding globulin
and thyroxine-binding globulin also increase during pregnancy. There is also a two-
fold increase in fibrinogen, and similar increase in factors VII, VIII, IX, and X.
Levels of prothrombin and factor V remain relatively unchanged. Prothrombin time
and activated partial thromboplastin time are not significantly changed.
Palmar erythema and spider angiomas, often seen with chronic liver disease,
may also appear transiently in pregnancy due to increased levels of estrogen.
Muscloskeletal System
Pregnancy and lactation is a period of high bone turnover; both bone resorption and
bone formation are increased throughout pregnancy, as is alkaline phosphatase, a
marker for bone formation. However, this seems to be confined to trabecular bone
and reversible with delivery and weaning of breastfeeding. There does not appear to
be an association between increase parity and decreased bone marrow density or
osteoporosis later in life [15, 16]. Pregnancy also results in several anatomic changes
that predispose women to musculoskeletal discomfort during pregnancy. Increased
pregnancy levels of estrogen and relaxin result in increased ligamentous laxity and
increased joint discomfort throughout the body, particularly the pubic symphysis
and sacroiliac joints [17]. To compensate for the growing uterus, there is an increas-
ing lordosis of the lumbar spine to maintain the center of gravity over the woman’s
legs. The hyperlordosis of the lower back, increased pelvic joint laxity, and increased
maternal weight cause opposing forces resulting in substantial mechanical strain on
the lower back and pelvis. Lower back pain in pregnancy affects roughly two thirds
of women and is likely worse for women with a history of back pain, prior preg-
nancy, or older age. The pain is usually exacerbated by physical activity, particularly
weight bearing activity. Tenderness over the paraspinal muscles and sacroiliac joints
is often appreciated on exam. Pain is often improved with postural and activity
modification, and the prognosis is generally favorable.
Routine Pregnancy Features and Prenatal Care
Preconceptional Considerations
Ideally, the woman contemplating pregnancy will seek preconceptional education

and take preventive care measures. Though not exhaustive, Table 2.2 outlines basic
preconception recommendations, some of which are easily accomplished in a gen-
eral medical practice setting.
Table 2.2 Basic preconception educational considerations and recommendations

Consideration/recommendation Comment
Prevention of fetal anomalies and syndromes
Neural tube defects Women of childbearing age who are Women with a previously affected
capable of becoming pregnant child should consume 4 mg of
should consume 0.4 mg of folic folic acid daily from 4 weeks
acid daily (available in before conception through the
multivitamin supplements) first 3 months of pregnancy
Alcohol Heavy drinking is a risk for fetal
alcohol syndrome and should be
avoided; most experts
recommend avoiding any
alcohol during pregnancy
because no level of drinking is
known to be safe
Smoking Smoking during pregnancy is Risks increase with the number of
associated with fetal growth cigarettes smoked per day
restriction and increased
perinatal morbidity and
mortality due to placental
abruption and preterm birth
Caffeine Moderate caffeine consumption Consumption of more than 300
(<200 mg/day) is not thought to mg of caffeine per day may be
be associated with miscarriage, associated with low birth
preterm birth, or fetal growth weight
restriction
Sauna and hot Probably prudent to restrict sauna Extensive animal data show
tub exposure exposure to 15 min or less and hyperthermia is teratogenic
hot tub to 10 min or less and can cause neural tube
defects; human data are scant
Methyl mercury Theoretical concern of exposure in See www.fda.gov/Food/
seafood has prompted FDA and ResourcesForYou/
EPA to recommend pregnant ucm110591.htm
women to consume no more
than 12 ounces of a variety of
fish and shellfish per week
Vitamin A Excessive consumption of vitamin standard prenatal vitamins
A (more than 10,000 IUs per contain 4,000–5,000 IUs
day) may be associated with
fetal malformations
Infection
Rubella Check titer and immunize Women should avoid becoming
susceptible nonpregnant women pregnant for 28 days after
vaccination
Varicella Check titer or immunize, depending Women should avoid becoming
upon history pregnant for 28 days after
vaccination
Diphtheria Immunize women who have not May be given if pregnant or likely
received immunization with past to become pregnant
10 years
(continued)
Table 2.2 (continued)

Consideration/recommendation Comment
Influenza Recommended for all women who May be given if pregnant or likely
will be pregnant (in any to become pregnant
trimester) during influenza
season (October through March)
because pregnant women are
more severely affected than their
nonpregnant counterparts
Hepatitis B Immunize women at risk (having May be given if pregnant or likely
more than one sex partner to become pregnant
during the previous 6 months,
been evaluated or treated for an
STD, recent or current injection
drug use, or having had an
HBsAg-positive sex partner)
CMV, listeriosis, Routine screening for immunity or Prudent to discuss preventive
toxoplasmosis, infection not recommended measures, i.e., handwashing,
Parvovirus B19, gloves for changing cat litter
HSV or gardening, washing of
produce and cutting boards
with bleach, avoidance of raw
or undercooked meats and raw
eggs or unpasteurized dairy
Genetic conditions
Carrier state Screen appropriate populations for
screening genetic disease carrier states
such as Tay–Sachs disease,
Canavan disease, cystic fibrosis,
or hemoglobinopathies
Medical conditions Appropriate control of some
medical conditions, such as
diabetes mellitus, SLE,
phenylketonuria, and
hyperthyroidism, before
conception can positively
influence pregnancy outcome
Obesity Linked to higher rates of Weight reduction may improve
preeclampsia, diabetes, labor pregnancy risks
disorders, cesarean delivery, and
peripartum complications
For many women with rheumatic disease, important preconceptional consider-

ations are the risks, if any, that pregnancy poses with regard to the interplay between
their underlying rheumatic disease and pregnancy, as well as the risks their anti-
rheumatic disease medications might pose to the fetus or pregnancy. These risks are
discussed in detail in the relevant chapters of the text.
Diagnosing Pregnancy
Pregnancy is typically first recognized by a woman when she notices breast sore-
ness or tenderness, fatigue, perhaps some nausea, and then misses her expected next
menses. Of course, some women with established rheumatic disease will be track-
ing their potential for conception using widely available, over-the-counter ovulation
test kits. These tests detect a surge of luteinizing hormone in urine as a predictor of
ovulation within the following 24–48 h.
hCG is first detectable using sensitive tests in the urine and blood of pregnant
women 8–10 days after conception (day 22–24 of a 28-day menstrual cycle).
Concentrations of hCG rise rapidly in early pregnancy, peak at 9–10 weeks, and
decline thereafter to a nadir at 20 weeks.
Establishing the Expected Date of Delivery (Dating the Pregnancy)
The duration of human pregnancy averages 280 days from the first day of the last
menstrual period. This amounts to 10 lunar months, or about 9 calendar months. By
historical convention, the first day of the last menstrual period is used to mark the
“beginning” of pregnancy and gestational age is measured by menstrual weeks.
This assumes a 28-day menstrual cycle with ovulation occurring on day 14; thus,
this method of dating the pregnancy includes approximately 2 weeks that the woman
was not actually pregnant. Nonetheless, obstetrical references to pregnancy dura-
tion, including those obtained by obstetrical ultrasound, are in terms of the conven-
tion of dating the pregnancy according to the last period.
Most pregnancies in the USA also are dated by ultrasound using standard
biometric measurements of the crown-rump length in early pregnancy or a mathe-
matically modeled composite of the measurements of the fetal head, abdomen, and
femur in later pregnancy. Generally, and especially if the menstrual dates are uncer-
tain, the ultrasound-determined dates trump menstrual dates when they differ by
more than 3 days from 6 to 10 weeks, more than 5 days from 11 to 14 weeks, and
more than 7 days from 15 to 20 weeks. Fetal size varies considerably as pregnancy
advances such that measurement of the fetus is a less reliable tool for estimation of
gestational age past the mid-second trimester and especially in the third trimester.
Thus, the composite gestational age assessment has a variability (±2 standard devia-
tions) in excess of 2 weeks beyond 30 weeks.
Initial Prenatal Visits and Laboratory Tests
The initial prenatal visit includes a history and physical examination as well as labo-
ratory studies. Typical “prenatal labs” are shown in Table 2.3 and normal laboratory
values for the pregnant woman can be found in Table 2.4. Though not required for
good care, many practitioners obtain first or early second trimester fetal ultrasound
to firmly establish the gestational age and due date. Accurate dating is critical to
Table 2.3 Typical routine prenatal evaluations of the first 20 weeks of pregnancy
Screening or diagnostic
evaluation Comment
Tests
Prenatal “panel”
Hemoglobin or Typically obtained as complete blood count
hematocrit
Blood type and Rh status
Anti-erythrocyte antibody A positive screen should prompt identification and titers of
screen antibodies. Women who are Rh negative should have a repeat
screen at 28 weeks prior to Rh immune globulin administration
Rubella titer A negative titer is an indication for immunization after
pregnancy—MMR vaccine is not recommended during
pregnancy
RPR False positive result is not uncommon among women with
autoimmune disorders, particularly SLE
HBsAg Used to detect chronic carriers of HBV
HIV Routine screening (typically offered as an “Opt-out” test) and
treatment recommended by ACOG; treatment significantly
decreases rate of perinatal transmission
Other routine tests
Pap smear
Urine culture or Asymptomatic bacteriuria is more common during pregnancy
assessment for urine and more likely to progress to pyelonephritis
nitrites and leukocytes
esterase
Genetic tests
Carrier screening based Screening may include testing for hemoglobinopathies, Tay–Sachs
on racial and ethnic disease, Canavan disease, cystic fibrosis
background
Carrier screening based Screening may include testing for such conditions as fragile X
on family history syndrome and Duchenne’s muscular dystrophy
Screening for trisomies A combination of maternal biomarkers and/or ultrasound markers
21, 18, 13 is typically offered to all patients; recently available maternal
plasma cell-free fetal DNA for pregnancies at high risk for
Down syndrome
obstetric decision-making and contributes to the reduction in unnecessary induction

of labor for postterm pregnancy.
By the end of the first trimester, the new prenatal patient should be apprised of
the risks of genetic conditions such as Down syndrome and of the available screen-
ing tests (Table 2.3) [18]. Within the last two decades, Down syndrome screening
tests have evolved considerably, primarily because Down syndrome occurs in about
1 in 800 liveborns in the general obstetric population. The risk of Down syndrome
and a number of other fetal chromosomal abnormalities increase with increasing
maternal age due to increasing rates of meiotic nondisjunction. At a maternal age of
35 years, the risk of a Down syndrome birth is 1 in 385, and the risk of any feto-
neonatal chromosome abnormality at birth is 1 in 204. By a maternal age of 40 these
risks are 1 in 106 and 1 in 65, respectively.
Table 2.4 Normal reference Normal pregnancy range

ranges for the pregnant
Hemoglobin 9.5–15.0 g/dL
woman
White blood cell count (5.6–16.9) × 103/mm3
Platelets (7.7–10.4) × 109/L
Sodium 129–148 mEq/L
Potassium 3.3–5.1 mEq/L
Chloride 97–109 mEq/L
Bicarbonate 20–24 mmol/L
Serum creatinine 0.5–0.7 mg/dL
Blood urea nitrogen 9–11 mg/dL
Serum bicarbonate 18–22 mEq/L
Uric acid 2.0–6.3 mg/dL
Fibrinogen 244–619 mg/dL
INR 0.8–01.05
Partial thromboplastin time, 24.2–38.9 s
activated (aPTT)
Prothrombin time (PT) 9.5–13.5 s
Aspartate transaminase (AST) 3–33 IU/L
Alanine transaminase (ALT) 2–33 IU/L
Total bilirubin 0.1–1.1 mg/dL
Alkaline phosphatase 30–418 IU/L
Albumin 2.3–5.1 g/dL
Lipase 21–112 U/L
Amylase 15–83 g/dL
C-reactive protein CRP 0.4–20.3 mg/L
Erythrocyte sedimentation 4–70 mm/h
rate (ESR)
C3 complement 62–111 mg/dL
C4 complement 18–36 mg/dL
Arterial pH 7.39–7.45
PO2 90–107 mmHg
PCO2 25–33 mmHg
HCO3– 16–22 mEq/L
Modified from 23rd edition of Williams Obstetrics (2010)
Invasive procedures enable direct testing of fetal cells for chromosomal abnor-
malities, but carry a risk of attributable fetal loss. Amniocentesis performed by
experienced personnel as early as 15 weeks has a procedure-related loss rate as low
as 1 in 400. Chorionic villus sampling may be performed as early as 9 weeks, but
with a slightly higher loss rate than amniocentesis, although the difference is mini-
mal in experienced hands. Though low, these risks have prompted the development
of screening paradigms for fetal chromosomal abnormalities that enable targeting
invasive procedures for women at higher than average risk. Among low risk patients,
e.g., a 30-year-old patient without a suspicious history, who desires screening for
fetal chromosomal abnormalities, screening paradigms using a combination of
maternal age, maternal serum biochemical analytes (reflective of fetal-placental
production), and fetal ultrasound findings may be used to establish a probability
that the fetus has a chromosomal abnormality such as trisomies of the 21,18, or
13 chromosomes [18]. The ultrasound aspect of the most commonly used Down
syndrome screening paradigm is fetal nuchal translucency measurement at
11–13 weeks [6, 7]. An increase in nuchal translucency is an early presenting fea-
ture of a broad range of fetal chromosomal, genetic, and structural abnormalities.
Using a 5 % false positive threshold, these screening paradigms provide a high
“detection rate” for Down syndrome, though definitive diagnosis requires direct
genetic testing of the fetus by such methods as amniocentesis.
More recently, the FDA has approved testing using cell-free fetal DNA in mater-
nal blood as a noninvasive approach to Down syndrome screening in high-risk
patients, e.g., a 40-year-old obstetric patient, as early as 10 weeks [19]. In high risk
patients, this technology will detect more than 97 % of Down syndrome cases with
a false positive rate of less than 0.5 %. It may perform similarly in low risk patients
and studies are currently underway. This test likely performs similarly in low-risk
women and studies in the population are currently underway.
Subsequent Prenatal Visits and Care
In healthy women without underlying medical conditions, subsequent prenatal visits

are typically every 4 weeks until 28 weeks, every 2–3 weeks until 36 weeks, and then
once weekly until delivery. These visits are used to assess the growth of the fetus by
palpation of the uterus and measurement of the fundal height (done after 20 weeks),
listen for a normal fetal heart rate, obtain periodic maternal blood pressure readings,
and screen for urinary tract infection and proteinuria using urine dipsticks. After
20–22 weeks, the mother is also questioned routinely regarding fetal movement,
with decreased fetal movement possibly indicating fetal compromise. Visits at
36 weeks and beyond allow for assessment of fetal presentation (cephalic, breech, or
transverse) and appropriate management of presentations other than cephalic.
The now-standard, mid-trimester obstetric ultrasound at approximately 20 weeks
is obtained with two primary goals in mind. First, fetal biometric measurements are
used to confirm (or refute) the expected gestational age. Second, the fetal anatomy
is assessed by way of well-established, standardized views of numerous fetal struc-
tures. The mid-trimester fetal anatomic survey does not, however, exclude more
subtle defects such as mild-to-moderate stenotic lesions of the cardiac outflow
tracts, less severe obstructions of the gut, isolated cleft palate, and a variety of other
less visually dramatic anomalies. The standard mid-trimester fetal ultrasound also
has no better than modest utility as a predictor of Down syndrome.
Most gestational age discrepancies found at the time of the mid-trimester ultrasound
are due to uncertain menstrual dating information or longer than average menstrual
cycles reflective of delayed ovulation. If the mid-trimester fetal biometric measure-
ments do not agree with the menstrual gestational age or the gestational age established
by an earlier ultrasound, common practice is to obtain another set of fetal measure-
ments 3–4 weeks later in an effort to discern a meaningful pattern of fetal growth.
Universal screening for gestational diabetes mellitus (GDM) between 24 and
28 weeks gestation is recommended by most experts. In the USA, the orally
administered 50 g glucose challenge, with venous glucose drawn 1 h later, is the

standard screening test. It may be prudent to perform the test earlier in patients at
higher risk for gestational diabetes, such as obese women, women with a history of
having delivered a previous large-for-gestational age infant, or women with a strong
family history of type 2 diabetes mellitus. The most commonly used threshold for
an abnormal result is a glucose of 140 mg/dL, though some choose to enhance
sensitivity by using a lower threshold. Women who screen positive are recom-
mended to undergo a 3-h oral glucose tolerance test using a 100 g oral glucose load.
This test scheme involves a fasting glucose determination and additional determina-
tions at 1, 2, and 3 h after the glucose load. A formal diagnosis of GDM is made
when two or four determinations are above predefined thresholds, though women
with a single abnormal result should also be considered at risk for worsening glu-
cose tolerance as pregnancy advances.
Rh-negative women also have a repeat anti-erythrocyte antibody screen at
28 weeks. If negative for antibodies, the patient is a candidate for Rh immune globu-
lin to prevent antepartum alloimmunization to possible fetal Rh positive cells. Note
that the male partner’s Rh status is most commonly unknown, but is assumed to be
likely Rh positive based on known population blood type genetics. Additional Rh
immune globulin is given to the Rh-negative, anti-erythrocyte antibody-negative
mother soon after delivery if the neonate is confirmed Rh positive.
In otherwise normal women, prenatal visits after 20 weeks are thought to aid in
the detection of fetal growth restriction and hypertensive disorders of pregnancy
based on pertinent clinical inspections. Visits at 36 weeks and beyond allow for
assessment of fetal presentation (cephalic, breech, or transverse) and appropriate
management of presentations other than cephalic.
A sizeable proportion of women managed in an American obstetric setting
undergo periodic fetal surveillance testing for evidence of placental insufficiency
(see below) or fetal hypoxemia of other causes. By far, the most common fetal sur-
veillance tests in routine use are the non-stress test (NST), assessment of amniotic
fluid volume as an index (AFI), and the biophysical profile (BPP) test. Such testing
has been a practice fixture since the 1970s (non-stress testing) and 1980s (AFI and
BPP), though evidence of benefit is derived from retrospective and cohort studies;
proper trials to are lacking.
The NST test uses a Doppler monitoring system to record a continuous fetal
heart rate tracing and assumes that the presence of fetal heart accelerations with
fetal movement is indicative of a neurologically intact brainstem-cardiac circuitry;
the absence of these raises concern for severe impairment in maternal–placental
circulation and severe fetal hypoxemia.
Amniotic fluid volume with AFI is normally in excess of 5 cm by 4-quadrant
measurement; values below 5 cm are concerning for worsening maternal–placental
circulation. Common indications for testing include maternal chronic hypertension
or gestational hypertensive disorders, suspected fetal growth restriction, maternal
diabetes, advanced maternal age, as well as autoimmune disorders such as systemic
lupus erythematosus (SLE) or antiphospholipid syndrome (APS).
More recently, analysis of in utero vascular Doppler velocimetry waveforms has
been added to fetal surveillance testing for selected patients. The most commonly
used fetal vascular Doppler assessment is measurement of resistance to flow in the

umbilical arteries, with evidence of increasing resistance to flow reflective of wors-
ening maternal–placental circulation and the potential for worsening fetal oxygen-
ation of the fetus. Randomized trials have been done for umbilical artery waveform
analysis in some high-risk pregnancy populations, and the current Cochrane review
concludes that this method of fetal surveillance in high-risk pregnancies reduced the
risk of perinatal deaths and resulted in less obstetric interventions [20].
Mode of Delivery
Determining fetal presentation is a critical step in determining mode of delivery.

The most common fetal presentation during labor is cephalic. Presentations not
amenable to vaginal delivery are persistent breech and oblique or transverse lie. An
attempt at rotating the fetus to cephalic with a procedure called external cephalic
version may be made and if not successful, a cesarean is indicated. In rare cases
where there is both an experienced provider and adequate maternal pelvis, a vaginal
breech delivery may be attempted. Likewise, any anatomic malformation of the
fetus that impedes flexion or extension of head such as a large neck mass would be
an indication for cesarean delivery. Other fetal indications relevant to woman with
rheumatic disease include fetal dysrhythmias not amenable to external fetal heart
rate monitoring.
Other factors in determining mode of delivery include antenatal and intrapartum
factors. Antepartum indications for a cesarean delivery include history of classical
cesarean or uterine surgery involving the active portion of the uterus, two or more
prior cesareans, placenta previa, placenta accreta spectrum disorders, and higher
order multifetal gestation (three or more). Cesarean delivery may also be indicated in
cases where obstetric complications require expedited delivery [such as acute fatty
liver of pregnancy (AFLP), hemolysis, elevated liver enzymes, low platelets (HELLP),
and severe preeclampsia] that is not likely to be achieved with vaginal induction
given unfavorable clinical assessment of the cervix. Rarely is cesarean indicated for
women with rheumatic or osteoarthritis unless passive hip abduction is not possible.
Intrapartum indications for cesarean delivery include fetal distress, maternal distress,
arrest of dilation, or arrest of descent. The latter two may reflect feto-pelvic dispro-
portion. In cases of fetal macrosomia, commonly defined as estimated fetal weight is
>4,500 g for the diabetic and >5,000 g for the non-diabetic woman, a cesarean may
be offered given the significantly increased risk for shoulder dystocia.
Selected Pregnancy Complications
Some pregnancy complications are more common in women with rheumatic dis-
eases, e.g., preeclampsia in women with SLE. A primer on selected pregnancy com-
plications that are somewhat more likely to occur in women with rheumatic disease
is offered below.
Pregnancy Loss
Human conception and pregnancy may be characterized as somewhat inefficient.

Assisted reproductive technology programs find that well under half of preimplan-
tation conceptions succeed. Overall, at least 30 % of human spontaneous pregnan-
cies recognized by the presence of β-hCG, representing implantation, fail [21].
Most of these are lost before the missed menses that typically heralds the patient’s
recognition of pregnancy, but 10–15 % are lost after recognition of pregnancy, usu-
ally within the first 12 weeks of gestation. Among these, most fail in the pre-
embryonic or embryonic periods, though the clinical features of miscarriage often
do not ensue for up to several weeks. The fetal period is most commonly defined as
beginning at 10 weeks, and the death of the conceptus in utero thereafter is a “fetal”
death. Historically, pregnancy losses prior to 20 weeks gestation have been termed
“miscarriages” or “spontaneous abortions,” and the delivery of a dead fetus at or
beyond 20 weeks has been referred to as “stillbirth.” In the general obstetric popula-
tion, fetal death occurs in some 1.5–2 % of pregnancies, with most of these occur-
ring between the 10th and 15th week. From 16 weeks forward, approximately 1 %
of live fetuses expire in utero [22]. After 20 weeks, fetal deaths occur in approximately
5–7 per 1,000 births in the general US population [23].
Within the general obstetric population, variables well recognized to influence
pregnancy loss include maternal age and prior pregnancy loss. Pre-embryonic,
embryonic, and fetal loss rates increase with increasing maternal age. Even among
women with no prior pregnancy losses, the likelihood of pre-embryonic or embry-
onic loss per pregnancy exceeds 20 % by age 36 years and approaches 40 % by
age 40 years. A sizeable proportion of these losses are aneuploidy conceptions,
though certainly not all. Most pregnancy losses in the pre-embryonic or embry-
onic period go unexplained since chromosomal analysis of abortus tissue is not
common practice.
Fetal deaths also are increased in relation to maternal age and prior fetal death,
as well as with obesity, smoking, chronic hypertension, and black race [24]. Fetal
deaths at or beyond 20 weeks are twice as likely in women more than 35–39 years
of age compared to those less than 35 years of age and 1.5–3 times as likely in
women with a prior stillbirth. BMI > 30, smoking more than ten cigarettes per day,
chronic hypertension, and black race also are associated with a twofold increased
risk compared to the general population. By comparison, insulin-requiring diabetes
and SLE carry increased risks at least several fold higher than that of the general
population.
Apart from the well-recognized associations with specific maternal condition
such as diabetes or SLE, fetal death may be due to fetal infections, chromosomal
abnormalities, syndromes of a Mendelian or polygenic origin, uterine malformations
(e.g., uterine septum), or feto-maternal hemorrhage. Some experts hold that heritable
thrombophilias may play a role in fetal death. A recently completed population-
based study of fetal deaths at 20 weeks or later, with thorough maternal, fetal, and
placental evaluations, found that fetal deaths were most commonly attributable to
placental disease, infection, fetal genetic or structural abnormalities, or obstetric
complications (e.g., maternal hemorrhage). Importantly, the “placental disease”

category includes histopathological lesions that are nonspecific in nature. Lupus
anticoagulant and anticardiolipin were present in less than 5 % of women tested.
Intrauterine Growth Restriction
Fetal access to nutrients and gas exchange depends upon the development of an
adequate maternal–placental–fetal circulation, with the villous trophoblast as the
primary site of exchange. The placenta actively transports glucose, amino acids, and
free fatty acids from the maternal to the fetal circulation. The rate of fetal growth
accelerates at 24–28 weeks and slows somewhat at 32 weeks forward. However, most
fetal fat gain occurs after 28 weeks and particularly after 32 weeks.
Pathologic restriction of fetal growth can be grouped into several categories,
though overlap of these is common. Perhaps the most important etiology of intraute-
rine growth restriction (IUGR) is poor placental vascular development, a condition
commonly termed “uteroplacental insufficiency” or more simply, “placental insuf-
ficiency.” Placental insufficiency is easily the single most common cause of IUGR
in singleton US pregnancies. It is also well known to be associated with maternal
hypertensive or vascular conditions, including maternal renal disease of diverse
etiologies ranging from acquired nephritis to inherited nephropathies. The mecha-
nism of poor placental development leading to placental insufficiency is not well
understood.
Other etiologies of restricted fetal growth include inherent conditions of the
fetus, such as fetal chromosomal or genetic conditions and fetal infection. Low pre-
pregnancy maternal weight or poor weight gain in pregnancy also are associated
with impaired fetal growth, though these are not major contributors to IUGR in the
USA. Maternal smoking, cocaine use, and alcohol use also are associated with
IUGR.
Experts have identified two patterns of restricted fetal growth. Asymmetric
IUGR entails restricted somatic growth with sparing of fetal head growth. Such
fetuses have smaller abdominal circumference measurements with relatively nor-
mal head measurements. This is the type of IUGR most commonly seen with pla-
cental insufficiency. In symmetric IUGR, all fetal measurements are similarly
reduced, including head measurements. Symmetric fetal growth restriction is typi-
cally associated with early insults, such as fetal genetic abnormalities or syndromes,
or insults that impair growth in numerous organ systems, such as with certain viral
infections.
Hypertensive Disorders of Pregnancy
Hypertensive disorders complicate up to 10 % of pregnancies in unselected obstet-

ric populations and are a major cause of maternal and feto-neonatal morbidity and
mortality. The two most common forms of hypertensive disorders of pregnancy are
Table 2.5 Criteria for severe preeclampsia

Blood pressure ≥160 mmHg systolic or ≥110 mmHg diastolic, recorded on at least two occasions
at least 4 h apart with patient on bedrest
Progressive renal insufficiency (serum creatinine > 1.1 mg/dl or two times normal value)
New-onset cerebral or visual disturbances
Pulmonary edema
Severe persistent epigastric or right upper-quadrant pain
Impaired liver function (serum transaminase at least two times normal value)
Thrombocytopenia (<100,000 platelets/ML <100 ×109/L)
Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’
Task Force on Hypertension in Pregnancy. American College of Obstetricians and Gynecologists;
Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov; 122(5):1122–31
gestational hypertension and preeclampsia, both of which are more common among
women with SLE and among women with renal disease of virtually any etiology,
including autoimmune.
Gestational hypertension and preeclampsia are vasospastic hypertensive disor-
ders marked by abnormal maternal arteriolar reactivity to vasoactive agents such as
prostacyclin, thromboxane A2, nitric oxide, and endothelins. The hallmark of gesta-
tional hypertension and preeclampsia is new elevation of blood pressure (BP) to
more than a systolic of 140 mmHg or a diastolic of 90 mmHg after 20 weeks gesta-
tion and present on two more occasions at least 4 h apart. Such elevated BPs prior
to 20 weeks most likely represent chronic hypertension.
Preeclampsia is distinguished from gestational hypertension by the presence of
new proteinuria (≥0.3 g per 24 h, protein/creatinine ratio ≥0.3, or 1+ by dipstick) or
any of several other clinical features representing maternal end-organ injury, includ-
ing cerebral symptoms, serum urate >5.5 mg/dL, hemoconcentration, thrombocyto-
penia, hepatic dysfunction, or placental insufficiency resulting in fetal growth
restriction. By definition, these maternal or fetal features are absent in gestational
hypertension, though gestational hypertension develops into preeclampsia in at least
25 % of patients. Women with chronic essential hypertension are also predisposed
to preeclampsia as manifest by worsening hypertension and other clinical features
in the second half of pregnancy.
Preeclampsia exists on a continuum of severity and is generally described as
either mild or severe (note that there is no “moderate” preeclampsia). Accepted
criteria for the diagnosis of severe preeclampsia are shown in Table 2.5. Mild pre-
eclampsia is defined as new-onset BP of 140–159 mmHg systolic and 90–109 mmHg
diastolic and proteinuria of 0.3–4.9 g per 24 h.
The cause(s) and pathophysiological details of hypertensive disease of preg-
nancy remain unclear, in part because hypertensive disorders of pregnancy occur in
a wide array of clinical situations, e.g., in normal nulliparous women, as well as in
women with chronic renal disease and related hypertension. Many experts hold
that the key event is abnormal trophoblast invasion, including suboptimal forma-
tion of the maternal–placental circulation (see IUGR above). Evidence points to
varied factors such as imbalances in angiogenesis or coagulation, underlying
genetic predisposition to vascular hyperreactivity, increased oxidative stress,

dysfunctional cardiovascular adaptation to pregnancy, and exaggerated inflamma-
tory responses at the maternal–fetal interface. The latter may be particularly impor-
tant to the predisposition to hypertensive disorders of pregnancy among certain
autoimmune populations.
Regardless of the exact cause, inadequate placentation is established by
18–20 weeks of gestation and, depending upon the degree of inadequacy, can result
in two major and often overlapping clinical features and their sequelae. The first is
IUGR, discussed in the preceding section. The other is pregnancy-related hyperten-
sion. One popular and credible theory is that the feto-placental unit response to
inadequate maternal–placental circulation is the elaboration of vasoactive sub-
stances that promote increased blood flow to the placenta. This works up to a point,
but eventually in predisposed individuals results in adverse maternal vascular
effects. These can include vasospasm-induced ischemia in cerebral, hepatic, and
renal beds, as well as in the maternal–placental circulation.
The management of IUGR, gestational hypertension, and preeclampsia includes
serial observation of the mother and fetus to detect evidence of more severe involve-
ment requiring delivery. For the fetus, a typical observational plan would include
“surveillance” using NSTs, amniotic fluid volume assessment, BPPs, fetal vascular
Doppler assessment, or a combination of these. In most centers, twice weekly fetal
assessment is standard.
Maternal observation is generally aimed at detection of severe preeclampsia
(Table 2.5) and may be done as an outpatient or inpatient, depending upon the
degree of concern. Ultimately, ongoing care of IUGR, gestational hypertension, and
preeclampsia depends upon (1) the gestational age and (2) the severity of maternal
or fetal disease. For practical purposes, pregnancies that have reached 36–37 weeks
are candidates for delivery, even in the setting of mild fetal growth restriction or
gestational hypertension.
For gestational ages less than 36 weeks, delivery decisions are influenced by the
severity of disease as manifest by such parameters as the estimated fetal weight or
the degree of oligohydramnios in fetal growth restriction and the degree of BP ele-
vation or the presence of features of severe preeclampsia in hypertensive disorders.
With infrequent exceptions at very early gestational ages, severe preeclampsia is an
indication for delivery. In both IUGR and hypertensive disorders of pregnancy,
abnormal fetal testing results suggestive of fetal hypoxemia are also an indication
for delivery. Determining the mode of delivery involves consideration of gestational
age, cervical evaluation, parity, and whether the woman is in labor. If these factors
suggest a likely prolonged induction (>24 h), cesarean delivery may be reasonable.
For gestational age ≤32 weeks, induction of labor is not likely to be successful, with
only a third achieving vaginal delivery [25]. Conversely, induction of labor for ges-
tational age ≥ 34 weeks will be successful for roughly two thirds of women [26].
It is worth noting that the treatment of gestational hypertension and preeclampsia
with antihypertensives does little to influence disease progression or alter the timing
of delivery. Medications such as hydralazine, labetalol, and nifedipine are, however,
used to control severely elevated maternal BPs. Ultimately, the definitive treatment
is delivery.
Table 2.6 Criteria for Hemolysis

HELLP syndrome Abnormal peripheral smear
AND
Serum lactate dehydrogenase LDH > 600 IU/L
OR
Total bilirubin ≥ 1.2 mg/dL
Elevated liver enzyme
AST at least two times normal value
ALT at least two times normal value
Thrombocytopenia
Platelets < 100 × 109/L
HELLP syndrome is the presence of hemolysis, elevated liver enzymes, and low
platelets and is considered a variant of severe preeclampsia. HELLP syndrome com-
plicates 0.5–0.9 % of all pregnancies [27]. The most frequently used diagnostic
criteria is the Tennessee Classification System (Table 2.6). Note that the diagnosis
of HELLP does not require the presence of hypertension or proteinuria, though the
former is present in all but the exceptional case. If only one or two of the three diag-
nostic criteria are met, some experts distinguish a “partial HELLP.” Liver failure
and coagulopathy is rare in HELLP syndrome, and such findings should prompt
workup of other causes such as acute fatty liver or hepatitis. The development of
significant nausea and vomiting, right upper-quadrant pain, or epigastric pain should
prompt consideration of liver involvement and swelling. Although the development
of subcapsular liver hematoma and/or liver rupture is rare (1 %) and not well under-
stood, it can be dramatic and pose significant risk for maternal and fetal morbidity
[28]. Similar to preeclampsia, delivery is the only definitive treatment. Though
maternally administered non-fluorinated corticosteroids may improve the maternal
platelet counts, such agents do not improve maternal or neonatal outcomes [29]. As
HELLP syndrome is progressive with serious potential for rapid maternal deteriora-
tion, prompt delivery should follow the diagnosis but does not preclude vaginal
delivery as long as vaginal delivery is likely to be successful in <24 h. Delay in
delivery may be undertaken for completion of antenatal corticosteroid administra-
tion in cases of prematurity if continuous maternal and fetal monitoring ensures
stable condition. Like severe preeclampsia, intravenous magnesium sulfate for sei-
zure prophylaxis and antihypertensives for treatment of dangerously high blood
pressure should be initiated.
Eclampsia is the occurrence of generalized tonic clonic seizure in the presence of
proteinuria and hypertension and in the absence of other neurologic conditions.
Although historically thought to be the final evolution of preeclampsia, eclampsia is
simply but one of several manifestations of severe preeclampsia due to small arte-
riolar vasospasm and peripheral ischemia. It is not uncommon for eclampsia to be
the first presentation of hypertensive disease. In the absence of magnesium seizure
prophylaxis, eclamptic seizure will occur in 0.5 % of women with mild preeclamp-
sia and 2–3 % of women with severe preeclampsia, and recurrent seizure will occur
in 10 % of eclamptic women. Most seizures occur during the antepartum period,
followed in frequency by intrapartum and first 48 h postpartum periods, and will

typically terminate spontaneously within 1–2 min. Fetal bradycardia during and
immediately after the seizure is common and does not necessitate emergent cesar-
ean delivery unless severe fetal compromise is apparent despite maternal and fetal
resuscitation. The management of eclampsia should include protection of airway,
maintenance of maternal oxygenation, delivery, treatment of any hypertension, and
prevention of recurrent seizure.
Prevention of recurrent seizure is with administration of magnesium sulfate.
Multiple trials have demonstrated that magnesium sulfate is superior to other anti-
epileptic medications, such as diazepam or phenytoin, for primary seizure preven-
tion, seizure recurrence, and maternal death. Its use is associated with a 59 %
reduction in seizure, a 36 % reduction in placental abruption, and a nonsignificant
reduction in maternal mortality [30]. Magnesium seizure prophylaxis is typically
given as a 4–6 g intravenous bolus over 15–20 min followed by a maintenance dose
of 2 g/h continued through 24 h postpartum. Aggressive antihypertensive treatment
should also be initiated as up to 20 % of eclamptic deaths are due to hypertensive
stroke.
Eclampsia does not preclude vaginal delivery, although delivery should be expe-
dited (<24 h). As with severe preeclampsia, determining the mode of delivery
involves consideration of gestational age, cervical evaluation, parity, and whether
the woman is in labor. If these factors suggest a likely prolonged induction (>24 h),
cesarean delivery may be reasonable and is often the case for gestational
age ≤ 32 weeks.
Preterm Birth
Historically, preterm birth is defined as birth after 20 weeks and before the com-
pletion of the 37th menstrual week of gestation. The rate of preterm birth in the
USA is 12 %, a rate that is nearly twice as high as in Western Europe. In the USA,
preterm birth accounts for over 85 % of all infant deaths in the USA and myriad of
neonatal morbidities, respiratory distress syndrome, intraventricular hemorrhage,
bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis,
sepsis, apnea, and retinopathy of prematurity. Long-term medical problems
include chronic lung disease, neurodevelopmental disabilities, and visual and
hearing impairment.
The major etiologies of preterm birth are preterm labor (PTL) with intact mem-
branes, preterm premature rupture of membranes (PPROM) with subsequent labor
or need for delivery, and indicated delivery for such complications as bleeding (e.g.,
from a placenta previa or placental abruption), severe preeclampsia, or other serious
maternal or fetal conditions.
With regard to PTL and PPROM, numerous associations have been reported
(Table 2.7). In particular, a history of prior spontaneous preterm birth is now well
recognized as a major risk for recurrent spontaneous preterm birth.
Table 2.7 Some factors • Genital and urinary tract infections

associated with singleton • Cervical disease, e.g. precancerous lesions, and treatment
spontaneous preterm birth
• African American race
• History of a previous spontaneous preterm birth
• Uterine malformation
• Tobacco abuse
• Substance abuse
• Poor nutrition and low pre-pregnancy BMI
• Peridontal disease
• Low socioeconomic status
• Limited education
Table 2.8 Some indications for iatrogenic preterm delivery

• Hypertensive disease, chronic or gestational
• Placental disorders (previa, abruption, accreta)
• Maternal thrombosis or embolism
• Rheumatic diseases, e.g., SLE or APS
• Prior uterine surgery involving the upper uterus, e.g., prior classical cesarean or transmural
myomectomy
• Poor fetal growth or oligohydramnios
• Fetal distress, e.g., abnormal fetal surveillance testing
• Fetal compromise as evident by imaging, e.g., fetal hydrops, fetal cardiac dysfunction,
life-threatening fetal defect(s) or by other tests
Indicated preterm births occur for numerous reasons, but in general fall into cat-
egories of either serious maternal or serious fetal conditions for which delivery
represents the best management option (Table 2.8). For indicated preterm births, of
course, the gestational age is a key component of timing. Thus, for the mother on
full anticoagulation because of recurrent thrombotic episodes, early delivery at 37
or 38 weeks might be a reasonable plan with regard to balancing maternal risks
(spontaneous onset of labor while fully anticoagulated) against neonatal risks. On
the other hand, severe preeclampsia at 28 weeks threatens the well-being of both
mother and fetus and is not amenable to long delays in delivery.
Multifetal gestation, most commonly twins or triplets, is another important cat-
egory of preterm birth. Twins and triplets are more frequent today than in the past
due to assisted reproductive technology in infertility and are associated with higher
rates of both dizygotic and monozygotic pregnancies. Multifetal gestations not only
have higher rates of spontaneous preterm birth due to PTL and PPROM but also are
more likely to develop complications requiring early delivery such as fetal growth
restriction and preeclampsia. The average gestational age of twin and triplet deliver-
ies in the USA is 36 and 32 weeks, respectively.
Among pregnancies threatening to delivery prematurely, the most important
medical consideration is the use of fluorinated steroids administered to mother.
Fluorinated steroids, unlike their unfluorinated counterparts, are less extensively
metabolized by placental enzymes and cross the placenta prior to birth and enhance
fetal maturity, in particular pulmonary maturity. The most commonly used agent in
the USA is betamethasone. Optimal neonatal benefit is achieved if delivery can be
delayed for 48 h after administration of the steroid to the mother. Thus, if PTL is
suspected, an agent to retard labor and delay delivery is often administered in con-
junction with the steroid. The most commonly used agents in the USA are indo-
methacin and nifedipine. The former is little used after 32 weeks gestation because
of adverse fetal effect (constriction of the ductus arteriosus). With PPROM, a course
of amoxicillin-ampicillin and erythromycin may prolong pregnancy and reduce
infection-related complications.
GI Disorders
Nausea and Vomiting of Pregnancy
Nausea and vomiting is a common problem in pregnancy, affecting 70–85 % of

pregnant women [31]. The mechanism(s) of this very common gestational disorder
remains uncertain, although elevated levels of estrogen and progesterone, gastric
reflux, and decreased gastric motility may contribute. Onset is typically at about
6 weeks and resolves by 16 weeks. Nausea and vomiting in pregnancy exists as a
continuum. At its extreme, the condition is known as hyperemesis gravidarum.
Although there is no single standard diagnostic criteria for hyperemesis gravi-
darum, roughly 0.5–2 % of pregnant women are affected with a constellation of
persistent emesis, dehydration, ketonuria, and weight loss. Management includes
avoidance of triggers and small, frequent meals. Commonly used medications
include vitamin B6, doxylamine, promethazine, metoclopramide, and ondansteron,
though none are supported by robust clinical studies.
Gastroesophageal Reflux Disease
Gastric reflux is the most common gastrointestinal complaint in pregnancy, affecting

50–80 % of women by the third trimester. Diagnosis is clinical, and symptoms are
same as those in nonpregnant women: epigastric burning or pain, nausea, dysphagia,
regurgitation, vomiting, chronic cough, or asthma. Management is primarily lifestyle
and dietary changes and medication. Avoiding dietary triggers, eating small low-fat
meals, avoiding eating within a few hours of sleeping, and sleeping with the head of
the bed elevated may be helpful. Pharmacologic therapy includes antacids and H2
receptor antagonists, both of which are safe in pregnancy, with the latter being FDA
pregnancy category B. If symptoms persist, a proton pump inhibitor is typically
added. All proton pump inhibitors are FDA pregnancy category B except for omepra-
zole, which is category C. If symptoms persist and are refractory to medical manage-
ment, an upper gastrointestinal endoscopy may be considered, but is rarely needed.
Intrahepatic Cholestatis of Pregnancy
Intrahepatic cholestatis of pregnancy typically presents with pruritus starting in the

second or third trimester. The incidence ranges from 0.1 to 15.6 % depending on
geographic and ethnic variations, with increased frequency among Hispanics [32].
Pruritus is typically whole body, worse on the palms and soles, and peaks at night.
There is no skin lesion present except as a result of excoriation. Intrahepatic cho-
lestasis of pregnancy is associated with increased frequency of adverse obstetric
outcomes including preterm delivery, intrapartum fetal distress, fetal death, and
neonatal demise. It is not understood why fetal death occurs, although in rat models,
impaired cardiac contractility and arrhythmias occurred with exposure to high levels
of bile acids [33–35].
Diagnosis requires elevated bile acids greater than 10 μmol/L, the exclusion of
other forms of liver disease, and resolution after delivery (symptoms typically
resolve within 4 weeks after delivery). Other laboratory findings may include mildly
elevated liver enzymes, bilirubin, and alkaline phosphatase. In 10 % of cases patients
will be jaundiced. Ursodeoxycholic acid is considered the mainstay of treatment. It
is associated with improvements in liver enzyme and bile acid parameters and is
thought to reduce perinatal complications. As noted above, cases of unexplained
intrauterine demise have been reported in cholestasis of pregnancy, typically after
36 weeks. Management with ursodeoxycholic acid and delivery by 37–38 weeks
may improve outcomes [36–38]. Though of unproven efficacy, antenatal testing,
such as with twice weekly NSTs, starting at 32–34 weeks gestation is usually rec-
ommended by experts.
Acute Fatty Liver of Pregnancy
AFLP is rare and a potentially life-threatening condition that affects 1 in 10,000 to

1 in 15,000 deliveries [39]. The onset is almost exclusively in the third trimester,
with an average of 36 weeks [40]. AFLP appears to be associated with a defect in
beta-oxidation of fatty acid and occurs in greater frequency among women who are
heterozygous for long-chain 3-hydroxyacyl-enzyme deficiency (LCHAD) and car-
rying a fetus who is homozygous for LCHAD. Although the mechanism is not well
understood, it is believed the mother is unable to sufficiently compensate for the
fetal inability to metabolize fatty acids, resulting in liver damage. It typically mani-
fests in the third trimester with 1–2 weeks of nausea, vomiting, abdominal pain,
malaise, and anorexia. Laboratory values are significant for elevated liver enzyme,
thrombocytopenia, hypoglycemia, and elevated ammonia. AFLP may be difficult to
distinguish from HELLP, but AFLP is typically notable for severe hepatic insuffi-
ciency resulting in hypoglycemia, encephalopathy, and coagulopathy. Although
definitive diagnosis is with a liver biopsy demonstrating microvesicular fatty infil-
tration of hepatocytes, this procedure is infrequently used in clinical practice due to
its invasive nature and the typical presence of maternal coagulopathy. Thus, diagno-
sis is typically based on clinical and laboratory findings. Treatment is primarily
prompt delivery followed by maternal stabilization, typically in a critical care unit

with a multidisciplinary team. Like preeclampsia, AFLP is not an indication for
cesarean delivery; the mode of delivery should depend on the likelihood of a suc-
cessful and timely vaginal delivery (<24 h) [39]. Patients will usually improve
2–3 days after delivery, although deterioration may continue for up to a week in
some cases.
Venous Thromboembolism/Pulmonary Embolism
Pregnancy is a prothrombotic state. There is an increase in procoagulants such as

von Willebrand factor, fibrinogen, and factors VII, VIII, IX, and X, a decrease in
fibrinolytic factors such as plasminogen activator, and a decrease in the activity of
some endogenous anticoagulant mechanisms such as protein S function and an
increased resistance to activated protein C. There is also increased venous stasis due
to compression of the vena cava by the gravid uterus and increased vascular compli-
ance. Finally, vascular damage is inherently part of delivery, with the net effect of a
particularly prothrombotic state in the postpartum period. The incidence of throm-
botic events in pregnancy is about 1 in 1,000 women. About 50 % of these cases
have an underlying genetic disorder. The diagnosis of VTE in pregnancy requires a
high level of clinical suspicion.
Dermatologic Conditions in Pregnancy
Relatively common, benign dermatological changes of pregnancy include spider

angiomas and teleangiectasia, palmar erythema, gingival hyperplasia, hyperpig-
mention (particularly of the areola and linea nigra), and postpartum “hair loss”
(telogen effluvium). The latter is due to hormone-induced prolongation of the ana-
gen phase of hair during pregnancy, with subsequent synchronized telogen phase
after delivery.
Several pregnancy-specific dermatoses are to be distinguished. Pruitic urticarial
papules and plaques of pregnancy (PUPPP) occurs in about 1 in 200 pregnancies. It
usually affects primigravidae in the last weeks of gestation. The pruritic, polymor-
phic eruption tends to start within abdominal striae and characteristically spare the
umbilicus. The papules coalesce into plaques that may spread to the buttocks and
proximal thighs. Though small (2–4 mm) vesicles may form, blisters do not.
Treatment with topical steroids and antihistamines is typically sufficient for control
of the condition.
Atopic eruption of pregnancy, also known as prurigo of pregnancy, is a condition
of eczematous or papular lesions typically with onset before the third trimester.
A history of atopic dermatitis is found in many patients. The common features are
eczematous lesions in common atopic sites and erythematous papules on the trunk
and limbs. Atopic eruption of pregnancy may not be easily distinguished from
PUPPP in many cases, but the treatment with topical steroids is the same.
Intrahepatic cholestasis of pregnancy, usually referred to cholestasis of pregnancy,

is a fairly common cause of pruritus in later pregnancy. The skin itself appears nor-
mal, except as it might be affected by the patient scratching. Though the molecular
cause is uncertain, the immediate cause of cholestasis of pregnancy is impaired
excretion of bile salts resulting in elevated circulating bile acids. The itching often
involves the palms and soles and becomes generalized (“everything itches”).
Elevated serum bile acids are diagnostic. Hepatocellular enzymes and bilirubin are
mildly elevated in some cases. Adverse fetal outcomes are associated with cholesta-
sis of pregnancy and include an increased frequency of fetal death particularly in
severe cases. Management aims to reduce circulating bile acids with ursodeoxycho-
lic acid. Fetal surveillance testing and somewhat early delivery is recommended by
many experts.
Pemphigoid gestationis (PG) is an infrequent autoimmune bullous disorder
typically occurring in late pregnancy and the postpartum period. It is due to a
complement-fixing autoantibody directed against an antigen in the hemidesmo-
somes of the dermal-epidermal junction. PG presents with marked pruritus associ-
ated with erythematous papules and plaques. The lesions usually begin on the
abdomen and typically involve the umbilicus. They may, however, be widespread and
include most skin surfaces in severe cases. Biopsy shows linear C3 deposition along
the dermal-epidermal junction. Treatment is severity -dependent and includes topi-
cal steroids in mild cases and oral (or parenteral) steroids or other immunosuppres-
sives in severe cases. Peri-delivery exacerbation is common. A small percentage of
neonates will have blistering skin lesions secondary to passive transplacental trans-
fer of the autoantibody.
Pre-pregnancy Assessment and General Obstetric Approach

to the Pregnant Rheumatic Disease Patient
Women with rheumatic disease who are contemplating pregnancy should undergo
preconceptional counseling with an obstetrician and rheumatologist in order to dis-
cuss maternal and fetal risks of pregnancy and if necessary to adjust her drug ther-
apy in an attempt to maximize her disease management and minimize fetal harm
(Table 2.9). For example, women with APS and prior thrombosis who are on warfa-
rin should switch to heparin before 6 weeks gestation to avoid warfarin embryopa-
thy (Table 2.9).
The risks of anti-rheumatic agents are discussed in full detail in Chap. 14.
Reproductive-aged women are disproportionately affected by rheumatic dis-
eases, and in some cases an initial diagnosis is made in the course of an evaluation
for adverse obstetric outcomes, e.g., diagnosis of APS after a 20 week fetal death.
Systemic lupus and APS are unquestionably associated with an increased obstetric
risk profile. This is especially true in patients with underlying hypertension, a his-
tory of renal disease, or a history of thrombosis. Preconceptional evaluation includ-
ing laboratory testing can help establish baseline disease activity (Table 2.9).
58
Table 2.9 Recommended practices in pregnancies of women with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis
(RA), and systemic sclerosis (SSC)
Assessment/test Preconception First trimester 18–20 weeks 22–24 weeks 26–28 weeks 30–32 weeks 32–34 weeks 36–38 weeks
SLE
Adjustments of drug therapy to X
minimize risks
Laboratory assessments X X
Antiphospholipid antibodies X
CBC with platelets X
Renal function and protein X X X
excretion (e.g., 24-h urine
for CRCL and total protein)
Screen for gestational diabetesa
Obstetric ultrasound for fetal X X X X X X
growth and amniotic fluid
volume
Fetal surveillance testsb X------------------------------------------
APS
Adjustments of drug therapy to X Xc
minimize risks
Laboratory assessments CBC X X
with platelets X X X X
Assessment of
anti-coagulationd
Obstetric ultrasound for fetal X X X X X X
volume
Fetal surveillance testsb X------------------------------------------
RA
minimize risks
D.W. Branch and L.F. Wong
2
Obstetric ultrasound for fetal X Xe X X

volume
Fetal surveillance testsb Xf-----------------------------------------
SSC
minimize risks
Laboratory assessments
Renal function and protein X
excretion (e.g., 24-h urine
for CRCL and total protein)
Obstetric ultrasound for fetal X X Xe X X X
volume
Fetal surveillance testsb Xf-----------------------------------------
a
Routine gestational diabetes screening is performed at 24–28 weeks gestation in otherwise low risk patients. However, for women on chronic glucocorticoids,
earlier and more frequent screening is recommended
b
May include NSTs, amniotic fluid volume assessment, BPPs, fetal vascular Doppler assessment, or a combination of these. Fetal surveillance testing is typically
performed on a twice weekly basis, though practices may vary according to the degree of clinical concern
c
If the patient is on warfarin, it should be discontinued before 6 weeks gestation to avoid warfarin embryopathy
d
For women in whom full anticoagulation is the goal. Note that there is considerable variation in practice as to how often assessment of anticoagulation status is
done. Women with lupus anticoagulant, which can prolong standard activated partial thromboplastin times should be assessed using anti-factor Xa assays, as should
women on low-molecular-weight heparin agents
e
The clinical utility of serial obstetric ultrasound to assess fetal growth and amniotic fluid volume in women with RA or SSc and an otherwise uncomplicated preg-
nancy is uncertain
f
Normal Pregnancy, Pregnancy Complications, and Obstetric Management
The clinical utility of fetal surveillance testing in women with RA or SSc and an otherwise uncomplicated pregnancy is uncertain
59
It is our practice to have all women with rheumatic disease followed closely by
their rheumatologist during pregnancy, with the frequency of visits left to the discre-
tion of the rheumatologist. Women with SLE, APS, and SSc are generally followed
more frequently with visits at least every several weeks in early pregnancy.
At and beyond 20 weeks gestation, these patients are usually seen every
1–2 weeks for obstetric care, with primary goals of screening for gestational hyper-
tensive disease and fetal growth impairment. With regard to the former, home blood
pressure monitoring may be helpful; with regard to the latter, obstetric ultrasound
examinations every 3–4 weeks are usually employed. Additional assessments, typi-
cally started after 26–28 weeks, may include fetal surveillance using NSTs, amni-
otic fluid volume assessment, BPPs, fetal vascular Doppler assessment, or a
combination of these. Women taking chronic glucocorticoids are at increased risk
for gestational diabetes and should be assessed for this condition, generally around
20, 28, and 32 weeks gestation (Table 2.9).
In contrast to SLE, women with otherwise uncomplicated RA do not typically
require increased obstetric surveillance during pregnancy, and the same may be true
in women with mild, stable SSc in the absence of cardiac, pulmonary, or renal
involvement. Similarly, routine antenatal testing, including serial ultrasounds,
NSTs, and BPPs are not necessary in these women and should generally be reserved
for typical obstetric indications.
Conclusion
Significant changes in maternal physiology occur during pregnancy and may result
in conditions similar to those suffered by women with underlying rheumatic dis-
ease. This overview of the obstetric patient serves to familiarize the rheumatologist
with features of normal and complicated pregnancy. The following chapters build
upon this understanding, addressing the nuances of pregnancy management in each
specific rheumatologic disease.
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15. Ensom M, Liu P, Stephenson M. Effect of pregnancy on bone mineral density in healthy
women. Obstet Gynecol Surv. 2002;57:99.
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17. Keriakos R, Bhatta SR, Morris F, Mason S, Buckley S. Pelvic girdle pain during pregnancy
and puerperium. J Obstet Gynaecol. 2011;31(7):572–80.
18. American College of Obstetricians and Gynecologists. ACOG practice bulletin 77: screening
for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109:217–27.
19. Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP, et al. Genome-wide
fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:
890–901.
20. Alfirevic Z, Stampalija T, Gyte GML. Fetal and umbilical Doppler ultrasound in high-risk
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29. Woudstra DM, Chandra S, Hofmeyr GJ, Dowswell T. Corticosteroids for HELLP (hemolysis,
elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database Syst Rev
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review). In: The Cochrane library, issue 4. Chichester: Wiley; 2003.
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of current evidence. J Womens Health. 2007;16(6):833–41.
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(Lond). 2001;100(4):363–9.
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V, Gorelik J. Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of
pregnancy. Dig Dis. 2011;29(1):58–61.
36. Kenyon AP, Percy CN, Girling J, et al. Obstetric cholestasis, outcome with active manage-
ment: a series of 70 cases. BJOG. 2002;109(3):282–8.
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39. Sibai BM. Imitators of severe pre-eclampsia. Semin Perinatol. 2009;33:196–205.
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193–5.
Chapter 3
General Approach: Pre-pregnancy Assessment
of the Rheumatic Disease Patient
Lisa R. Sammaritano and Bonnie L. Bermas
Introduction
Rheumatic diseases disproportionately affect women during their reproductive

years. Advances in effective rheumatology therapies, clarification of pregnancy risk
factors, and improved obstetric monitoring and management have given increasing
numbers of rheumatic disease patients the option of pursuing pregnancy with a high
likelihood of favorable outcome. Knowledge of the immunology and physiology of
pregnancy as described in Chaps. 1 and 2 provides the groundwork for understand-
ing the specifics unique to individual rheumatic diseases during pregnancy. These
specifics are detailed in the chapters that follow, as are other particular issues for
these patients with regard to fertility, contraception, medication use, and offspring
(both neonatal and long term). This chapter focuses on the pre-conception evalua-
tion and counseling of the rheumatic disease patient, emphasizing a general approach
and introducing the issues common to most rheumatic disease patients planning
pregnancy. For any rheumatic disease patient, a structured pre-pregnancy assess-
ment of that individual’s risk for maternal and obstetric complications is paramount;
equally important, however, is the communication of that risk and prognosis through
effective counseling with the patient and her partner. Ideally, every rheumatic dis-
ease patient should have coordinated rheumatology and obstetric care with planning
that is individualized to her diagnosis and particular clinical and social situation.
L.R. Sammaritano, M.D. (*)

Division of Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College,
535 East 70th Street, New York, NY 10021, USA
e-mail: sammaritanol@hss.edu
B.L. Bermas, M.D.
Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School,
75 Francis Street, Boston, MA 02115, USA

64 L.R. Sammaritano and B.L. Bermas
Dynamic Interplay of Rheumatic Disease and Physiology

of Pregnancy
For any woman, whether or not she has an underlying medical condition, pregnancy
brings changes in physiology and the development of new (and occasionally puz-
zling) symptoms. It is critical that both the physician and the patient understand and
anticipate these changes. For the woman with rheumatic disease, pregnancy-related
immune changes may impact the course of her underlying disease: examples include
the increased risk of systemic lupus erythematosus (SLE) flare during pregnancy as
well as the possibility of pregnancy-induced remission in rheumatoid arthritis (RA).
Conversely, the immune system dysfunction particular to specific rheumatic dis-
eases can adversely affect pregnancy outcome, as with antiphospholipid antibodies,
which may lead to increased risk of miscarriage, fetal loss, and preeclampsia. In
addition, transplacental passage of pathogenic autoantibodies can directly affect the
fetus, notably anti-Ro/SS-A and La/SS-B antibodies that may cause neonatal lupus
erythematosus (NLE). Both severe maternal disease activity and preexisting dam-
age from autoimmune disease can have significant negative effects on maternal and
fetal/neonatal outcomes. Lastly, the potential adverse fetal effects of medications,
rheumatic and otherwise, must be assessed and communicated to the patient, with
appropriate adjustments made before conception.
Physiologic changes induced by pregnancy are described in detail in Chap. 2.
Briefly, however, potential interaction with rheumatic disease manifestations occurs
in nearly every organ system during pregnancy. Patients who have significant under-
lying renal or cardiac disease may fail to tolerate the anticipated increase in intra-
vascular volume. A roughly 50 % pregnancy-induced increase in glomerular
filtration rate (GFR) generally leads to increased urinary protein measures in
patients with preexisting proteinuria which may be confused with reactivation of
nephritis or development of preeclampsia. Pregnancy induces a prothrombotic state,
based on changes in both procoagulant and fibrinolytic systems; this, together with
mechanical factors such as venous stasis, compression by the gravid uterus, or bed
rest, leads to an increased risk for thromboembolic disease in all pregnant women,
which may be exacerbated by presence of nephrotic syndrome, antiphospholipid
antibodies, and active inflammatory disease. Gastroesophageal reflux increases,
potentially worsening symptoms in patients with systemic sclerosis. Frequent gum
swelling and bleeding may exacerbate oral and dental issues in Sjogren’s syndrome
patients. Finally, potentially significant reversible bone loss due to pregnancy and
lactation is common, which may be worrisome for patients with preexisting steroid-
induced or disease-related osteoporosis.
Normal pregnancy changes and the changes associated with pregnancy compli-
cations can mimic autoimmune disease activity, making it challenging to differenti-
ate between pregnancy and disease flare. For example, the facial flushing or
hyperpigmentation of normal pregnancy may look like a lupus malar rash, and pal-
mar erythema may be mistaken for cutaneous vasculitis. Hemodilution leads to ane-
mia and lowered platelet counts in many healthy patients, mimicking hematologic
3 General Approach: Pre-pregnancy Assessment of the Rheumatic Disease Patient 65
manifestations of connective tissue disease (CTD). The erythrocyte sedimentation

rate (ESR) increases throughout pregnancy due to an elevation in fibrinogen, and so
becomes less useful as a marker of disease activity; similarly, pregnancy-induced
elevation in white blood cell count may be confusing in certain conditions such as
the vasculitides or adult-onset Stills disease. Diffuse arthralgias and even bland joint
effusions are common, and may raise the question of arthritis flare.
Preeclampsia, characterized by hypertension, proteinuria, renal insufficiency,
and edema usually requires urgent delivery, but may be difficult to differentiate
from flare of lupus nephritis or vasculitis, or scleroderma renal crisis in certain situ-
ations. The earliest reported cases of polyarteritis nodosa in pregnancy presented in
the third trimester and symptoms were most often initially attributed to preeclamp-
sia, leading to delay in diagnosis and high maternal mortality [1]. HELLP syn-
drome, characterized by a low platelet count, increased liver function tests,
hemolysis, and abdominal pain, and eclampsia, which includes seizures and rarely
stroke, can also be mistaken for active SLE or vasculitis. One of the greatest chal-
lenges of caring for rheumatic disease patients through pregnancy is ultimately
being able to make these distinctions—when possible—between pregnancy and
autoimmune disease manifestations.
Pre-pregnancy Assessment
Assessment of rheumatic disease patients considering pregnancy should follow the

same general pattern regardless of the specific diagnosis. Determination of risk for
a given individual patient should include identification of serious disease-related
organ damage that might affect the patient’s ability to safely carry a pregnancy,
evaluation of current and recent disease activity, serologic evaluation for identifica-
tion of autoantibodies associated with adverse fetal or neonatal outcome, and review
of current medications and their safety in pregnancy, both rheumatology-specific
and other medications (Fig. 3.1).
Severe Disease Damage
Severe manifestations of disease damage may preclude pregnancy and include car-
diomyopathy or severe cardiac valve disease, pulmonary issues such as pulmonary
hypertension or severe interstitial lung disease, serious neurologic manifestations,
or renal insufficiency with significantly decreased clearance (see Table 3.1).
Pulmonary arterial hypertension (PAH) in particular is associated with a high
risk of pregnancy-related mortality. Although pregnancy-related mortality for
patients with CTD-related PAH has decreased slightly in recent years, from 36 to
28 %, risk is still prohibitive even with current aggressive therapies. Essentially all
deaths occur in the postpartum period, most within 72 h of delivery and due to right
Fig. 3.1 Pre-pregnancy evaluation of the rheumatic disease patient
heart failure [2]. Patients with systemic sclerosis and mixed CTD should have base-
line echocardiograms and pulmonary function tests to rule out asymptomatic PAH
prior to conceiving.
Preexisting renal disease is a common issue for CTD patients, particularly those
with SLE. The most important predictors of permanent renal disease in pregnant
women with chronic kidney disease (CKD) are GFR < 40 mL/min/1.73 m2 and
Table 3.1 Common • Cardiac disease including heart failure, severe valvular
rheumatic disease-related disease, or aneurysm
organ damage representing • Pulmonary disease including severe interstitial lung
contraindication to pregnancy disease or pulmonary hypertension
• Renal disease including severe renal failure/insufficiency
• Recent arterial thrombosis, particularly cerebral vascular
accident (CVA)
• Previous life-threatening eclampsia or HELLP
syndrome despite prophylactic treatment
proteinuria greater than 1 g/24 h [3]. The risk for poor renal outcome in patients
with quiescent renal disease is dependent on impairment in renal function, not the
underlying disease diagnosis. One comprehensive review of studies (many dating
from the 1980s) of pregnant SLE patients with CKD suggested pregnancy-induced
acute kidney injury in 10 %, permanent decline in renal function in 3 %, and end-
stage renal failure in 6 % of patients [4]. Another meta-analysis of 37 studies includ-
ing 2,751 pregnancies in lupus nephritis patients suggests a better renal prognosis,
however, with only 2 % patients developing deterioration in renal function and only
1 % requiring dialysis. The patients in these studies had milder disease at outset,
with only 11 % having CKD stage 3: the authors suggest that more effective coun-
seling may be limiting the numbers of high-risk lupus nephritis patients choosing to
enter into pregnancy, thus improving outcome [5].
In general the potential morbidity and mortality associated with severe chronic
disease manifestations make pregnancy unacceptable for patients who have these
complications. If patients with severe disease-related damage are intent on having a
biological child, it may be appropriate to consider the safety of in-vitro fertilization
(IVF) with surrogacy. A patient with underlying disease-related damage who is con-
sidered unable to safely carry a pregnancy herself may incur less risk with the more
limited duration and physiologic changes associated with IVF (discussed in detail
in Chap. 12). Issues surrounding surrogacy, however, may be complex, depending
in part on financial and legal constraints. For patients open to consideration of adop-
tion, this is an alternative option.
The Risk of Disease Activity
Once patients are assured they have no identifiable disease-related damage that pre-
cludes consideration of pregnancy, the discussion then focuses not on “if” but on the
more favorable “when” and “how” to proceed toward pregnancy. It is essential to
assess for disease activity and other risk factors: if patients have ongoing active
disease, studies and reports from pregnancy in almost all autoimmune diseases sug-
gest this to be a poor time to conceive. Patients should defer pregnancy, use suitable
contraception, and be treated aggressively: when disease has been inactive for a
period of time usually estimated at 6 months, they may be re-assessed.
While active disease at the time of conception (or within the immediate preceding
months) has been shown to increase risk of complications based on available data for
most rheumatic disease patients, for lupus in particular there are numerous studies
confirming the importance of stable disease at the time of conception and the adverse
effect of flare during pregnancy [6, 7]. A high level of lupus disease activity during
pregnancy has been associated with a lower chance of live birth, greater chance of
perinatal death, and lower chance of full-term delivery [8]. Women with long-standing
remission in SLE are more likely to complete their pregnancies uneventfully [9].
Active vasculitis patients are also advised to defer pregnancy until disease is
under control, as active disease at conception (or disease onset during pregnancy)
increases risk for adverse outcome. Initial severity of disease presentation, however,
does not predict activity during pregnancy [10].
Although most patients with systemic sclerosis without severe disease-related
damage have successful pregnancies (although often with preterm delivery), patients
with early diffuse disease are advised to defer pregnancy for several years: they
appear to be at increased risk for developing renal crisis during pregnancy [11].
In general, pregnancy outcome for rheumatoid arthritis (RA) patients is compa-
rable to the general population. Even in rheumatoid arthritis patients, however, dis-
ease activity during pregnancy may impact outcome: recent studies suggest a small
but significant increase in the risk of lower birth weight and preterm delivery for RA
patients who have active disease during pregnancy, with a slight increase in perina-
tal mortality and higher frequency of Cesarean sections [12]. Disease activity may
be associated with the lower birth weight, and prednisone use with risk of preterm
delivery [13].
Medication Review
If disease is inactive and there is no indication of severe damage, it is appropriate to

next assess the patient’s present medical regimen. When current medications are
contraindicated for use in pregnancy, options include taper and discontinuation—if
disease permits—or a change to permissible medications. It is ideal to have stable
disease on pregnancy-safe medications for 6 months before conceiving. Detailed
guidelines for medication use and safety are reviewed in Chap. 14. In general, in
addition to prednisone, immunosuppressive medications that are considered permis-
sible during pregnancy include azathioprine and cyclosporine. Use of tacrolimus is
increasingly considered an effective alternative for patients who fail azathioprine:
studies from the transplant literature suggest safety and tolerability in pregnancy [14]
and pilot studies suggest efficacy for lupus nephirits [15], including a case report of
successful treatment of lupus nephritis with tacrolimus during lupus pregnancy [16].
For inflammatory arthritis patients, the safety of TNFα-inhibitors during preg-
nancy continues to be controversial although a number of practitioners feel comfort-
able continuing these drugs throughout pregnancy. Published reports are reassuring
concerning safety with use immediately before conception and in the first trimester:
a common approach for women with RA on combination methotrexate and

TNFα-inhibitor therapy is to stop the methotrexate and continue the TNFα-inhibitor,
waiting 3 months before trying to conceive. Once pregnancy is confirmed, patients
should discontinue the TNFα-inhibitor if possible.
Non-rheumatology medications should also be assessed and modified as neces-
sary in conjunction with the obstetrician and other involved specialists. Angiotensin
converting enzyme-inhibitors (ACE-I) may be changed to pregnancy-safe substi-
tutes several weeks before attempting to conceive, with careful follow-up of blood
pressure and proteinuria after discontinuation. Warfarin should be changed to hepa-
rin; low-molecular-weight heparin can be monitored with factor Xa levels, most
often in conjunction with a hematologist. In general, it is recommended that the
patient change to heparin prior to conception; when this is not possible, the change
must be made prior to the sixth week of pregnancy to avoid warfarin embryopathy.
There are particular medications that may have a beneficial effect on pregnancy
outcome in specific cases. Women with SLE on hydroxychloroquine (HCQ) have
been shown to have lower disease activity scores and to be on lower prednisone doses
at delivery [17]. Patients discontinuing HCQ within 3 months of conceiving have a
greater risk of flare than those who continue their medications and also require a
higher prednisone dose [18]. In addition, HCQ-treated patients may have a lower risk
of NLE [19]. If SLE patients or patients with anti-Ro/SS-A or La/SS-B antibodies
have no contraindications to HCQ, there may be benefits for both mother and child.
The addition of low-dose aspirin during pregnancy in CTD patients has varying
support: it is generally used for preeclampsia prevention in patients with risk factors
(hypertension, renal insufficiency, and history of preeclampsia) [20] and is often
used in patients with asymptomatic aPL, although no controlled studies support
this practice.
Folic acid is advised pre-pregnancy and during the first trimester to reduce risk
of neural tube defects; patients on the folate antagonist sulfasalazine are generally
advised to further increase their folic acid intake before and during pregnancy.
Assessment of Autoantibodies
Assessment of autoantibodies will help to determine the type and frequency of preg-
nancy monitoring, the need for potential additional therapy for antiphospholipid
obstetric prophylaxis, and to inform both physician and patient regarding risk.
Antiphospholipid Antibodies
Every patient with SLE and as well as patients with other CTD with an adverse
obstetric history or a history of thrombosis should be evaluated for presence of
antiphospholipid antibodies (aPL). Patients should be counseled regarding risk of
aPL in pregnancy, which include miscarriage, fetal loss, preterm birth, intrauterine
growth restriction (IUGR), and preeclampsia. Adverse outcome is most strongly
associated with lupus anticoagulant (LAC). Other risk factors in patients with posi-
tive aPL include history of thrombosis, history of prior fetal loss, and presence of
SLE. Patients with low titer aCL and anti-beta 2 glycoprotein I (anti-β2GPI), espe-
cially those without a history of prior fetal loss or thrombosis, can be reassured that
their risk is relatively low [21].
Treatment for antiphospholipid syndrome (APS) pregnancy prophylaxis is sum-
marized in Chap. 6. In general, many patients will be on low-dose aspirin before
conception, with plans for unfractionated or low-molecular-weight heparin after
diagnosis of pregnancy if indicated. Current recommendations are to monitor for
fetal distress during the third trimester, utilizing non-stress tests, umbilical artery
Dopplers, or serial ultrasounds.
Anti-Ro/SS-A and La/SS-B Antibodies
Patients with SLE, RA, undifferentiated connective tissue disease (UCTD), and
Sjogrens syndrome should be evaluated for presence of anti-Ro/SS-A and La/SS-B
antibodies. Positive patients will require periodic fetal echocardiograms beginning
at 16–18 weeks: for high-risk patients, i.e. those with a previous child with NLE,
echocardiograms are recommended weekly from weeks 18–26 and every 2 weeks
until week 32 (see Chap. 13). Patients should be counseled regarding the spectrum
of NLE manifestations, including rash, thrombocytopenia, liver function abnormal-
ities, and risk of congenital heart block (2–3 %), as well as the associated mortality
and long-term morbidity in the children with heart block. Risk of congenital heart
block in the offspring of an anti-Ro/SS-A positive patient who has already had a
child with NLE is higher, about 17 %.
Counseling
Counseling is important for both the patient and her partner: for most patients,
knowing what to expect makes a difference. In general, it is recommended that one
review the full reproductive spectrum of fertility through lactation during the pre-
conception visit. Education should include the risk of pregnancy in general for the
given diagnosis and then the risk of pregnancy for the individual patient with her
particular risk profile, based on damage, disease activity, renal function, aPL, anti-
Ro/SS-A and La/SS-B, and medications. Each patient needs to understand the risk
to her own health, the anticipated pregnancy outcome, and the potential risk to off-
spring (most often these are the complications associated with preterm birth or
small size for dates). One should review necessary follow-up and monitoring during
pregnancy, and assure availability of neonatal supportive care if early delivery or
other complications develop.
Fertility Issues: Can I Get Pregnant?
In patients likely to be at risk for infertility, it is advisable to address fertility issues

even before the couple begins attempting to conceive. Although fertility is gener-
ally normal in patients with rheumatic diseases—decreased fertility has been sug-
gested but not confirmed in systemic sclerosis [11]—the primary reason for lowered
fertility is the use of alkylating agents, generally cyclophosphamide. Most other
patients can be reassured that their risk of infertility is similar to that in the general
population. The risk of infertility with cyclophosphamide is related to greater age
at administration as well as higher cumulative dose. Overall risk of sustained
amenorrhea was 62 % for patients over age 31 in early studies [22]; risk may be
lower now for patients treated with ovarian protection therapy with synthetic
gonadotropin-releasing hormone analogs during the course of their cyclophospha-
mide treatment [23].
Although fertility in patients is comparable to the general population in the
absence of cyclophosphamide treatment, the rate of fertility problems in the general
population is not insignificant, at about 20 %. Some of this is age-related, and cer-
tainly a patient who is counseled to wait for quiescent disease to conceive may start
her pregnancy attempts at a somewhat older age. Given the complexity of the rheu-
matic disease patient, as well as the fact that they may be treated with less effective
(pregnancy safe) second- or third-line medications during this period, it seems rea-
sonable to be proactive and aggressive with referral to reproductive medicine spe-
cialists, especially in patients over age 35.
Pregnancy Risk and Outcome: Will My Pregnancy Be Normal?
Although pregnancy outcome in patients with CTD has improved in recent years,
many diagnoses are still associated with an increased risk of adverse outcome when
compared to the general population. It is important for patients to understand this,
in both general and personal terms. Much of the literature has focused on SLE and
APS, given the large number of patients as well as the long-recognized increased
risk of adverse outcome. A recent national study of complications in pregnancies of
patients with the diagnosis of SLE revealed that lupus patients have a two to four-
fold increase in pregnancy complications including preeclampsia, preterm labor,
and IUGR; medical complications are similarly increased, including thrombosis,
major infection, and thrombocytopenia [24]. First pregnancies after SLE diagnosis
were followed prospectively in the LUMINA multiethnic SLE cohort: 76.2 % of
patients had some complication and there was a small but significant increase in
irreversible damage postpartum [25]. In addition to risk of pregnancy-related com-
plications, most but not all studies support some increased risk of flare of lupus
during pregnancy including the postpartum period [26]. Most reviews of pregnan-
cies in systemic sclerosis, the vasculitides, and inflammatory myositis find increased
rates of preterm birth and/or small-for-gestational-age (SGA) infants (reviewed in

detail in Chaps. 8–10).
Patients should be aware that risk of flare during or after the pregnancy exists for
most rheumatic diseases, even when disease is quiescent at conception. They should
be counseled regarding the need for pre-pregnancy testing and pregnancy monitor-
ing, which will vary by disease, autoantibody status, and individual clinical history.
Postpartum risks should also be defined, including risk of postpartum flare or
thrombosis.
Delivery Options: Must I Have a Cesarean Section?
In general, Cesarean section is reserved for those with obstetric indications such as
previous Cesarean delivery, breech presentation, dystocia, and fetal distress. Rarely,
orthopedic impairments due to severe rheumatoid arthritis or bilateral hip replace-
ments with limited hip range of motion may preclude vaginal delivery. Other con-
cerns regarding mode of delivery and anesthesia may be relevant for particular
diseases and should be discussed. For example, patients with severe rheumatoid or
spondylitic involvement of the cervical spine should be assessed, as with any surgery,
for instability should endotracheal intubation be necessary. Patients with history of
vasculitis, primarily Takayasu’s, may require baseline vascular imaging pre-pregnancy
and anesthesia involvement for hemodynamic monitoring at the time of delivery due
to variable hyper and hypo-perfusion. Subglottic stenosis in patients with granulo-
matous polyangiitis (GPA, formerly Wegener’s granulomatosis) may complicate
delivery, requiring temporary tracheotomy to protect the airway (see Chap. 9).
Pregnancy Outcome: What Is the Risk to My Baby?
The major risk to the child is the constellation of complications associated with
prematurity and small size, which may include neurologic, ophthalmologic, pulmo-
nary, and gastrointestinal issues, some with long-term implications for disability.
Rates of preterm delivery vary depending on diagnosis and disease severity but may
be as high as 30–40 % in certain situations. Neonatal lupus is an additional risk in
women with anti-Ro/SS-A and La/SS-B antibodies. There are extremely rare case
reports of passively acquired neonatal autoimmune syndromes including neonatal
APS (thrombosis in the fetus or neonate of a patient with APS) [27], elevated cre-
atine kinase levels in several infants of mothers with myositis [28], and babies with
transient skin lesions born to mothers with vasculitis [29].
Long-term outcome of children of mothers with rheumatic disease has only
recently been studied, and is described in detail in Chap. 15. A small increase in risk
of learning disability in children of women with SLE and APS has been suggested
by the literature, although numbers are small and this can be difficult to distinguish
from the long-term effects associated with preterm birth.
Postpartum Course: Can I Breastfeed My Baby?
Breastfeeding is possible for many but not all patients. Patients with recurrence of
active disease should be treated with the most effective medication, which may
preclude breastfeeding. Breastfeeding also may be a concern for the patient with
known or suspected osteoporosis, since it may further lower bone density beyond
the expected pregnancy-induced decrease and lengthen the time until recovery,
increasing risk of fracture.
A number of medications are compatible with breastfeeding. These are detailed
in Chap. 14. Corticosteroids in low dose are considered safe, with administration of
the dose more than four hours prior to nursing if possible. Aspirin, heparin, warfa-
rin, HCQ, sulfasalazine, and even ibuprofen may be used in patients who are breast-
feeding. In general, one would like to avoid immunosuppressive medications during
this period, although many rheumatologists feel comfortable with the use of aza-
thioprine or TNF-inhibitors in women who are breastfeeding.
Postpartum risk of flare should be discussed, particularly for patients with rheu-
matoid arthritis or other inflammatory arthritis, as the need for medication may
impact a woman’s ability to breastfeed. A plan should be in place before delivery
concerning treatment for postpartum flare if and when it occurs. A common approach
is to treat with low-dose corticosteroid while the mother weans the infant, with
resumption of disease-modifying or immunosuppressive therapy after weaning.
Patients on prophylactic anticoagulation therapy during pregnancy for aPL are gen-
erally advised to continue anticoagulation for approximately 6 weeks postpartum to
minimize risk of venous thrombosis; those requiring long-term anticoagulation may
switch back to warfarin postpartum, as this is compatible with breastfeeding.
Contraception: What Contraception Can I Use While I Am

Waiting for the Right Time to Conceive?
One cannot effectively discuss planning of pregnancy without considering avail-

ability and safety of contraception. Contraception is discussed in detail in Chap. 11.
Oral contraceptives that contain estrogen can be used in most rheumatic diseases
including lupus if disease is quiet and if patients do not have antiphospholipid anti-
bodies. For patients who cannot use combined hormonal contraceptives (such as
patients with positive antiphospholipid antibodies), the levonorgestrel (progesterone-
containing) IUD is a good option. It is recommended even for nulliparous women,
risk of infection is low, and it can remain in place for up to 5 years. It significantly
decreases menstrual blood flow, a benefit for patients who are on warfarin.
Summary
Pregnancy in rheumatic disease patients is most successful when the rheumatolo-

gist, obstetrician, other involved specialists, and patient work together as a team,
with identification and understanding of potential risks particular to that individual
patient. In general, the best chance for optimal maternal and fetal outcomes depends
on planning for pregnancy during a period of well-controlled disease in the rheu-
matic disease patient without serious end-organ damage who is taking pregnancy-
compatible medications.
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28. Messina S, Fagiolari G, Lamperti C, Cavaletti G, Prelle A, Scarlato G, et al. Women with
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Part II
Pregnancy in Specific Rheumatic Diseases
Chapter 4
Systemic Lupus Erthematosus
Sara Wasserman and Megan E.B. Clowse
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a diagnosis made based on laboratory val-

ues, symptoms, and signs. To be diagnosed with SLE a woman must have at least 4
out of 11 positive American College of Rheumatology Criteria (see Table 4.1).
Positive anti-nuclear antibody in the serum will be found in over 95 % of women
with SLE. Smith antibodies, anti-dsDNA antibodies, anti-Ro/SSA, and anti-La/SSB
can aid in a diagnosis of SLE, but are not necessary. Patients who meet some, but
not 4 or more criteria are sometimes given a diagnosis of undifferentiated connec-
tive tissue disease (UCTD) which is a disease that usually has a milder course and
only rarely progresses to SLE. To make a diagnosis of SLE, one should consult with
a rheumatologist.
Preconception Counseling
The importance of preconception counseling should not be underestimated as it is a

critical time to establish a women’s pregnancy risk, adjust medications, and discuss
pregnancy treatment options. It is generally recommended that a woman be moni-
tored for 6 months prior to attempting conception as significant lupus activity within
6 months of conception was associated with a fourfold increase in pregnancy loss
rate in the Hopkins Lupus Cohort [1]. A thorough history and physical should be
S. Wasserman, M.D. • M.E.B. Clowse, M.D., M.P.H. (*)

Division of Rheumatology and Immunology, Duke University Hospital,
3535 Trent Drive, Durham, NC 27710, USA
e-mail: megan.clowse@duke.edu

80 S. Wasserman and M.E.B. Clowse
Table 4.1 1997 Updated American College of Rheumatology Criteria Classification for SLE
Malar rash Over malar eminences, spares the nasolabial folds
Discoid rash Erythematous raised patches with follicular plugging. Leaves a scar
Photosensitivity Skin rash as result of reaction to the sun
Oral ulcers Usually painless
Arthritis 2 or more peripheral joints, morning stiffness
Serositis Pericarditis or pleurisy
Renal disease • Proteinuria > 3(+) or
• 0.5 grams daily protein or
cellular casts
Neurologic disease Seizures or psychosis
Hematologic disease • Hemolytic Anemia-with reticulocytosis or
• ≥2 occasions of one of the following:
• Lymphopenia (<4,000 mm3) or
• Leukopenia (<1,500 mm3) or
• Thrombocytopenia (<100,000/mm3)
Antibodies • Anti-DNA
• Anti-Smith
• Anti-phospholipid Antibodies:
a) Abnormal level of IgG or IgM anticardiolipin antibodies
b) A positive test of lupus anticoagulant
c) False positive RPR testing
Positive ANA
performed to help stratify pregnancy risk, focusing on prior lupus nephritis and
recent lupus activity. In addition, initial lab testing should be completed including
screening for lupus activity, antiphospholipid antibodies, and anti-Ro/SS-A and
anti-La/SS-B antibodies associated with neonatal lupus. Medications used to treat
SLE as well as other medications should be thoroughly reviewed and all teratogens
should be discontinued or substituted for other medications.
Impact of SLE on Pregnancy Outcome
Pregnancy Loss
The rate of miscarriage and stillbirth in lupus pregnancies is higher than that of the
general population. A large retrospective case–control study comparing women
with lupus to their healthy friends and relatives demonstrated a rate of pregnancy
loss of 21 % in those with lupus compared to a rate of 8–14 % in the friends and
relatives [2]. Pregnancy loss rates ranging between 15 and 30 % have been reported
in different lupus cohorts [3–6]. While the risk of miscarriage does not differ much
from that of the general population, it is the stillbirth rate (>20 weeks gestation) that
is significantly elevated in the lupus population around 5 % [7]. One of the greatest
risk factors for pregnancy loss is high lupus disease activity and thus avoiding
4 Systemic Lupus Erthematosus 81
pregnancy during periods of high disease activity or within 6 months of periods of

high disease activity is important and can help avoid complications [7]. There was
a threefold increase in pregnancy loss in those with high activity lupus in the first
and second trimesters in a prospective study looking at the Hopkins Lupus cohort
over 16 years [7].
In addition, antiphospholipid syndrome is a significant risk factor for pregnancy
loss and thus aspirin and low-molecular-weight heparin is recommended to aggres-
sively modify this risk factor when present [8] (management of obstetric antiphos-
pholipid syndrome is discussed in detail in Chap. 2). Other risk factors for pregnancy
loss include proteinuria, thrombocytopenia, lupus nephritis, and hypertension [9].
Preterm Birth
Another complication that frequently occurs in lupus pregnancies is preterm birth,

which is defined as delivery before 37 weeks gestation. The rate of premature deliv-
ery in women with lupus was 21 % in a case–control population-based study, six-
fold higher than that seen in healthy controls [10]. Preterm birth rates suggested by
different cohorts range from 14 % to over 50 % [3, 5, 11–13]. In some cases, early
deliveries are medically necessary and induction of labor is performed to avoid fetal
and maternal complications, such as preeclampsia or fetal distress. However, some
preterm births are spontaneous and a proportion are due to preterm premature rup-
ture of membranes (PPROM) [14, 15]. PPROM was found to be higher in the SLE
population than in a control population [15]. In the general population, PPROM is
often related to antepartum infections such as chorioamnionitis and endometritis
whereas the etiology of increased incidence of PPROM in women with lupus is
currently unclear.
Other risk factors for premature birth include antiphospholipid syndrome, hyper-
tension, increased lupus activity during pregnancy and conception, and prednisone
use during pregnancy [5, 7, 14, 16]. In the Hopkins Cohort, two thirds of women
with high activity lupus based on the physician’s estimate of lupus activity delivered
prematurely, while only one third of those with low lupus activity did [7]. Again this
lends support for aggressive risk reduction to avoid pregnancy complications.
Small for Gestational Age
Small for gestational age (SGA) is defined as birth weight less than the tenth
percentile for gestational age and low birth weight is defined as birth weight less
than 2,500 g. Fetal growth restriction is a major cause of morbidity and mortality.
In a report published by the Center for Disease Control for 2009, the low birth
weight rate of the general population in the USA was estimated to be 8.16 % [17].
There has been disagreement between different studies on the rate of low birth
weight and SGA in different lupus cohorts. Some studies show rates of 5–10 %
[4, 5], similar to the normal population, while others demonstrate an increased risk
with rates of SGA above 30 % in lupus pregnancies [16, 18]. Thus evidence for
increased risk of SGA in lupus is somewhat controversial. Some risk factors that
have been associated with low birth weight rate include C4 hypocomplementemia,
hypertension during pregnancy, and renal disease [16, 18].
Neonatal Lupus
Another neonatal complication that can be encountered is neonatal lupus. Neonatal

lupus is a clinical spectrum of disease seen in infants whose mothers have anti-Ro/
SSA or anti-La/SSB antibodies. It most commonly manifests with cardiac or derma-
tologic manifestations. The risk of congenital heart block is 2 % [19] in offspring of
mothers with anti-Ro/SSA and/or anti-La/SSB antibodies, and often leads to the
need for pacemaker. The rash resembles that of subacute cutaneous lupus, and those
with only skin involvement have an excellent prognosis. A recent case–control study
suggests hydroxychloroquine may be protective in lowering the risk of cardiac man-
ifestations in infants born to mothers with anti-Ro/SSA antibodies [20]. (The topic of
neonatal lupus and information on the long-term outcome for children of women
with lupus is discussed in detail elsewhere in this volume, in Chaps. 13 and 15).
Preeclampsia
Hypertensive conditions, including preeclampsia, eclampsia, and HELLP syndrome

(hemolysis, elevated liver enzymes, and low platelet counts) pose a significant risk
to SLE women during their pregnancies. Proteinuria (more than 300 mg protein in
the urine in 24 h) and hypertension (blood pressure greater than 140/90) that occur
usually after 20 weeks of gestation define preeclampsia. Severe preeclampsia mani-
fests with any of the following; hypertension (blood pressure greater than 160/110),
proteinuria (more than 5 g in 24 h), oliguria, renal failure, pulmonary edema, elevated
liver function tests, epigastric pain, thrombocytopenia, visual or cerebral distur-
bances, and hemolytic anemia. With the addition of grand mal seizure, preeclamp-
sia becomes eclampsia. Since the maternal risks subside after delivery of the fetus
and placenta, delivery is regarded as the most definitive treatment [21].
Women with SLE unfortunately are at an increased risk for preeclampsia during
pregnancy. Ten to 30 % of pregnancies were complicated by preeclampsia and
hypertension in prior SLE cohorts which is several fold higher than the rate seen in
other women [22]. The risk is heightened in those with pre-pregnancy hypertension,
renal insufficiency, and lupus nephritis. In addition, greater than 10 mg daily
prednisone during pregnancy significantly increases the risk of hypertension and
preeclampsia [23].
Table 4.2 Distinguishing factors for active lupus, preeclampsia, and HELLP syndrome
Signs and symptoms Active SLE Preeclampsia HELLP syndrome
Timing in pregnancy Any trimester Third trimester Third trimester
Blood pressure Normal or high Greater than 140/90 Normal or high
Proteinuria Normal or elevated Greater than Normal or elevated
300 mg/24 h
Active urine sediment Yes Usually negative Usually negative
(casts, RBCs, WBCs)
Serum creatinine Stable or rising Stable Stable
Platelets Low or normal Normal Low, less than 100,000
Hemolysis Maybe No Microangiopathic
hemolytic anemia
Anti-dsDNA antibody May be elevated Negative or stable Negative or stable
Complement: C3, C4 May be low Usually normal Unknown
Liver function testing Normal or high Normal Transaminases elevated
greater than 1,000
Uric acid Normal or high High High
Urine calcium Normal or high Low Unknown
SLE symptoms: arthritis, Present Absent Absent
rash, oral ulcers
CNS dysfunction Sometimes present Headache may Not usually
be present
Distinguishing a flare of lupus nephritis from that of preeclampsia can be a

dilemma. They both present with hypertension and proteinuria during pregnancy.
However, making this distinction is important as management is different for the
two conditions. For preeclampsia and eclampsia, delivery is indicated whereas for
SLE nephritis, there is a need for immunosuppressive therapy. Some helpful meth-
ods to aid in differentiating between them are outlined in Table 4.2. For one, pre-
eclampsia very rarely occurs before 20 weeks of gestation and lupus nephritis can
occur at any time during pregnancy. Some clinical features that help point toward
lupus nephritis as opposed to preeclampsia include active urinary sediment with
white blood cells, red blood cells and casts in addition to SLE activity in other
organs such as rash, arthritis, and oral ulcers. A patient with proteinuria with a rising
anti-dsDNA and falling complement is more likely to be having an SLE nephritis
flare. In contrast, complement in pregnancy often rises and can rise or stay stable in
preeclampsia [24, 25]. Some clues in support of a diagnosis of preeclampsia include
serum uric acid elevation and decreased urine calcium excretion (<195 mg/24 h
urine collection) [26]. Unfortunately, abnormal liver function tests, thrombocytope-
nia, and hemolytic anemia can occur in both conditions and are not helpful in dis-
criminating between these conditions. Sometimes, it is not possible to discern
between the conditions and treatment for both may be necessary.
The precise etiology and mechanism of preeclampsia has not been fully eluci-
dated and remains under investigation. It is hypothesized that abnormal placental
development leads to preeclampsia, specifically limited invasion of the trophoblast
into the uterus and its spiral arteries which leads to diminished placental perfusion.
This is thought to result from abnormal angiogenesis, oxidative stress, and immuno-
logical alterations [27, 28].
Due to the fact that excessive production of thromboxane, a platelet-derived
vasoconstrictor and platelet activator, has been demonstrated in preeclampsia, daily
low-dose aspirin may help with prevention. In 2007, a Cochrane Review [29] was
published which included 59 trials and a total of 37,560 women and evaluated the
use of aspirin in pregnancy. This study demonstrated that for women who were high
risk for preeclampsia, daily low-dose aspirin is associated with a 25 % risk reduc-
tion. There were risk reductions of 8 and 14 % for preterm birth and fetal or neonatal
death, respectively, when daily low-dose aspirin was used during pregnancy [29].
While none of the trials specifically looked at women with autoimmune disease,
because women with SLE are particularly at high risk for preeclampsia, 81 mg daily
aspirin should be considered for all women with lupus during pregnancy.
Maternal Complications
Maternal Mortality
The maternal mortality rate may be as much as 20-fold higher than the non-SLE
population with a rate of 325 deaths per 100,000 lupus pregnancies [22]. However,
pregnancy probably does not add to the mortality risk of women with SLE as the
nonpregnant SLE annual death rate is between 790 and 3,208 deaths per 100,000
patient years which is two to tenfold higher than that of the pregnant SLE death rate.
Maternal deaths have been documented in the literature in patients who had active
lupus nephritis, uncontrolled hypertension, HELLP syndrome, preeclampsia,
thrombosis with pulmonary embolism, severe SLE exacerbation, and pregnancy
associated cardiomyopathy [3, 6, 22, 30]. Women with SLE and pulmonary hyper-
tension, prior cerebrovascular event, or myocardial infarction are at increased risk
for pregnancy mortality and should consider avoiding pregnancy.
Lupus Manifestations and Flares During Pregnancy
Approximately 30–70 % of women with lupus will experience a lupus flare during
pregnancy [5, 8, 16, 31]. The rate of flares during pregnancy varies between differ-
ent studies, which is likely a result of studying different patient populations and
using varying definitions for flare. Whether pregnancy is a risk factor for increased
lupus flare is controversial as some studies show increased flares during pregnancy,
others decreased and some the same [3, 16, 23, 32, 33]. Flares occur in all trimesters
and in the postpartum without a clear preference to time. Fortunately, most flares
during pregnancy are mild to moderate with manifestations of arthritis, constitu-
tional and cutaneous symptoms [3, 8], as shown in Table 4.3. Up to 30 % of women
Table 4.3 Types of lupus activity during pregnancy

Cortes-Hernandez Carmona Georgiou
et al. [16] (n = 39) et al. [5] (n = 15) et al. [3] (n = 59)
Arthritis 27 (69 %) 3 (20 %) 48 (81 %)
Skin lesions 13 (33 %) 8(53 %) 55 (93 %)
Lupus nephritis 4 (10 %) 2 (13 %) 6 (10 %)
a
Fever 3(8 %) 28 (47 %)
Serositis 1 (3 %) 3 (20 %) 5 (8 %)
a a
Hepatitis 1 (3 %)
a a
CNS involvement 2 (3 %)
a
Hemolytic anemia 4 (10 %) Hematologic involvement: 6 (10 %)
Thrombocytopenia 1(3 %) 5 (36.3 %)
a
Data not provided
with SLE will experience more severe flares during pregnancy including thrombo-
cytopenia or nephritis [3, 14] (see Table 4.3). These more severe flares can put a
pregnancy in jeopardy and increase the risk of preeclampsia, premature birth, and
even pregnancy loss. The rate of pregnancy loss in those with thrombocytopenia in
the first trimester was 43 %, compared with a rate of 13 % in those without in a
cohort study [9]. Conception at times of active disease should be avoided as it has
poor prognostic implications for the health of the newborn and mother.
High lupus activity within 6 months of conception is a predictor for a significant
SLE flare during pregnancy [14]. In a cohort study, 58 % of women with active lupus
prior to pregnancy experienced high lupus activity during pregnancy, whereas only
8 % with inactive lupus prior to pregnancy did [7]. Also women with history of fre-
quent and significant flares are more likely to have high lupus activity during preg-
nancy [16]. Since high lupus activity during pregnancy increases risk of poor
outcomes like preeclampsia, fetal loss, and prematurity, educating patients to avoid
conception close to times of high lupus activity is a preventative measure. In addition,
the use of contraception in patients with high disease activity should be addressed.
Discontinuation of needed immunosuppressive therapy and particularly discon-
tinuation of hydroxychloroquine can also increase the risk of lupus flares during
pregnancy [16, 34]. In a study looking at hydroxychloroquine in the Hopkins Lupus
Cohort, 30 % of the patients who remained on hydroxychloroquine during preg-
nancy had flares in comparison with 55 % who discontinued the drug during
pregnancy [34]. In addition, women who continued hydroxychloroquine were on a
lower average prednisone dose [34, 35]. Higher prednisone dosage is associated
with premature birth. Studies have shown no adverse effects of hydroxychloroquine
on the fetus or the pregnancy [36]. For these reasons, it is recommended that
hydroxychloroquine be continued during pregnancy to manage disease activity.
A successful lupus pregnancy involves careful planning in terms of conception
timing and modification of immunosuppressive therapy. Immunosuppression, when
needed, is preferable to SLE activity. For women with significant history of organ
involvement and disease activity, particularly those with a history of lupus nephritis
or thrombocytopenia, discontinuing immunosuppressive therapy for pregnancy is

not recommended. This in itself can lead to disease flares and poor pregnancy out-
comes. Whenever possible, teratogenic medications like cyclophosphamide and
mycophenolate mofetil should be discontinued at least 3–6 months prior to concep-
tion and switched to an alternative immunosuppressive medication, such as azathio-
prine or cyclosporine. Azathioprine has been documented to be safe in pregnancy
with little teratogenicity in studies of transplant and inflammatory bowel disease
populations in the setting of pregnancy [37]. Similarly cyclosporine has also been
studied in pregnant transplant patients and the observed rate in newborns of con-
genital malformations did not differ significantly from that seen in the general popu-
lation [37]. It is recommended that cyclosporine be maintained at the lowest effective
dose. In those with active lupus who risk preterm birth, pregnancy loss and pre-
eclampsia, the advantage of continuing immunosuppression such as hydroxychloro-
quine, cyclosporine, and azathioprine, which have all demonstrated no or minimal
teratogenicity, should not be underestimated.
Lupus Nephritis
The prevalence of lupus nephritis flares during pregnancy in different lupus cohorts
has ranged from 16–36 % [11, 12, 33, 38]. The wide range of incidence can be
accounted for by the variation in definitions for nephritis and heterogeneity in
patient populations. Whether renal flares have a higher prevalence in pregnant lupus
patients than in nonpregnant lupus patients is controversial and studies have had
conflicting results [23, 32, 39]. This again may be a result of no standard definition
for renal lupus disease amongst different studies.
While lupus nephritis can be devastating to the pregnancy, in the majority of
cases it does not result in end stage renal disease or hemodialysis-dependent renal
failure. Due to both the maternal and the pregnancy risk of active lupus nephritis, it
must be treated during pregnancy.
Several studies have suggested that active renal disease at the time of conception
and within 6 months prior to pregnancy are significant predictors for pregnancy
complications and adverse outcomes [39, 40] (see Table 4.4). In a retrospective
study which included women with SLE and active nephritis and those with SLE
who did not have nephritis, preterm delivery happened more frequently at a rate of
52 % in those with renal disease and only 19 % in those without renal disease [40].
Fetal loss was also more frequent in the group with active nephritis at a rate of 35 %
compared to 9 % in those who did not have nephritis [40]. Women with active lupus
nephritis in pregnancy have higher rates of hypertension, preeclampsia, and stroke
[40]. Due to the great risk that active renal disease has on a pregnancy, it is ideal to
wait for at least 6 months of quiescence before conception.
The rate of relapse of renal disease during pregnancy in women with a prior his-
tory of lupus nephritis is about 30 % [16, 33]. Women who do not have active
nephritis during pregnancy, but rather a history of nephritis, still have a significant
4
Table 4.4 Pregnancy outcomes in women with prior lupus nephropathy (LN) and pregnant women with SLE without nephropathy
Saavedra et al. [41] Bramham et al. [42] Wagner et al. [40]
Systemic Lupus Erthematosus
Prior LN, but Prior LN

Prior LN No prior Prior LN No prior quiescent and active No prior renal
(n = 35) LN (n = 60) P value (n = 43) LN (n = 64) P value (n = 20) (n = 23) disease (n = 47) P value
a a a a
Rate of renal flare 16 (45.7 %) 4 (6.6 %) 0.00001 6 (14 %) 1 (1.5 %) N/A
a a a
Rate of all flares 19 (54.2 %) 15 (25 %) 0.004 14 (36 %) 25 (40 %) a N/A
Preeclampsia 8 (22.8 %) 8 (13.3 %) 0.2 12 (28 %) 10 (16 %) a 7 (35 %)b 13 (57 %)b 5 (11 %)b <0.001
Preterm birth 17 (48.5 %) 24 (40 %) 0.4 13 (30 %) 7 (11 %) 0.029 6 (30 %) 12 (52 %) 9(19 %) 0.007
a
Pregnancy loss 7 (20 %) 6 (10 %) <0.05 0 1 (1.6 %) 5 (25 %) 8 (35 %) 4 (9 %) 0.031
Low birth weight (<2,500 g) 10 (28.5 %) 21 (35 %) 0.06 14 (33 %) 14 (22 %) a 1 (5 %) 1 (4 %) 2 (4 %) 0.98
a
Not reported
b
Maternal complications including preeclampsia, hypertension, eclampsia, stroke, HELLP syndrome, and maternal death
87
increase in pregnancy complications. In a meta-analysis, 16.3 % of pregnant patients

with a history of nephritis had gestational hypertension and 7.6 % experienced pre-
eclampsia, a statistically significant increase over background rates of these disor-
ders [43]. Pregnancies in patients with previous nephritis also had higher rates of
fetal loss than women without history of renal disease [16].
Thrombosis
Pregnancy itself is a hypercoaguable state and increases even a healthy woman’s

risk of thromboembolism about fourfold [44]. In addition, independent of antiphos-
pholipid syndrome, SLE patients have a significantly increased risk of thrombosis,
even outside of pregnancy. Thus when a lupus patient is pregnant her risk of throm-
boembolism increases to an even greater degree. In a large retrospective study in
California, which included all women with deliveries during a 2-year period, the
rate of DVT during pregnancy was sevenfold higher in those with lupus as com-
pared to the other women [10]. In another nationwide retrospective study which
looked at all pregnancy-related admissions from 2000 to 2003, the risk of venous
thromboembolism during pregnancy was five to eightfold higher in those with SLE
as compared to other women. In the same study, the risk of stroke during pregnancy
was 6.5-fold higher in those with SLE as compared to other women [22].
It is important to evaluate a woman’s risk of thromboembolism early on in preg-
nancy. Antiphospholipid syndrome is caused by autoantibodies and manifests with
symptoms of venous or arterial thrombosis and pregnancy loss. This syndrome
occurs both in the presence and in the absence of lupus or another autoimmune dis-
ease. Up to 40 % lupus patients will have antiphoshpolipid antibodies, but only
15 % will have symptoms, thrombosis and have antiphosholipid syndrome [45, 46].
For more information on antiphospholipid syndrome during pregnancy, please refer
to Chap. 6. Some thrombotic risk factors, such as antiphospholipid syndrome or
history of other hypercoaguable disorder, are modifiable. SLE patients with prior his-
tory of antiphospholipid syndrome manifesting as thrombosus should be put on
full-dose therapeutic low-molecular-weight heparin during pregnancy. Alternatively,
those SLE patients with history of antiphospholipid syndrome with obstetrical
complications but no prior clotting events can be treated with prophylactic low-
molecular-weight heparin during pregnancy. SLE patients without associated APS
or other clotting disorders do not need to be treated with heparin during pregnancy.
Diabetes and Hypertension
Studies have demonstrated a fourfold increase in the prevalence of hypertensive

disorders in SLE patients who are pregnant as compared to healthy pregnant con-
trols [10]. Risk factors for gestational hypertension include renal disease and a
former diagnosis of hypertension [47]. Both diabetes and hypertension diagnosed

prior to pregnancy are more common in women with SLE than in healthy controls
[22, 48], most likely because treatment with corticosteroids can increase the risk of
both these disorders. While studies have not shown a statistically significant increase
in incidence in gestational diabetes in SLE pregnancies [22, 49], it is certainly a
concern nonetheless, especially in those on corticosteroids during pregnancy [23].
Cesarean Section Deliveries
Higher rates of women with lupus have Cesarean section deliveries when compared
to the general population [22, 23]. Greater than a third of women with lupus are
delivered by C-Section, a rate higher than is typical. [5, 13, 22, 23]. The indications
for Cesarean section in lupus pregnancies are the same as those in the general popu-
lation; however, since complications necessitating C-section such as preeclampsia
and gestational hypertension affect lupus pregnancies more often than those of
healthy women, there are more C-sections performed in lupus pregnancies. In one
retrospective study in Canada, more women with a preterm delivery were either
induced or had a C-section in the face of hypertension, HELLP syndrome, fetal
distress, or preeclampsia than those who delivered at term [4]. Other indications in
the literature seen for delivery by C-section include placenta previa, breech, cephalo-
pelvic disproportion, and failed induction. Nonetheless, nothing precludes a woman
with lupus who has an uncomplicated pregnancy from delivering by standard vagi-
nal delivery. In fact, most women with lupus undergo successful vaginal delivery.
Diagnostic Investigations and Monitoring
Laboratory Testing
Full lab testing prior to pregnancy helps to establish a baseline and risk stratify a
woman with lupus (see Table 4.5). Laboratory testing to assess lupus activity is
important to monitor at the onset and throughout pregnancy. This assessment
includes complement levels, anti-dsDNA titer, complete blood counts, urinalysis,
and kidney function. Complement (C3 and C4) which frequently increases during
healthy pregnancy may fall with increased lupus activity. The anti-dsDNA antibody
can be positive in up to half of lupus pregnancies and may be associated with
increased lupus activity, particularly in the kidneys. The complete blood count
should be monitored to assess for hemolytic anemia and thrombocytopenia due to
lupus activity. Leukopenia and especially lymphopenia is common in lupus and
does not necessarily reflect disease activity. Lupus nephritis frequently starts asymp-
tomatically, so monitoring for this with a complete urinalysis and serum creatinine
is very important. Lupus nephritis generally presents with proteinuria, red and white
cells in the urine, and granular casts. Serum creatinine typically decreases during
Table 4.5 Laboratory testing during lupus pregnancy

Screening at To discriminate
initiation of Monitoring between preeclampsia
pregnancy for lupus activity and lupus flare
Complete blood count with X X X
differential
Chemistries with liver and X X X
kidney function
Anti-dsDNA antibodies X X X
Complement levels: C3 and C4 X X X
Complete urinalysis X X X
Urine protein:creatinine ratio X X X
24 h urine for protein and If urine protein:
creatinine creatinine increased
or serum creatinine
elevated
Anti-cardiolipin antibodiesa X
Lupus anticoagulant: dilute X
Russell viper venom time
and sensitive PTTa
B2-glycoprotein 1 antibodya X
Anti-Ro (SSA) and anti-La X
(SSB) antibodies
24 h urine for calcium X
Uric acid level X
a
If tests positive, repeat in 6–8 weeks to confirm antiphospholipid syndrome positivity
pregnancy due to increased renal blood flow, so a patient without a decline in creati-
nine should be very closely monitored for developing or worsening nephritis.
At the initial pregnancy visit, assessment of antiphospholipid antibody status
should be obtained, including anti-cardiolipin antibodies, lupus anticoagulant anti-
bodies, and anti-beta2-glycoprotein-1 antibodies. The interpretation of the labs,
however, can be challenging in women without a prior pregnancy and this is dis-
cussed in detail in Chap. 6. Also the risk of neonatal lupus should be assessed during
the initial visit by checking anti-Ro/SSA and anti-La/SSB antibodies.
Fetal Monitoring and Surveillance
All women with lupus should consider having a maternal–fetal medicine consulta-
tion to help guide obstetrical management throughout the pregnancy.
Beyond the usual pregnancy screening followed in all pregnancies, pregnancies in
women with lupus can benefit from increased monitoring in the third trimester. The
goal of this screening is to identify possible placental insufficiency that would prompt
an early delivery to improve long-term outcomes. Periodic ultrasounds should be
performed to assess amniotic fluid quantity and fetal growth. This is usually started
Table 4.6 Treatment options in lupus pregnancy based on lupus activity

Lupus activity Corticosteroid Immunomodulator
No lupus activity None Hydroxychloroquine
Mild lupus activity Low-dose prednisone (<10 mg) Hydroxychloroquine
Moderate lupus Moderate-dose prednisone Hydroxychloroquine and
activity (10–40 mg) azathioprine or cyclosporine
Severe lupus activity High-dose prednisone Hydroxychloroquine and
(1 mg/kg/day) and/ azathioprine or cyclosporine
or pulse-dose IVIG
methylprednisolone (1 g/day) Cyclophosphamide if the life or organs
of the mother are threatened in the
second or third trimesters
once or twice weekly around 28–32 weeks gestation. Some methods used to assess
for hypoxemia include non-stress test, biophysical profile, and umbilical artery
Doppler velocimetry wave form analysis. In the USA, the most commonly used
method is the “modified” biophysical profile. This involves a non-stress test and
amniotic fluid measurement twice weekly. Abnormal results in fetal surveillance test-
ing should cause contemplation of either medication intervention or prompt delivery.
Treatment
General Principles of Treatment for All Pregnant Women

with SLE
When considering treatment of lupus during pregnancy, it is important to consider and

balance the risks of medication to the developing fetus and the benefits of the medica-
tion in controlling lupus activity. The prevention of active SLE is of primary impor-
tance. Considering that many medications have minimal risks, immunosuppression
when needed is preferable to SLE activity. Please refer to Chap. 14 for further informa-
tion about the medications discussed in this section. See Table 4.6 for an overview
guide to lupus treatment during pregnancy.
All women should be started on a prenatal multivitamin preferably prior to preg-
nancy or as soon as possible during it. The vitamin should contain at least 800 μg
folic acid and 27 mg of iron.
All of a woman’s medications should be reviewed thoroughly ideally prior to
conception. Women on azathioprine and hydroxychloroquine should continue these
medications. The risk of discontinuing these medications and having the disease
flare outweighs the minimal risk of the medications themselves. Methotrexate,
mycophenolate mofetil, and cyclophosphamide should be stopped at least 3 months
prior to pregnancy as all are teratogenic and should be changed to safer medications
like azathioprine or cyclosporine. The transition from mycophenolate mofetil to
azathioprine or cyclosporine can be challenging and is usually safest if they are
crossed over several months to avoid a lupus flare. Pregnancy should be delayed
until the patient has been stabilized for at least 3 months on the new medication to
avoid an unexpected flare during pregnancy.
Pregnancy outcomes can be improved with 81 mg aspirin. As discussed earlier in
the chapter, low-dose daily aspirin has been associated with a decrease in pre-
eclampsia, preterm birth, and fetal and neonatal death [29]. Nonsteroidal anti-
inflammatory medications (NSAIDS) should be generally avoided during the first
trimester of pregnancy as they are associated with problems with embryo implanta-
tion and miscarriage and also during the third trimester as they promote premature
closure of the ductus arteriosus and prolonged labor. The risk of oligohydramnios
induced by NSAIDs remains throughout all trimesters of gestation as NSAIDs have
effects on fetal renal function and can cause a reduction in amniotic fluid [37].
No Lupus Activity
Women with lupus require no specific treatment during pregnancy in the absence of
signs or symptoms of active SLE. In the past, prophylactic corticosteroids were
standard practice, but this is no longer recommended due to increased rates of dia-
betes, hypertension, and preterm delivery [5]. Women who are already taking
hydroxychloroquine should continue it throughout pregnancy, even if lupus activity
has been quiescent for any period of time prior to conception. On the other hand, the
rare patient with years of quiet activity without hydroxychloroquine probably does
not need to start this drug for pregnancy. Women with positive anti-Ro/SS-A or anti-
La/SS-B antibodies, regardless of symptoms, may benefit from hydroxychloroquine
because this might decrease the risk for cardiac neonatal lupus [50].
Mild Lupus Activity
Hydroxychloroquine is the cornerstone therapy to treat mild lupus flares in preg-

nancy. For more symptoms that impact quality of life, low-dose corticosteroids can
be used during pregnancy. The preferred corticosteroids to use during pregnancy are
prednisone and prednisolone, as less than 10 % will cross the maternal–fetal mem-
branes [37]. Mild lupus activity—rashes, mouth ulcers, mild alopecia, and mild
arthritis—will not generally have a negative impact on pregnancy outcomes.
Therefore, the risks of corticosteroids need to be balanced with the impact of lupus
on the woman’s quality of life. The use of steroids does not come without risks and
the dose should be kept as low as possible. Steroids are associated with gestational
hypertension, diabetes, and premature birth [23]. Exposure to corticosteroids in any
form and dose in the first trimester may be associated with an increase in the risk of
cleft lip or palate, but the absolute risk of this still remained low at 3 per 1,000
infants with steroid exposure [51]. In addition, very infrequent use of NSAIDs in
the late first and second trimester to treat mild symptoms of arthritis, pain and
serositis is considered safe although it is important to remember that the risk of

oligohydramnios induced by NSAIDs does exist throughout all trimesters.
Moderate Lupus Activity
Azathioprine and higher doses of prednisone can be used for those with moderate
lupus activity that is not controlled with the previously mentioned medications.
In women who require an immunosuppressant before pregnancy to control moder-
ate to severe lupus activity, azathioprine is a good choice and should be continued
throughout pregnancy. In addition, women on other more teratogenic medications,
like methotrexate or mycophenolate mofetil, may be switched to azathioprine prior
to pregnancy. Cyclosporine has primarily been studied in the transplant population
during pregnancy and there has been no increase in neonatal deaths or recurring
patterns of congenital anomalies [52]. The rate of congenital malformations did not
exceed the 3 % reported in the general population [37]. There have been a few case
reports in SLE patients that support its safe use during a lupus pregnancy [53, 54].
While mycophenolate mofetil is a very effective drug for active lupus, it has been
associated with a high pregnancy loss rate and a fetal anomaly rate of 25 %. [52] For
these reasons, it should not be continued during pregnancy.
Methotrexate is also teratogenic and should be avoided during pregnancy. Ideally
it should be discontinued at least 3 months prior to a planned pregnancy and folic
acid should be supplemented.
Belimumab has limited data in pregnancy and has been listed as pregnancy class C
likely due to the fact that B cell and immunoglobulin levels decreased in infant
monkeys exposed in utero. In studies performed in monkeys, no increase in pregnancy
loss or congenital malformations was noted, though there was a high degree of trans-
placental transfer [55]. Unintended pregnancies that occurred during the phase 2 and
3 drug trials of belimumab make up the current human data. There were 83 reported
belimumab exposed pregnancies with known outcomes. Of these 83 pregnancies;
24 % were elective terminations, 27.7 % were miscarraiges and 42 % were live births.
There were 3 reported congenital malformations (3.6 % rate) amongst these belim-
umab exposed pregnancies; however one was caused by a chromosomal translocation
also found in the mother [56]. Based on current data, no recommendations or con-
clusions regarding the use of belimumab in pregnancy can be made. Hopefully with
growth of the registry, the safety of the drug will be better understood.
Severe Lupus Activity
When organ threatening lupus arises during pregnancy, it puts maternal and fetal
health in danger. In these situations, pulse dose steroids in a regimen of 1 g intrave-
nous methylprednisolone daily over three consecutive days is necessary especially
in cases of severe organ activity such as in CNS or renal disease. This has the benefit
of controlling disease activity rapidly. There are no studies on the administration of

high-dose steroids and the fetal effects and thus the risk of this therapy remains
unknown.
In addition, IVIG may be used, particularly for renal or hematologic disease
[57]. While data on IVIG is limited, the literature has reported no adverse effects on
the fetus [37]. A small study which included 12 patients who received IVIG during
pregnancy demonstrated a significant decrease in SLE activity and symptoms and
positive fetal outcomes after IVIG administration [58].
While we like to avoid cyclophosphamide during pregnancy because of the risk
of teratogenicity and pregnancy loss, sometimes it is required as a last resort when
disease activity is putting the life of the mother at risk. Data on pregnancy outcomes
following cyclophosphamide are limited, but most pregnancies exposed to the drug
for lupus activity end in a pregnancy loss [59]. There is uncertainty about whether
it is the cyclophosphamide or the severe lupus activity in these women that was the
cause of their pregnancy losses. Interestingly, there have been no reports of fetal
loss or congenital abnormalities in pregnant women who have gotten cyclophospha-
mide for treatment of breast cancer in the second or third trimesters [60]. When
cyclophosphamide is warranted during pregnancy, healthcare professionals must
discuss frankly with the mother the high risk of fetal demise associated with this
medication.
Conclusion
Pregnancy in a woman with lupus has the potential for many risks and complica-
tions; however, most pregnancies result in the delivery of a healthy baby. The main
barrier to pregnancy success is high activity lupus. Therefore, the risk of poor out-
come can be mitigated by avoiding conception during periods of lupus flare, con-
tinuing immunomodulation during pregnancy, and monitoring for and treating lupus
flare during pregnancy. Women with SLE are best served by following with a medi-
cal team consisting of a high risk obstetrician and a rheumatologist throughout preg-
nancy. Fortunately, many women during pregnancy remain in good health and have
successful deliveries of healthy infants.
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Chapter 5
Pregnancy in Sjogren’s Syndrome,
Mixed Connective Tissue Disease,
and Undifferentiated Connective
Tissue Disease
Bonnie L. Bermas and Lisa R. Sammaritano
Introduction
Sjogren’s syndrome (SS), mixed connective tissue disease (MCTD), and undifferen-
tiated connective tissue disease (UCTD) are some of the less common disorders seen
in rheumatology. Like many of the other rheumatologic diseases, these disorders
have a higher incidence in women; thus, reproductive issues are part of the manage-
ment of these patients. This is less the case in those patients with Sjogren’s syndrome,
as this disorder predominately impacts women towards the end of their reproductive
years. Because of the age distribution of Sjogren’s and the relative rarity of MCTD
and UCTD, there is a paucity of information on pregnancy outcome and the impact
of pregnancy on maternal disease in patients with these syndromes. Nonetheless,
some conclusions about these disorders during pregnancy can be drawn from the cur-
rent literature. This chapter will discuss the pregnancy outcomes in individuals with
these disorders and what is known about how pregnancy impacts disease activity.
Sjogren’s Syndrome
Relatively rare (prevalence rate of 4/100,000), Sjogren’s can be seen as an entity

unto itself (Primary Sjogren’s, 70 %) or in conjunction with other rheumatologic
disorders (Secondary Sjogren’s, 30 %). Manifestations of Sjogren’s include kerato-
conjunctiva sicca, vaginal dryness, sinusitis, some types of renal tubular acidosis,
B.L. Bermas, M.D. (*)

75 Francis Street, Boston, MA 02115, USA
e-mail: bbermas@partners.org
L.R. Sammaritano, M.D.

100 B.L. Bermas and L.R. Sammaritano
peripheral neuropathy, and CNS disorders. Generally, the diagnosis is made by a

Schirmers test confirming decreased lacrimal flow and a salivary gland biopsy that
reveals a characteristic lymphocytic infiltrate. In 60 % of the cases, patients have the
anti-Ro/SS-A and/or anti-La/SS-B antibodies [1].
Anti-Ro/SS-A and anti-La/SS-B antibodies are the pathogenic antibodies in con-
genital complete heart block (CCHB) and neonatal lupus, and so concern regarding
autoantibody transfer to the offspring is the major pregnancy risk in antibody-positive
Sjogren’s syndrome patients. This topic is discussed in detail in Chap. 13. Nonetheless
it is important to note that often it is the birth of a child with CCHB that first prompts
the search for these autoantibodies in an otherwise asymptomatic mother. Thus,
sometimes pregnancy complicated by CCHB is the trigger for the investigation and
diagnosis of Sjogren’s syndrome and other connective tissue diseases [2].
Mixed Connective Tissue Disease
MCTD is a disorder often grouped with systemic lupus erythematosus (SLE) as

there is an overlap of symptoms in these diseases. The similarities of the disorders
are such that many individuals who are ultimately diagnosed with MCTD are first
diagnosed with SLE. Distinguishing features of MCTD include high titer ANA anti-
bodies and the presence of an isolated anti-RNP antibody. Hand swelling, Raynaud’s,
myositis, and interstitial lung disease are also key features of MCTD [3].
Undifferentiated Connective Tissue Disease
The term UCTD is generally used to describe those patients who have features
strongly suggestive of an autoimmune rheumatologic condition such as Raynaud’s
phenomenon, rashes, or an inflammatory arthritis. These patients do not, however,
have features that will enable them to be clearly classified into a specific rheumato-
logic disorder [4]. Estimates of the percentage of patients who will evolve into a
clear rheumatologic disorder range from 5 to 35 % [5, 6].
Fertility and Contraception
Sjogrens Syndrome
In general, primary fertility is preserved in women with Sjogren’s syndrome.

There have been conflicting data (discussed below) on the presence of secondary
infertility, defined as the ability to conceive but subsequent pregnancy loss, in this
patient population. In one study comparing 51 patients with primary SS with 57
5 Pregnancy in Sjogren’s Syndrome, Mixed Connective Tissue Disease,… 101
healthy controls, gynecologic and obstetric histories were reviewed retrospectively.

No difference was found between the groups in terms of fertility and parity.
However, 40 % of women with SS compared to 3 % of women without Sjogren’s
experienced dyspareunia. In only half of these SS patients was the dyspareunia
directly attributable to the SS [7]. In another study of 110 patients with primary SS,
vaginal dryness did have a negative impact on health-related quality of life, thus
patients with SS should be asked about and counseled for this symptom [8]. There
are no restrictions in the type of contraception that can be used in women with pri-
mary SS unless they have concomitant antiphospholipid antibodies.
MCTD and UCTD
There is no reduction in fertility in individuals with MCTD or UCTD other than the
secondary infertility that can be found in some patients who have coexisting
antiphospholipid antibodies.
Pregnancy Outcome
Sjogrens Syndrome
There have been conflicting data on the risk of pregnancy loss in SS. One early
report retrospectively evaluated the outcomes of pregnancy in women with autoim-
mune rheumatic diseases including 21 women with primary SS, where pregnancy
occurred prior to disease diagnosis. Women with primary SS reported a higher inci-
dence of spontaneous abortion (21 %) when compared to controls [9]. In another
study of 55 pregnancies in women with primary SS, 47 pregnancies occurred prior
to the diagnosis of primary SS. Twenty percent of the pregnancies ended in fetal
loss [10]. The reported increased relative risk of fetal loss of 2.7 was not associated
with the presence of anticardiolipin antibodies or antibodies to anti-Ro/SS-A or
anti-La/SS-B. In contrast, in a retrospective review of 117 pregnancies in 40 women
with Sjogren’s (13 primary SS, 27 secondary SS), the frequency of spontaneous
abortions was not higher in this patient group when compared to 129 healthy con-
trols. However, in those patients with coexisting SLE and antiphospholipid antibod-
ies, spontaneous abortions were more common [11].
Pregnancy complications other than CCHB and neonatal lupus seen in anti-Ro/
SS-A and anti-La/SS-B positive patients with Sjogren’s syndrome have been
reported in small retrospective case series. In one nested case–control series of 16
patients, 10 patients were diagnosed with SS before pregnancy and the six remain-
ing patients were diagnosed after pregnancy. These women’s pregnancies were
compared to the pregnancies of 80 healthy women: the mean age at delivery
was higher in the SS patients than in controls (33.6 vs. 29.8). While there was no
difference in pregnancy duration, there was a slightly increased rate of forceps and
cesarean section delivery in the women with primary SS. Reasons for these inter-
ventions at delivery were not explored. Additionally, offspring of mothers with SS
were of lower weight and more likely to be small for gestational age (SGA) [12]. In
a larger case–control questionnaire study, reproductive histories of women with SS
were compared to a control population. In this study, only four patients were diag-
nosed with SS before their last pregnancy, while 58 were diagnosed with SS after all
pregnancies were completed. Two patients were never pregnant. The expected rate
of CCHB, 3.4 %, was found in the offspring. While preeclampsia, proteinuria, and
premature labor were seen more frequently in patients than in controls, this finding
was not statistically significant once smokers were excluded from the analysis [13].
In another study of pregnancies in anti-Ro/SS-A positive women who had SLE and
other connective tissue diseases, there was no increase of pregnancy complications
seen in anti-Ro/SS-A positive women other than CCHB [14].
While there have been some reports of increased spontaneous pregnancy losses
in women who ultimately go on to be diagnosed with SS, this data is confounded by
its retrospective nature. More frequent complicated deliveries (instrumental and
cesarean section) have been reported in women with Sjogren’s syndrome although
this finding has not been consistent in the literature and patient and physician prefer-
ence for mode of delivery is not discussed. Thus, outside of neonatal lupus and
CCHB, Sjogren’s syndrome does not appear to impact pregnancy outcome in a
significant manner.
There are a handful of case series that explore the outcomes of pregnancy in women
with MCTD. In one large study of 22 women who had 96 pregnancies before the
diagnosis of MCTD, fertility rate was not different than controls. There were eight
elective terminations, 12 spontaneous abortions, and three cases of intrauterine fetal
demise (IUFD), leading to a 17 % fetal loss rate. In the 10 patients who had 17
pregnancies after their diagnosis of MCTD, there were four elective terminations,
six spontaneous abortions, three cases of IUFD, and four live births [15]. This very
high fetal loss rate has not been reported in other series. In Lundberg’s and Hedfors’
study of 20 women who had high titer anti-RNP antibodies, four women had 17
pregnancies before the diagnosis of MCTD and the live birth rate was 88 %. The
live birth rate was 78.6 % in those women who had MCTD diagnosed prior to preg-
nancy [16]. Neither of these rates is above the expected rate of pregnancy loss. In
another series of eight pregnancies in six women with MCTD, there were three
preterm deliveries, and 63 % of the infants were SGA. There were no fetal losses.
There have been three reports of infants born of mothers who have MCTD with
chondrodysplasia punctata manifested by micrognathia and depressed nasal bridge
and other skeletal abnormalities [17, 18]. The authors suggest that maternal autoan-
tibodies crossing the placenta may affect normal fetal growth plates. This finding
should be interpreted conservatively, however, as it has not been reproduced in

larger case series.
The data are inconsistent as to whether MCTD diagnosed prior to pregnancy
causes higher rates of fetal loss. Moreover, the existing studies are retrospective,
giving rise to recall bias. Due to the limited information in the literature, it is impos-
sible to conclude whether MCTD increases the risk of other pregnancy complica-
tions such as preeclampsia, prematurity, and SGA infants. Thus, one can reassure
patients that the existing information suggests that pregnancy outcome in women
with MCTD appears to be good.
There have been several case series that have looked at pregnancy outcome in
patients with UCTD. In one study by Castellino et al., 55 pregnancies in 50 patients
with UCTD were followed. There were three miscarriages, two in the first trimester
and one loss of a twin in the third trimester. There were five cases of preterm pre-
mature rupture of membranes (PPROM), two cases of preeclampsia and two of
intrauterine growth restriction (IUGR). Delivery mode was notable for 30 cesarean
sections. Reasons for the high cesarean section rate, including patient and physician
preference, were not given. Average pregnancy duration was 38.6 weeks and the
mean birth weight was 3,190 g. Thus, other than a high cesarean section rate there
was not a higher than expected untoward pregnancy outcome [19]. In another study
in which 62 women were identified as having UCTD during their first trimester of
pregnancy, complications of pregnancy including fetal loss, preeclampsia, and fetal
growth restriction as well as premature delivery was 2.81 times more common than
in healthy controls [20]. In another case series of 25 pregnancies in 20 patients with
UCTD, 88 % of pregnancies were term pregnancies while 12 % ended in first tri-
mester abortions [1]. In one case–control study that compared 41 patients diagnosed
with UCTD during the first trimester with 82 controls, the women with UCTD had
higher rates of SGA infants (30 vs. 13 %). The rate of overall pregnancy complica-
tions including preterm delivery, SGA, preeclampsia, and late fetal loss was 39 %
among cases and 13.4 % amongst controls [21]. This group may not be representa-
tive of all patients with UCTD, as disease diagnosis occurred in the setting of preg-
nancy. It is well known that in other connective tissue diseases such SLE, myositis,
and vasculitis, disease onset during pregnancy is often related to high disease activ-
ity and poor pregnancy outcome.
One recent study evaluated uterine artery Doppler velocimetry and obstetric out-
comes in connective tissue diseases diagnosed during the first trimester of preg-
nancy. In 66 patients diagnosed with UCTD, the patients had increased rated of first
trimester bilateral uterine artery notches when compared with controls [22].
While there are limited data on the outcomes of pregnancy in UCTD, there is
evidence to suggest that most patients do well, although there are risks of PPROM,
preeclampsia, IUGR, and higher cesarean section rate, echoing what is found in
other connective tissue disorders.
Impact of Pregnancy on Disease Activity
Sjogren’s Syndrome
There are no large-scale studies evaluating the impact of pregnancy on Sjogren’s

syndrome. There was one case report of a women with Sjogren’s disease who pre-
sented with acute renal failure due to mesangial proliferative glomerulonephritis at
her 20th week of pregnancy. At 28 weeks, she underwent a cesarean section due to
PPROM [23]. A healthy baby boy resulted. In another case report, a 35-year-old
woman who had Sjogren’s had a pregnancy that was complicated by pericarditis.
She was successfully treated with prednisolone 30 mg/day as well as heparin. This
patient also gave birth to a healthy baby [24]. While there is insufficient data to
conclude how pregnancy impacts disease activity during pregnancy, it is probably
best to use the approach applied to other rheumatologic disorders that disease should
be in remission at the time of conception.
Pregnancy may impact maternal MCTD disease onset and activity. In ten patients
reported by Kitridou, five had their disease onset during pregnancy and three
patients had disease flares during pregnancy. Disease manifestations included myo-
sitis, synovitis, serositis, and increases in proteinuria [15]. In Lundberg’s and
Hedfors’ series of 14 pregnancies in women with high titer anti-RNP antibodies,
proteinuria occurred in three patients, thrombocytopenia in one, preeclampsia in
two, and deep venous thrombosis (DVT) in one. Despite the high number of com-
plications, the authors concluded that these were not higher than the expected rate
of complications [16].
There have been two case reports of MCTD disease exacerbation during preg-
nancy manifesting as pulmonary hypertension [25, 26]. The limited data suggest
that there is a small risk of disease flare during pregnancy.
There are limited data on how pregnancy impacts disease activity in women with
UCTD. In one study of 25 pregnancies in 20 women with UCTD, 22 patients com-
pleted term pregnancies. Six patients experienced a disease flare. One of the patients
evolved into full-blown SLE. The other five patients had mild symptoms including
arthritis, fevers, and skin rashes. This flare rate was higher than seen in the nonpreg-
nant control UCTD population over a year (7 %) [1]. Thus, it may be that the immu-
nologic and hormonal changes seen during pregnancy can induce disease activity is
some patients with UCTD.
Treatment
As in other rheumatologic disorders, medications may need to be adjusted in antici-

pation of pregnancy: it seems prudent to make certain that patients are on medica-
tions compatible with pregnancy prior to conception. While hydroxychloroquine is
not as much the standard of care in individuals with MCTD and UCTD, in those
patients being treated with this medication, one can hypothesize that continuation of
this medication may potentially improve outcome in a similar fashion as is seen in
those patients who have SLE.
Conclusions
While there is limited data on pregnancy in women with Sjogren’s, MCTD, and
UCTD, some conclusions can be drawn. In general, fertility seems to be maintained
in these patients. Higher cesarean section rates have been reported for unclear rea-
sons and none of the reports in the literature account for patient and physician pref-
erence in delivery mode. Although those with increased disease activity in MCTD
are at higher risk for pregnancy complications such as preeclampsia and PPROM,
those patients whose disease is under control at conception generally fare well. It
may be reasonable to consider a pre-pregnancy echocardiogram to screen for
asymptomatic pulmonary hypertension in anti-RNP positive patients.
Pregnancy does not seem to contribute to disease activity in Sjogren’s and
MCTD. The story of those with UCTD is less clear: potentially, pregnancy may
cause patients with UCTD to evolve into more classical connective tissue disorders
such as rheumatoid arthritis or SLE. The question of whether pregnancy will trigger
development of “full-blown” SLE is a common one posed by patients, and the likely
low but finite risk should be discussed.
The same general approach should be used in the management of these patients
during pregnancy as in other rheumatic diseases. Ideally, pregnancies should be
planned. Disease activity should be minimized for 6 months prior to pregnancy,
preferably on medications compatible with pregnancy. Involvement of maternal–
fetal medicine and a team approach with the rheumatology and obstetrics services
are ideal.
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Chapter 6
Antiphospholipid Syndrome
Alana B. Levine and Michael D. Lockshin
Historical Perspective
The earliest investigations of antiphospholipid syndrome (APS) took place in 1906

when Wasserman et al. described autoantibodies in the sera of patients with syphilis
[1]. This led, in 1941, to a more sophisticated understanding of the association
between the false-positive test for syphilis and a substance in beef heart extract
(later described as cardiolipin) [2], and a description of the “biological false positive
test for syphilis” in 1952 [3]. Reports of women with adverse pregnancy outcomes
found to have “circulating anticoagulant” were first published in 1954 [4] and 1969
[5], and later further described in 1980 [6]. A comprehensive review of the seminal
reports that have contributed to our understanding of obstetric APS is available [7].
Pathogenesis of Adverse Pregnancy Outcome
Animal studies have elucidated the pathogenic role antiphospholipid antibodies (aPL)
play in pregnancy complications. When aPL from women with histories of fetal loss
were introduced into pregnant mice, adverse pregnancy outcomes, including lower
fecundity rate, increased resorption of embryos, lower number of embryos per preg-
nancy, and lower mean weights of embryos and placentae, were seen when com-
pared to mice injected with control immunoglobulin [8–10].
Various pathways have been implicated in the pathogenesis of obstetric APS.
Early theories focused on thrombosis in the uteroplacental circulation as the caus-
ative mechanism [11–13]. Antiphospholipid antibodies have been shown to reduce
A.B. Levine, M.D. (*) • M.D. Lockshin, M.D.

Division of Rheumatology, Hospital for Special Surgery, 535 East 70th Street,
New York, NY 10021, USA
e-mail: levinea@hss.edu
110 A.B. Levine and M.D. Lockshin
the levels of trophoblast-associated annexin A5, resulting in placental villus

thrombosis [14, 15]. These antibodies were also shown to increase monocytic
expression of tissue factor in mouse models [16].
Because not all affected placentas have signs of thrombosis or infarction, other
models invoking inflammatory (as opposed to thrombotic) mechanisms have been
considered. These include activation of complement [17–20], decreased levels of
interleukin-3 (IL-3) [21], and a direct effect of aPL on the human placental tropho-
blast [22]. One proposed mechanism for the genesis of preeclampsia in aPL-positive
patients invokes defective regulation of the complement system, allowing for exces-
sive complement activation which leads to abnormal placental development, pla-
cental damage, generalized endothelial activation, and release of antiangiogenic
factors toxic to glomerular endothelium and liver sinusoids [23].
Epidemiology
The lack of adequate standardized assays and variable interpretations of antibody titers
have made estimating the prevalence of aPL a challenging task. Antiphospholipid anti-
bodies are detectable in up to 5 % of asymptomatic individuals and, as with other
autoantibodies, become increasingly common with increasing age [24]. Their preva-
lence in women with uncomplicated pregnancies ranges from 0.3 to 7 % [25–30].
Antiphospholipid antibodies are more commonly detected in patients with
systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE) [31],
than in the general population. The frequency of aPL in SLE patients is approxi-
mately 30 % [31]. As many as 50 % of SLE patients with a lupus anticoagulant
(LAC) will go on to develop APS [32]. Antiphospholipid antibodies may also be
seen in association with a wide variety of infections, including viral hepatitis, Lyme
disease, Chagas disease, and leprosy [33–39]. They are also associated with medi-
cations (such as antiepileptic drugs, amoxicillin, oral contraceptives, and proprano-
lol) [40] and malignancies [41]. When seen in these contexts, aPL are typically
transient and are infrequently associated with thrombosis.
Classification Criteria for APS
The classification criteria for APS were first outlined in Sapporo, Japan in 1999
and subsequently updated in 2006 [42, 43]. These criteria were developed for
research purposes but are helpful both in making the diagnosis and in preventing
the overdiagnosis of APS. According to these guidelines, a definite diagnosis of
APS is made when at least one clinical criterion and one laboratory criterion are
met (Table 6.1) [43].
6 Antiphospholipid Syndrome 111
Table 6.1 Revised Sapporo classification criteria for antiphospholipid syndrome (adapted from
Miyakis et al. [43])
Clinical criteria
1. Vascular thrombosisa
One or more clinical episodesb of arterial, venous, or small vessel thrombosisc, in any tissue or
organ
2. Pregnancy morbidity
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th
week of gestation, or
(b) One or more premature births of a morphologically normal neonate before the 34th week
of gestation because of eclampsia, severe preeclampsia, or recognized features of
placental insufficiencyd, or
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of
gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal
chromosomal causes excluded
Laboratory criteriae
1. Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart,
detected according to the guidelines of the International Society on Thrombosis and
Haemostasis
2. Anticardiolipin antibody of immunoglobulin IgG and/or IgM isotype in serum or plasma,
present in medium or high titer (>40 GPL or MPL, or >99th percentile), on two or more
occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent
assay (ELISA)
3. Anti-β2-glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (>40 GPL or
MPL, or > 99th percentile), on two or more occasions at least 12 weeks apart, measured by a
standardized ELISA
Definite APS is present if at least one of the clinical criteria and one of the laboratory criteria are
met. Classification of APS should be avoided if fewer than 12 weeks or more than 5 years
separate the positive antiphospholipid antibody test and the clinical manifestation. In studies
of populations of patients who have more than one type of pregnancy morbidity, investigators
are strongly encouraged to stratify groups of subjects according to (a), (b), or (c) above
From Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the
classification criteria for definite antiphospholipid syndrome. J Thromb Haemost. 2006;4:295–306
a
Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from
APS trials. However, two subgroups of APS patients should be recognized, according to: (a) the
presence and (b) the absence of additional risk factors for thrombosis. Indicative (but not exhaus-
tive) of such cases include: age (>55 in men, and >65 in women), and the presence of any of the
established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL
or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease,
body mass index ≥30 kg/m2), microalbuminuria, estimated GFR <60 mL/min), inherited thrombo-
philias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus,
patients who fulfil criteria should be stratified according to contributing causes of thrombosis
b
A thrombotic episode in the past could be considered as a clinical criterion, provided that throm-
bosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of
thrombosis is found
c
Superficial venous thrombosis is not included in the clinical criteria
d
Generally accepted features of placental insufficiency include an abnormal or non-reassuring fetal
surveillance test (e.g., nonreactive non-stress test) suggestive of fetal hypoxemia, an abnormal
Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-
diastolic flow in the umbilical artery), oligohydramnios (e.g., an amniotic fluid index ≤5 cm), or a
postnatal birth weight less than the tenth percentile for the gestational age
e
Investigators are strongly advised to classify APS patients in studies into one of the following
categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone;
IIb, aCL antibody present alone; IIc, anti-β2 glycoprotein-I antibody present alone
Clinical criteria include thrombotic and/or pregnancy events with the following
definitions: (1) one or more episodes of arterial, venous, or small vessel thrombosis
in any organ or tissue, with unequivocal evidence (by imaging or histologic) of
thrombosis; (2) one or more unexplained deaths of a morphologically normal fetus
at or beyond 10 weeks of gestation or one or more premature births of a morpho-
logically normal neonate before 34 weeks of gestation due to eclampsia, severe
preeclampsia, or placental insufficiency or three or more consecutive unexplained
spontaneous pregnancy losses before 10 weeks of gestation without other explana-
tion (chromosomal, anatomic, or hormonal abnormalities).
Laboratory criteria include persistently positive aPL on at least two occasions
12 weeks apart as demonstrated by at least one of the following: (1) anticardiolipin
antibody (aCL) IgG and/or IgM in moderate or high titer (>40 units GPL or MPL or
>99th percentile for the testing laboratory), (2) anti-β2-glycoprotein-I (aβ2GPI) anti-
body IgG and/or IgM in moderate or high titer (>40 units GPL or MPL or >99th
percentile for the testing laboratory), and/or (3) LAC activity detected according to
published guidelines [44, 45].
Clinical Manifestations of APS
The clinical manifestations of APS can be divided into pregnancy-related and vas-
cular thrombotic events. Adverse obstetrical outcomes associated with APS include
recurrent early pregnancy loss, fetal demise, intrauterine growth restriction (IUGR),
pregnancy-related maternal thromboembolic disease, early and severe preeclampsia/
eclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome,
and catastrophic antiphospholipid syndrome (CAPS). Vascular thrombotic events
may be venous, arterial, or microvascular and can result in deep vein thrombosis
(DVT), pulmonary embolism (PE), or stroke. A variety of associated non-criteria
complications are also described, including livedo reticularis, thrombocytopenia,
and valvular heart disease. Individual patients may have experienced one or more
of these complications; therefore, each patient’s situation should be considered
unique.
Obstetric Manifestations of APS
Definitions of Pregnancy Loss
The imprecise terminology used to define adverse pregnancy outcomes in APS has
resulted in inconsistencies in the literature, with varied definitions amongst studies.
Here we define pregnancy loss at different gestational ages as follows:
Abortion is spontaneous or elective delivery of a pregnancy before 20 weeks
of gestation; spontaneous loss after 20 weeks gestation is defined as stillbirth.
An abortion through the end of the fourth week of gestation is referred to as

pre-embryonic loss while an abortion occurring between the fifth and ninth week is
an embryonic loss. Fetal demise is defined as an intrauterine death after 10 weeks of
gestation. Recurrent pregnancy loss (or recurrent abortion) is defined as three or
more consecutive spontaneous abortions in the same patient.
Recurrent Early Pregnancy Loss
The association of aPL with recurrent pregnancy loss prior to 10 weeks of gestation
is controversial. Due to the high rate and numerous possible causes of first trimester
loss (including chromosomal anomalies, maternal endocrinopathies, or abnormali-
ties of uterine anatomy), a causal relationship between aPL and recurrent early loss
has been difficult to establish; as Macklon et al. noted, more than 30 % of clinically
recognized pregnancies end before completion of the first trimester, with the major-
ity of those losses caused by fetal chromosomal abnormalities [46].
Several studies support the link between aPL and early losses [47–50], while
others have failed to define this association [51, 52]. A systematic review of 25
publications found significant associations between both aCL (OR 3.40; 95 % CI
1.33–8.68) and LAC (OR 2.7; 95 % CI 1.03–8.56) and recurrent loss before
10 weeks gestation [49]. A prospective study followed 20 aPL-positive women with
a history of at least two first trimester losses (exact number of gestational weeks not
defined) who declined treatment in their next pregnancy; 90 % of these women had
miscarriages compared to 34 % of aPL-negative control patients with recurrent mis-
carriage of unknown etiology [50]. In another report, LAC was found to be strongly
associated with loss before 10 weeks gestation, while aβ2GPI positivity was not
clinically relevant [47]. Conversely, Roque et al. failed to find an association
between maternal thrombophilias, including aCL, and embryonic loss in a cohort of
491 patients with a history of adverse obstetric outcomes [51].
Some literature actually suggests that maternal thrombophilias, including aPL,
confer protection against early loss [51]. In the case of aPL, this may be related to
the low oxygen environment of early pregnancy which prevents exposure of aPL to
the uteroplacental circulation [53, 54].
Fetal Demise/Death
The association of aPL with recurrent fetal demise has been well described [48–50,
55, 56]. A 2006 meta-analysis investigating the relationship between aPL and recur-
rent fetal loss demonstrated a strong association with both LAC (OR 7.79, 95 % CI
2.30–26.45) and moderate to high titer aCL IgG (OR 4.68, 95 % CI 2.96–7.40), but
no association with aβ2GPI [56]. Robertson et al. showed a significant association
between aCL and late pregnancy loss (OR 3.30, 95 % CI 1.62–6.70) [49]. A retro-
spective analysis of aPL-positive women with a history of two or more pregnancy
losses found that 50 % of those losses had been fetal deaths, compared to only 15 %
of losses to aPL-negative women, suggesting that fetal death is more characteristic

of aPL-related loss than early miscarriage [55].
To better understand the relationship between aPL and late fetal demise, the
National Institutes of Health (NIH)-sponsored Stillbirth Collaborative Research
Network sought to determine the frequency of immunoassay aPL in this population.
This large, multicenter, population-based study includes over 650 women with
stillbirth from five ethnically and geographically diverse catchment areas in the
USA who were enrolled between March 2006 and September 2008. Of the 190
women who were tested for LAC, 3.2 % had a positive result, while 4.8 % of the
458 women tested for aCL had a positive result [57]. Given the aPL prevalence of
up to 5 % in the general population, and the lack of a control group in this study, the
significance of this finding is unclear.
IUGR (also known as fetal growth restriction) describes a fetus that has not reached
its growth potential because of genetic or environmental factors. Definitions vary
among studies, some considering IUGR to have occurred if the fetus weighs less
than the tenth percentile, while others use less than the fifth percentile. While the
rate of IUGR in the general population is approximately 10 %, the frequency ranges
from 3 to 30 % in APS patients [58–60]. An association of aCL with IUGR has been
suggested. In a prospective study of 860 Japanese women, Yasuda et al. found a
strong association between IUGR and aCL (OR 6.91, 95 % CI 2.70–17.68) [61].
Another study of mothers of fetuses with IUGR found that one third of those women
had aCL; none had LAC [62].
Pregnancy-Related Maternal Thromboembolic Disease
Pregnancy and the puerperium are risk factors for thrombosis, independent of the
presence of thrombophilia. Women with APS are at greater risk for pregnancy-
related thrombosis than the general population with an incidence of 5–12 % [59, 60].
Women without LAC or with low levels of aCL are at lower risk for thrombosis [63].
Early and Severe Preeclampsia/Eclampsia
Severe preeclampsia at or before 34 weeks of gestation is one of the clinical criteria

used to define APS. The incidence of preeclampsia in APS patients ranges from 18
to 48 %, and studies of patients with preeclampsia show significant levels of aPL in
11.7–17 % of subjects [48].
In a meta-analysis, do Prado et al. found an association between aCL and pre-
eclampsia (pooled OR 2.86, 95 % CI 1.37–5.98); this association was strengthened
by selecting for subjects with severe preeclampsia (pooled OR 11.15, 95 % CI 2.

66–4.75) [64]. A systematic review demonstrated a similar relationship between
both mild and severe preeclampsia and aCL, with an odds ratio of 2.73 (95 % CI
1.65–4.51) [49].
In a study of 860 pregnant women, severe preeclampsia (defined by published
guidelines [65]) occurred more frequently in aCL-positive women (RR 22.2, 95 %
CI 5.27–93.5). A more recent study of 56 women with severe preeclampsia (defined
as diastolic blood pressure greater than 110 mmHg and proteinuria >3 g per 24-h
collection period) found positive aPL in 19.6 % of subjects, with a higher rate in
women with onset of preeclampsia before 34 weeks of gestation [66].
Despite its inclusion in the APS diagnostic criteria, some authors have suggested
a weaker association between preeclampsia and APS, with particular skepticism
about its association with mild or term preeclampsia [67–69].
HELLP Syndrome
A number of reports describe HELLP syndrome in pregnant APS patients [70–73].

Nausea, vomiting, and abdominal pain may be early signs of impending danger, and
infarcts of the liver, spleen, kidneys, and other organs of tissues may occur. This
syndrome can be considered on the severe end of the preeclampsia spectrum, is
likely associated with CAPS, and may also occur following delivery [74].
Non-obstetric Manifestations of APS
Vascular Thrombosis
Vascular thrombotic events are defined as one or more clinical episodes of arterial,
venous, or small vessel thrombosis, in any tissue or organ [43]. Venous thrombosis
occurs more commonly than arterial thrombosis. DVT of the calf is most common,
but other sites include veins of the upper extremities and vena cava; renal, hepatic,
retinal veins; and cerebral sinus thrombosis. Arterial thrombosis of the cerebral,
coronary, renal, and mesenteric arteries can result in stroke, myocardial infarction,
and infarcts of the kidneys and gut, respectively. Microvascular thrombosis of the
kidney, also known as thrombotic microangiopathy, may occur and causes a spec-
trum of disease including asymptomatic proteinuria, marked hypertension, end-
stage renal disease, and renal failure.
Thrombosis must be confirmed by objective validated criteria, i.e., unequivocal
findings of appropriate imaging studies or histopathology. For histopathologic con-
firmation, thrombosis should be present without significant evidence of inflamma-
tion in the vessel wall (which would suggest vasculitis). In making the diagnosis of
APS, superficial venous thrombosis does not qualify as a thrombotic event.
Catastrophic Antiphospholipid Syndrome
CAPS is a rare event occurring in fewer than 1 % of APS patients [31]. This
syndrome results in widespread thrombotic disease and multiorgan failure. Criteria
include (1) evidence of involvement of three or more organs, systems, and/or
tissues; (2) development of manifestations simultaneously or in less than a week;
(3) confirmation by histopathology of small vessel occlusion in at least one organ or
tissue; and (4) laboratory confirmation of the presence of aPL [75]. CAPS has a high
mortality rate of approximately 50 %, even when patients are treated with antico-
agulation and aggressive immunosuppression [76].
Non-criteria Manifestations
APS can cause a wide variety of clinical manifestations that are not included in the
classification criteria [77]. These include thrombocytopenia, hemolytic anemia,
livedo reticularis, cardiac valve disease and intracardiac thrombi, non-stroke central
nervous system disease (cognitive dysfunction, hyperintense non-enhancing white
matter lesions on brain MRI), and a renal lesion known as thrombotic microangi-
opathy. Rarely, these manifestations can occur in pregnancy.
Laboratory Considerations
Antiphospholipid antibodies are immunoglobulins directed against phospholipid-

binding plasma proteins. LAC, anticardiolipin, and anti-β2-glycoprotein-I antibod-
ies are known to play a role in thrombotic and pregnancy events. Formal definitions
for these tests exist [44, 45].
Lupus Anticoagulant
Of note, the name “lupus anticoagulant” is misleading. While LAC is frequently

seen (and was first identified) in lupus patients, many patients with LAC do not
actually carry a diagnosis of lupus. In addition, LAC-positive patients are, in fact,
more likely to develop thromboses in spite of the name “anticoagulant,” a term
derived from its in vitro but not in vivo function.
LAC is a heterogeneous population of immunoglobulins (IgG, IgM, and IgA)
that interferes with one or more phospholipid-dependent tests of in vitro coagulation,
including the activated partial thromboplastin time (aPTT), kaolin clotting time
(KCT), dilute Russell viper venom time (DRVVT), and dilute prothrombin time
(dPT). Two or more of these tests should be used to screen for LAC, followed by
a mixing study to confirm the presence of an inhibitor in the patient’s plasma
(as opposed to a factor deficiency). Finally, confirmatory testing is performed by

increasing the concentration of the phospholipid in the screening test (or tests) that
was abnormal.
The results of the LAC are unreliable in patients being treated with anticoagu-
lants due to the risk of false-positive results [78–80], although some believe LAC
activity can be accurately detected in patients taking warfarin if the international
normalized ratio (INR) is less than 3.5 [43].
Anticardiolipin and Anti-β2-Glycoprotein-I Antibodies
Anticardiolipin antibodies (aCL) and anti-β2-glycoprotein-I (aβ2GPI) antibodies of

the IgG, IgM, and IgA isotypes are detected using either the solid phase immunoas-
say or enzyme-linked immunosorbent assay (ELISA). The main antigenic target of
these antibodies is β2-glycoprotein-I (β2GPI), a cationic plasma protein that binds
phospholipid cell membranes. Antibodies should be present in moderate to high
titer (≥40 units or >99 % for all isotypes) to be considered “positive” [43].
Other Antibodies
Other antiphospholipid antibodies, including those directed against prothrombin,

annexin A5, phosphatidylserine, and phosphatidylinositol, have been described as
playing a role in the pathogenesis of APS. However, these tests have not been stan-
dardized against clinical populations or by international criteria committees and
their clinical and prognostic significance is not clearly understood [81].
Type of aPL and Risk
Certain subtypes of aPL seem to impose a greater risk of pregnancy complications

than others. It was long believed that “triple positivity,” i.e. the simultaneous pres-
ence of LAC, aCL, and aβ2GPI in the same woman, conferred the worst prognosis
[82, 83], and it has been suggested that aCL is the most sensitive assay to predict
fetal distress or death [84]. More recent reports contend that LAC alone portends the
greatest risk, independent of the presence of aCL or aβ2GPI [58].
The PROMISSE study (Predictors of PRegnancy Outcome: BioMarkers In
Antiphospholipid Syndrome and Systemic Lupus Erythematosus) is a large, multi-
center observational study on pregnancies of patients with APS, SLE, or both, com-
pared to healthy controls. Pregnancy outcomes of 144 aPL-positive patients have
been described [58]. Adverse outcomes, defined as fetal death at ≥12 weeks,
neonatal death, preterm delivery before 34 weeks due to gestational hypertension,

preeclampsia, or placental insufficiency, or fetal size <5th percentile, occurred in 28
women. Of LAC-positive women, 39 % had adverse pregnancy outcomes, com-
pared with only 3 % of LAC-negative women. Of women with moderate to high
titer IgG aCL, 43 % who were also LAC positive had adverse outcomes, whereas
complications occurred in only 8 % of women without LAC. IgM aCL, IgG aβ2GPI,
and IgM aβ2GPI did not independently predict adverse pregnancy outcome [58]
(Table 6.2).
A 2006 meta-analysis supports the role of LAC as the strongest predictor of poor
pregnancy outcome, showing LAC to be more strongly associated with recurrent
fetal loss before the 24th week of gestation than other aPL (OR, 7.79; 95 % CI,
2.30–26.45); aCL IgG at moderate to high titer (OR 4.68, 95 % CI 2.96–7.40) con-
ferred a lesser risk and there was no association with aβ2GPI [56]. Thus, the magni-
tude of the association between aPL and adverse pregnancy outcome varies
according to type of aPL; LAC is the best predictor of adverse outcome, low titer
aCL and aβ2GPI are seemingly unimportant, and the importance of high titer aCL
and aβ2GPI in the absence of LAC remains controversial.
Treatment Options
The mainstays of therapy in obstetric APS are low-dose aspirin (LDA) and heparin;
intravenous immunoglobulin (IVIG) and plasma exchange have been used with suc-
cess in refractory cases. Comparing treatment trials in the literature is challenging
due to variations in study design, patient selection, thresholds for positive aPL titers,
and treatment regimens.
Aspirin
LDA is recommended for subsequent pregnancies in APS patients with a history of

recurrent pregnancy loss [85]. In addition to its antiplatelet effects, aspirin modu-
lates the balance of prostacyclin, thromboxane, and IL-3 production which is criti-
cal to embryo implantation and placental development [86].
Aspirin is nearly universally used in the treatment of APS pregnancy. In an
observational study, the rate of adverse pregnancy outcome was lower among
patients who were regularly receiving aspirin at the time of the first study visit [58].
However, a randomized, placebo-controlled trial of LDA versus placebo in APS
patients with recurrent miscarriage failed to show a benefit in the LDA-treated
group [88]. This result is difficult to interpret as live birth rates in the placebo group
exceeded those in published studies.
Table 6.2 Adverse pregnancy outcome in aPL-positive patients, according to demographic,
clinical, and serologic characteristics at the first study visit (adapted from Lockshin et al. [58])
All patients with Patients with aPL and adverse
Characteristic aPL (n = 144)a pregnancy outcome (n = 28 [19 %])b P
Demographic
Race 0.11
White 117 26 (22)
Nonwhite 27 2 (7)
Age 0.05
<30 years 48 14 (29)
≥30 years 96 14 (15)
Clinical
SLE 0.52
Absent 87 15 (17)
Present 57 13 (23)
Prior thrombosis 0.00005
No 119 15 (13)
Yes 25 13 (52)
Serologic
LACc <0.0001
Negative 76 2(3)
Positive 64 25 (39)
IgG aCL 0.01d
<40 units/mL 77 9 (12) <0.0001e
With LAC 26 9 (35)
Without LAC 50 0 (0)
≥40 units/mL 66 19 (29) 0.002e
With LAC 37 16 (43)
IgM aCL 1.00d
<40 units/mL 120 24 (20) <0.0001e
With LAC 51 21 (41)
≥40 units/mL 23 4 (17) 0.10e
With LAC 12 4 (33)
IgG anti-β2GPI 0.09d
<40 units/mL 106 16 (15) <0.0001e
With LAC 36 13 (36)
≥40 units/mL 37 11 (30) 0.02e
With LAC 27 11 (41)
IgM anti-β2GPI 0.37d
<40 units/mL 121 21 (17) <0.0001e
With LAC 49 19 (39)
≥40 units/mL 22 6 (27) 0.35e
With LAC 14 5 (36)
aPL antiphospholipid antibody, SLE systemic lupus erythematosus, aCL anticardiolipin antibody,
anti-β2GPI anti-β2glycoprotein I
a
Values are the number of patients. For some tests, data were not available on all patients
b
Values are the number (%) of patients
c
Data missing for one patient
d
<40 units/mL versus ≥40 units/mL
e
With lupus anticoagulant (LAC) versus without LAC
Heparin
Heparin is thought to prevent adverse pregnancy outcomes in APS patients via anti-
thrombotic effects, direct aPL binding, inhibition of complement activation, and
ability to block tissue factor-mediated placental bed immunopathology [88]. While
most studies find pregnancy outcomes following heparin and aspirin combination
therapy to be superior to aspirin alone in preventing recurrent pregnancy loss in
aPL-positive patients [63, 89–93], others have found no benefit of combination
therapy over aspirin alone [94, 95]. In fact, one observational study found a higher
rate of adverse pregnancy outcomes among those patients receiving heparin [58].
Studies of unfractionated heparin (UFH) versus low-molecular-weight heparin
(LMWH) suggest that both formulations are safe and effective for preventing recur-
rent pregnancy loss [96, 97]. LMWH offers practical advantages, including once-
daily dosing and lower risks of hemorrhage, drug-induced thrombocytopenia, and
osteoporosis.
Table 6.3 provides a summary of major treatment trials of LDA and heparin.
Hydroxychloroquine
Hydroxychloroquine (HCQ), having both anti-inflammatory and anti-thrombotic

effects, may be an adjunctive therapy in the prevention of adverse pregnancy out-
comes in aPL-positive women. This drug was used for prevention of DVT and PE
after hip surgery [98] and was shown to reduce the incidence of thrombotic events
in SLE patients [99–102].
Mechanistic studies have suggested that HCQ reverses the effects of aPL on
syncytiotrophoblasts by reducing immunoglobulin binding and restoring annexin
A5 expression [15]. HCQ is used routinely in pregnant SLE patients and is consid-
ered safe in both pregnancy and lactation [103].
Intravenous Immunoglobulin
IVIG has been used in APS patients with recurrent fetal loss who are refractory to
more traditional treatments. An early report using IVIG for this indication described
a patient with a history of nine abortions who, after receiving two courses of IVIG
during her next pregnancy, delivered a healthy child at 34 weeks’ gestation.
Two randomized controlled trials have compared heparin and aspirin therapy to
IVIG alone; patients treated with IVIG had fewer live births and a greater number
of first trimester abortions [104, 105]. Another trial comparing combination hepa-
rin, aspirin, and IVIG with heparin and aspirin alone failed to show a significant
difference in outcomes between the two groups, although it should be noted that all
6
Table 6.3 Prospective APS pregnancy treatment trials and pregnancy outcomes (adapted from Ernest et al. [7])
Laboratory Results (live
Reference Study design Size Clinical criteria criteria Major exclusions Treatment 1 Treatment 2 birthrate)
Kutteh [63] Randomized 50 ≥3 unexplained aCL IgG ≥ 27 LAC positive, LDA LDA LDA/UFH 20/25
consecutive GPL or aPS SLE, preconception preconception (80 %) vs LDA
pregnancy IgM ≥23 anticoagulation and UFH alone 11/25
losses MPL, positive for another 5000U sc (44 %)
twice, reason twice daily
≥6 week apart with positive
pregnancy test
Rai et al. Randomized 90 ≥3 unexplained LAC positive or SLE, prior LDA with positive LDA with LDA/UFH 32/45
[92] consecutive aCL IgG ≥ 5 thrombosis pregnancy test positive (71 %) vs LDA
pregnancy GPL or aCL and UFH pregnancy test 19/45 (42 %)
losses IgM ≥3 MPL, 5000U twice
positive twice, daily with
≥8 week apart positive fetal
heartbeat
Pattison Randomized, 50 ≥3 pregnancy LAC positive or SLE, prior LDA Placebo LDA 16/20 (80 %)
et al. [87] double losses aCL IgG ≥ 5 thrombosis, vs placebo
blind or aCL IgM concomitant 17/20 (85 %)
≥5 MPL, medications in
positive twice pregnancy
Farquharson Randomized 98 ≥3 unexplained LAC or aCL IgG SLE requiring LDA and LDA LDA/dalteparin
et al. [94] consecutive >9 GPL or medications or dalteparin 40/51 (78 %) vs
pregnancy ACL IgM >5 with nephritis, 5000 U daily LDA 34/47
losses MPL, positive prior (72 %)
≤10 weeks twice, thrombosis,
or ≥2 ≥6 week apart concomitant
consecutive medications in
fetal demise pregnancy,
>10 weeks other
thrombophilia
121
(continued)
Table 6.3 (continued)
122
Laboratory Results (live

Reference Study design Size Clinical criteria criteria Major exclusions Treatment 1 Treatment 2 birthrate)
Stephenson Randomized 28 ≥3 unexplained LAC positive or Inherited LDA LDA LDA/dalteparin
et al. [97] consecutive aCL IgG or thrombophilia, preconception preconception 9/13 (69 %) vs
pregnancy IgM ≥4.6 prior heparin and dalteparin and UFH LDA/UFH 4/13
losses MoM, positive use 2500–7500 U 5000–10,000 (31 %)
<10 weeks twice, starting in U twice daily
or ≥1 fetal ≥6 week apart luteal phase or starting in
demise 1st trimester lueteal phase
or 1st trimester
Noble et al. Multicenter 50 ≥3 unexplained LAC positive or No major Center 1: LDA Center 2: LDA LDA/enoxaparin
[96] pilot consecutive aCL IgG >20 exclusions preconception preconception 21/25 (84 %) vs
pregnancy GPL or aCL and and UFH LDA/UFH
losses IgM >20 MPL enoxaparin 40 5000–6000 U 20/25 (80 %)
<20 weeks or aPS ≥3.0 mg with twice daily
MoM, positive positive with positive
twice, pregnancy test pregnancy test
≥6 week apart
Laskin et al. Randomized 88 ≥2 unexplained LAC positive or SLE, prior LDA LDA LDA/dalteparin
[95] consecutive aCL IgG >15 thrombosis, preconception preconception 35/45 (78 %) vs
pregnancy GPL or aCL peptic ulcer and dalteparin LDA 34/43
losses IgM >25 MPL disease, low 5000 U daily (79 %)
<32 weeks or ANA >1:80 bone density with positive
or inherited pregnancy test
thrombophilia
aCL anticardiolipin, ANA antinuclear antibody, aPL antiphosopholipid, GPL G phospholipid, Ig immunoglobulin, LAC lupus anticoagulant, LDA low-dose aspirin,
MoM multiples of the mean, MPL M phospholipid, SLE systemic lupus erythematosus, U units, UFH unfractionated heparin
A.B. Levine and M.D. Lockshin
pregnancies resulted in live birth [106]. Reports of IVIG dosing range from 400 to
1000 mg/kg daily for one to five consecutive days each month; some studies began
treatment after a positive pregnancy test, while others began at 13 weeks of gesta-
tion [106–108]. While IVIG is not indicated as a primary treatment strategy for
prevention of recurrent fetal loss in obstetric APS, it may serve as an adjunctive
therapy for refractory cases.
Plasma Exchange
Plasma exchange has been described in case reports and case series of obstetric APS
patients who failed treatment with heparin and aspirin combination therapy. Plasma
exchange reduces aPL titers following treatment [109, 110]. Regimens ranged from
one to four times weekly and success rates were generally high [109–113].
Additional studies of plasma exchange for the treatment of refractory APS
pregnancies are warranted.
Glucocorticoids
There is no evidence to support the use of glucocorticoids in the preventative treat-

ment strategies for obstetric APS. These drugs increase the risk of pregnancy com-
plications, including premature rupture of membranes, preterm delivery, IUGR,
infection, preeclampsia, and gestational diabetes, as well as maternal osteopenia
and avascular necrosis. Treatment with steroids is, therefore, not warranted in preg-
nant APS patients in the absence of other indications [114–118].
Manifestation-Specific Recommendations
Treatment for Patients with Recurrent Pregnancy Loss
Studies of recurrent pregnancy loss have generally not distinguished between

embryonic loss and fetal demise, instead combining patients into one heterogeneous
group. Recommendations include LDA and prophylactic doses of heparin.
Several randomized controlled trials have compared treatment with heparin and
LDA to LDA alone; while two of these studies demonstrated better outcomes in
patients receiving heparin, the third showed no additional benefit from this treat-
ment. In 1996, Kutteh described a single-center trial of 50 persistently aPL-positive
women, each with at least three consecutive spontaneous pregnancy losses, and
found significantly improved outcomes in the UFH with LDA group as compared to
the LDA alone group; live birth rates were 80 and 44 %, respectively [63]. Rai et al.
published a trial of 90 aPL-positive recurrent pregnancy loss patients randomized to

similar treatment arms; results were comparable, with live birth rates of 71 % in the
heparin plus LDA group and 42 % in those treated with LDA alone [92]. Finally,
Farquharson et al. randomized 98 persistently aPL-positive women to receive
LMWH and LDA or LDA alone; this study failed to show a difference in outcomes
between the two groups, although it should be noted that success rates in both
groups were high (72–78 % live birth rate, respectively) [94].
The effect of heparin plus aspirin therapy on pregnancy outcome was further
examined in a systematic review and meta-analyses by Ziakas et al. These authors
pooled data from five randomized controlled trials and found an overall benefit to
heparin therapy in decreasing the risk of first trimester losses (OR 0.39, 95 % CI
0.24–0.65, number needed to treat 6) [93]. On further analysis, the effect of UFH
was significant, while the effect of LMWH was not. Regarding fetal demise, no
formulation of heparin therapy combined with aspirin provided benefit [93].
Treatment of Patients with a History of Thrombosis
Recommendations dictate continued therapeutic anticoagulation throughout preg-

nancy and during the postpartum period for APS patients with a history of thrombosis
[119, 120]. Patients treated with long-term warfarin should be transitioned to thera-
peutic doses of LMWH upon confirmation of a positive pregnancy test, if not before,
as warfarin interferes with organogenesis between weeks 6 and 12 of gestation [121].
While many groups continue LMWH throughout pregnancy, others use warfarin
during mid- to late-pregnancy, transitioning from LMWH to warfarin at 14 weeks of
gestation, then back to heparin at 36 weeks or 2 weeks prior to a scheduled delivery.
The INR must be monitored closely, usually maintaining a range of 2–3 [122].
Treatment of Patients with a History of Early,

Severe Preeclampsia
Rigorous treatment trials for the prevention of preeclampsia in APS patients have
not been performed. Treatment with aspirin and heparin should be considered in
women with a history of this complication [123]. The treatment for preeclampsia,
once it occurs, is delivery.
Treatment of Patients with Asymptomatic aPL
Little data exists to direct the treatment of aPL-positive patients who have not
had thrombotic or pregnancy-related events. Greater than 50 % of such women will
go on to have uncomplicated pregnancies without additional treatment [26].
Table 6.4 Treatment recommendations for aPL/APS pregnancy based on clinical scenarios
APS patients with prior thrombosis LDA and LMWH, therapeutic dose
(e.g., enoxaparin 1 mg/kg subcutaneously,
twice daily)
APS patients with ≥3 consecutive embroyonic LDA and LMWH, prophylactic dose
losses, fetal demise, or early, severe (e.g., 0.5–1 mg/kg once daily)
preeclampsia
aPL-positive patients without prior thrombosis or LDA or Close monitoring and observation
adverse pregnancy event (asymptomatic
aPL-positive patients)
APS patients with recurrent pregnancy loss despite Consider adding IVIG, plasma exchange,
the use of LDA and LMWH and/or hydroxychloroquine
aPL antiphosphilipid antibody-positive, APS antiphospholipid syndrome, IVIG intravenous
immunoglobulin, LDA low-dose aspirin, LMWH low-molecular-weight heparin
Treatment possibilities include close monitoring and observation alone, LDA alone
or LDA with heparin prophylaxis; HCQ could also be considered.
Treatment recommendations are summarized in Table 6.4.
General Care and Monitoring of APS Pregnancy
Pregnancy in APS patients is considered high risk and should be managed by a team
of maternal fetal medicine specialists and a rheumatologist or hematologist with
experience in APS pregnancy. Women with APS who receive proper antenatal care
have a 75 % chance of live birth, as opposed to a 15 % chance if untreated [122].
Evaluating for the Presence of aPL
Recommendations for screening vary amongst medical societies. The American

College of Obstetricians and Gynecologists (ACOG) recommends testing in:
(1) women with a history of unexplained arterial or venous thromboembolism, or a new
arterial or venous thrombotic event during pregnancy and (2) women with a history
of one fetal loss or three or more recurrent embryonic or fetal losses [120]. The
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
recommends evaluating for aPL in women with a history of recurrent early preg-
nancy loss defined as at least three miscarriages before 10 weeks of gestation [119].
Expert groups agree that the presence of aPL should be confirmed on two sepa-
rate occasions at least 12 weeks apart. Of note, due to insufficient evidence that
screening and treating women with a history of early, severe preeclampsia and early
onset placental insufficiency leads to improved outcomes, the societies do not sup-
port testing for aPL in this population. Testing without indication should be avoided
due to the potential for uninterpretable results and ensuing treatment dilemmas.
Women with a history of SLE, persistently elevated aPTT, and/or a biological

false-positive syphilis test should also be considered for aPL screening in the setting
of pregnancy planning.
Preconception Counseling
Care begins with a preconception counseling visit in which an individualized plan

of care is set forth for each patient. Patients should be informed of the risks of APS
pregnancy, including fetal loss, IUGR, prematurity, maternal thrombosis, hyperten-
sion, and preeclampsia. Particular attention should be given to patients with signifi-
cant pulmonary hypertension or recent thrombotic events, including stroke, as the
risk of maternal complications and death are significant in these groups; alternative
methods of expanding a family, such as surrogacy or adoption, may be considered
in these situations.
Baseline renal function, liver function, complete blood counts, and quantity of
urine protein should be measured. Previously measured aPL profiles should be
reviewed and repeated prior to pregnancy; there is no need to repeat profiles
throughout pregnancy as a subsequent negative result does not reduce the risk of
complications.
Efforts should be taken to minimize or eliminate modifiable thrombotic risk fac-
tors, such as smoking, thereby affording the best possible outcome for both mother
and fetus. Prenatal vitamins should be prescribed prior to conception if possible
and, due to the risk of osteoporosis associated with heparin therapy, those patients
who will be treated with heparin throughout pregnancy should begin calcium sup-
plementation and have vitamin D levels repleted. Patients not yet taking LDA may
initiate treatment at this point, although no strong data exists to support this.
Physicians should ask to be notified immediately upon confirmation of a positive
pregnancy test.
Pregnancy Monitoring and General Care
Upon confirmation of an intrauterine pregnancy by ultrasound, patients with a his-

tory of recurrent pregnancy loss should initiate LMWH and LDA, if not already
begun. Due to its theoretical role in aiding implantation, an argument may be made
for initiating LMWH prior to conception; however, this may result in prolonged,
unnecessary exposure to the drug while trying to conceive with possible side effects
including osteoporosis and increased bleeding risk. Therefore, we suggest delaying
administration until intrauterine pregnancy is confirmed.
Initially, patients should be seen monthly to monitor for maternal and fetal well-
being. Blood pressure and urinary protein should be measured at each visit.
Patients should be educated about the signs and symptoms of venous

thromboembolism and preeclampsia, including headache, blurred vision, abdominal
pain, and elevated blood pressure, and should be advised to seek medical attention
immediately if these symptoms occur. They should also be taught to assess for fetal
movement as decreases in fetal movement may signify fetal distress [124]. The use
of home blood pressure monitoring should be considered on a case-by-case basis.
Most experts recommend serial ultrasonographic assessment with or without
umbilical artery Doppler velocimetry measurement to assess fetal growth and amni-
otic fluid volume beginning as early as 18 weeks of gestation. Abnormalities in
end-diastolic umbilical artery Doppler flow in the second trimester of patients with
APS and/or SLE have been associated with fetal and neonatal death [125]. Adverse
pregnancy outcomes were also seen in association with notched uterine arteries in
the second trimester; normal examinations are reassuring [125]. Such monitoring
may indicate that early delivery is necessary and allow physicians to act promptly
when fetal well-being is at risk.
Should pregnancy loss occur, obtaining the abortus to rule out loss due to chro-
mosomal abnormality may be useful.
Labor and Delivery
Scheduled delivery is preferred to spontaneous delivery in patients being treated

with anticoagulation. Heparin should be held 12 h before invasive procedures, such
as epidural anesthesia and cesarean delivery, and may be restarted 12 h after com-
pletion of the procedure. Anticoagulation should be resumed as soon as possible
following delivery.
Due to a slightly increased risk of perioperative bleeding, aspirin may be held
7–10 days prior to delivery; however, some authors recommend continuing aspirin
therapy in those patients with a history of arterial thrombotic events, including myo-
cardial infarction and stroke.
Postpartum Considerations
There are no well-defined guidelines for the postpartum care of obstetric APS
patients. Areas of interest include postpartum thromboprophylaxis, lactation, and
contraception.
Postpartum Thromboprophylaxis
Optimal postpartum management of obstetric APS patients has not been defined.
This is an area of great controversy and importance given the increased risk of
thrombotic events in the postpartum period. Conservative measures in the
prevention of thrombosis include early ambulation following vaginal delivery and

the use of pneumatic compression stockings following cesarean delivery.
APS patients with a history of thrombosis should resume therapeutic anticoagula-
tion as soon as possible following delivery; these individuals should be advised to
maintain lifelong anticoagulation, usually with warfarin [119]. Postpartum thrombo-
prophylaxis was discussed in great detail by the Obstetric APS Task Force of the 13th
International Congress on Antiphospholipid Antibodies in 2010 [126]. Experts rec-
ommended using a prophylactic regimen based on the treatment used throughout
pregnancy. For those women treated with LDA alone, most experts agreed that LDA
should be continued for a minimum of 6–8 weeks postpartum, although others would
continue LDA for life. For those women treated with UFH or LMWH during preg-
nancy, recommendations for the duration and choice of prophylactic treatment varied;
while one expert recommended no thromboprophylaxis, other suggestions included
warfarin, short-term heparin use (less than 1 week), and 6–8 weeks of heparin [126].
The American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines recommends 6 weeks of prophylactic- or intermediate-dose LMWH or
warfarin with a target INR of two to three for women with a history of prior VTE
[127]. Data to support guidelines for postpartum thromboprophylaxis is lacking.
Breastfeeding
Aspirin, heparin, and warfarin are safe for use in lactating women [128]. HCQ, a
treatment commonly continued throughout pregnancy in lupus patients, is also
safe to use while breastfeeding [128]. Calcium and vitamin D supplementation, as
well as prenatal vitamins, should be continued during lactation, particularly in
women receiving heparin thromboprophylaxis. (Refer to Chap. 14 for more
information.)
Contraception
Progesterone-containing contraceptive options, as well as barrier methods and

intrauterine devices, are available to aPL-positive women. Estrogen-containing
therapies are contraindicated in these patients [129]. (Refer to Chap. 11 for more
information.)
Neonatal APS
Thrombotic events in babies born to aPL-positive mothers have been rarely

described. Immunoglobulins of the IgG isotype can cross from mother to fetus
through the placenta and typically clear from the infant by 6–12 months of age [130].
It is uncertain if this passively acquired antibody has the same pathologic significance
as endogenously produced antibody.
Neonatal thrombosis in the presence of maternal aPL is exceedingly rare. Several
studies of neonatal outcomes of babies born to aPL-positive mothers have failed to
identify any cases of neonatal APS [130–134]. However, a 2007 review summarized
16 cases of perinatal thrombosis occurring in the presence of aPL [135]. Seven
infants were born to mothers with APS while eight were born to mothers without
APS but with aPL who were otherwise asymptomatic. Twelve of the 16 infants met
criteria for thrombotic APS, while four infants did not themselves have aPL (which
was present in the mother). Nearly all of these infants had additional risk factors for
vascular thrombosis, including vascular catheters, infections, and asphyxia, so
causality related to aPL could not be established.
APS and Infertility
The role of aPL in infertility is controversial. Proposed mechanisms for this associa-
tion include the interference of aPL with implantation, placentation, and early
embryonic development. At present, there is no evidence to support routine screen-
ing for aPL in patients with primary infertility [136]. Hatasaka et al. found no dif-
ference in the prevalence of aPL in women with unexplained infertility compared to
fertile controls [137]. There is also no clear association between aPL positivity and
implantation failure, clinical pregnancy, or live birth rates in women undergoing
in vitro fertilization (IVF) and embryo transfer [52, 136, 138–142].
Ovulation induction, in which estrogen levels are artificially elevated, has been
postulated to be particularly dangerous in aPL-positive patients who are already at
increased risk for thrombosis. The literature on this topic is scarce. However, one
retrospective cohort study of ten APS patients who underwent 47 cycles of ovula-
tion induction did not develop thrombosis during treatment; all patients were treated
with prophylactic LDA with or without heparin [143]. Another retrospective study
of eight women with SLE and/or APS undergoing 69 cycles resulted in two cases of
thrombophlebitis only [144]. The lack of evidence for increased thrombotic risk
may be related to the relatively short duration of elevated estrogens and/or the nature
of estrogens involved [145].
IVF in aPL-positive patients likely poses a greater risk of thrombosis than does
ovulation induction; the risk of thromboembolism is increased tenfold with IVF
compared to ovulation induction alone [124]. Ovarian hyperstimulation syndrome,
a feared complication of ovarian stimulation presenting with bilateral ovarian
enlargement, abdominal pain, ascites, and electrolyte imbalance, may be another
risk factor for thrombosis. In a systematic review of thromboembolic complications
related to assistive reproductive technologies, 79 % of thrombotic events were asso-
ciated with ovarian hyperstimulation syndrome [146]. Ovulation induction and IVF
in patients with APS are discussed in further detail in Chap. 12.
Long-term Risk of Thrombosis
Patients with obstetric APS may be at increased risk for lifetime thrombotic events.
Gris et al. followed 1,592 obstetric APS patients over 9 years and found a signifi-
cantly increased risk of DVT (adjusted HR 1.85, 95 % CI 1.50–2.28; annualized rate
1.46 %) and stroke (adjusted HR 2.10, 95 % CI 1.08–4.08; annualized rate 0.17 %)
compared to women without known thrombophilia [147]. Another study following
215 obstetric APS patients also found a significantly higher 12-year cumulative
thrombotic incidence rate compared to a control group [148].
Summary and Recommendations
Obstetric APS causes significant maternal and fetal morbidity, including recurrent
early miscarriage, fetal demise, IUGR, early, severe preeclampsia, and maternal
thromboembolic disease. LAC is the strongest predictor of poor obstetric outcomes.
Specialists with experience with APS pregnancy are essential to maternal and fetal
outcomes. Treatment trials are limited, but live birth rates exceed 70 % with heparin
and aspirin treatment. Though great advances have been made in recent decades,
ongoing research is needed to guide treatment recommendations.
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Chapter 7
Rheumatoid Arthritis and Seronegative
Spondyloarthropathy
Monika Østensen and Marianne Wallenius
Introduction
Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disorder of

unknown etiology occurring in about 0.5–1 % of the population worldwide. Women
are three times more often affected than men with a peak onset of RA between 35
and 55 years of age. The disease is characterized by symmetrical polyarthritis par-
ticularly in small and medium size joints, and extra-articular manifestations includ-
ing serositis, vasculitis, and subcutaneous nodules. The presence of autoimmune
features with the production of rheumatoid factor (RF) and cyclic citrullinated pep-
tide antibodies (ACPA) is a hallmark of RA. Susceptibility of RA is associated with
certain subtypes of HLA-DR4 (DR1 and DR14) [1].
The spondyloarthropathies (SpA) comprise a group of chronic inflammatory
arthropathies affecting joints, entheses, and certain extra-articular sites. Typical
sites of joint inflammation are the spine, the sacroiliac joints, and peripheral, mostly
large joints. SpA are characterized by absence of serum autoantibodies, and associ-
ated with HLA B27 [2, 3]. Disorders encountered among the SpA are reactive
arthritis (ReA), psoriatic arthritis (PsA), arthritis associated with inflammatory
bowel disease (IBD), juvenile spondyloarthritis and ankylosing spondylitis (AS),
the prototype of SpA. The prevalence of SpA varies in different ethnic populations
M. Østensen, M.D. (*)

Department of Rheumatology, National Service for Pregnancy and Rheumatic Disease,
University Hospital of Trondheim, Bevegelsessenteret, Olav Kyrres gt 13,
7006 Trondheim, Norway
e-mail: monika.ostensen@gmail.com
M. Wallenius, M.D., Ph.D.
Department of Rheumatology, National Service for Pregnancy and Rheumatic Disease,
University Hospital of Trondheim, Bevegelsessenteret, Olav Kyrres gt 13,
7006 Trondheim, Norway
Institute of Neuroscience, Norwegian University of Science and Technology,
Trondheim, Norway
140 M. Østensen and M. Wallenius
Table 7.1 Characteristics of rheumatoid arthritis and spondyloarthropathies

Organ
Disease manifestations Autoantibodies Therapy
Rheumatoid arthritis Serositis, sicca Rheumatoid factor Antimalarials, sulfasalazine,
syndrome, in 85 % of methotrexate, leflunomide,
interstitial lung patients, ACPA prednisone, intraarticular
disease (rare), in 60–70 %. corticosteroids, TNF
vasculitis Antiphospholipid inhibitors, abatacept,
(rare) antibodies and tocilizumab, rituximab,
anti-Ro/La can nonsteroidal anti-
occur in RA inflammatory drugs
(NSAIDs)
Spondylarthropathies
Ankylosing spondylitis Anterior uveitis None NSAIDs
Sulfasalazine, methotrexate,
intraarticular
corticosteroids, TNF
inhibitors
Psoriatic arthritis (PsA), Skin psoriasis None Sulfasalazine, methotrexate,
different subtypes of leflunomide, cyclosporine,
PsA exist associated intraarticular
with oligoarticular corticosteroids, TNF
or polyarticular inhibitors, abatacept,
joint involvement or ustekinumab, NSAIDs
spinal disease
Arthritis associated Ulcerative colitis, None Sulfasalazine, azathioprine,
with IBD Crohn’s prednisone, intraarticular
disease corticosteroids,
methotrexate, TNF
inhibitors
between 0.5 and 4 % and is related to the frequency of HLA B27 in the population.
The male:female ratio is 3:1 and the peak incidence is around age 26 years.
RA and SpA share the characteristics of chronicity, joint inflammation, and dam-
age in conjunction with symptomatic pain, stiffness, and reduced functionality.
However, the site of joint inflammation differs between these disorders as well as the
extent of systemic features [4]. The majority of patients with RA have autoantibodies
like RF and ACPA, whereas SpA do not. In both RA and SpA few internal organs are
involved which is one reason for the prevailing good fetal outcomes in these diseases
(Table 7.1). Because of the relative age of onset of disease in these disorders, women
with RA are more likely to have several pregnancies before disease onset whereas
women with AS are more likely to become pregnant during the course of their dis-
ease because of their younger age at disease onset. Therapy for the symptoms of joint
inflammation overlaps in RA and SpA whereas immunosuppressive therapy directed
at the underlying disease pathogenesis of these two disorders differs.
In this chapter, issues of reproduction are presented for patients with RA and
SpA. The effect of pregnancy on the activity of the disease during and after preg-
nancy has been studied in detail only for RA and AS; therefore, only data for these
two diseases are presented.
7 Rheumatoid Arthritis and Seronegative Spondyloarthropathy 141
Fertility in RA, SpA, and Other Inflammatory Arthritides
Rheumatic diseases can impair fertility (the actual production of children) and, more
often, fecundity (time to achieve pregnancy) in several ways as indicated in Fig. 7.1.
Conflicting results on fertility relate most often to study design, number and type of
patients included, and presence of a control group. A Norwegian population-based
study compared fertility in patients with inflammatory rheumatic diseases compris-
ing 338 patients with RA, 75 with juvenile idiopathic arthritis (JIA), and 218 patients
with other chronic arthritides (OCA) including PsA, AS, and unspecified arthritis
(UA) with age-matched women without rheumatic disease. Significantly more
patients than controls (32.6 versus 26.4 %) were nulliparous at entry in the study [5].
When patients childless at the time of diagnosis were compared with childless refer-
ences of corresponding age at the time of diagnosis, a higher proportion of patients
were childless at the end of the fertile period compared with references [6]. The
study was not able to examine reasons for childlessness. The probability of continu-
ing to a second pregnancy among women with one child was lower in arthritic
patients than in references (Fig. 7.2). Among patients with a first birth at 30 years of
age only 40 % continued to a second pregnancy versus 60 % among references [6].
In the Norwegian study [5] the mean number of children in patients was associ-
ated with age at the time of diagnosis (Fig. 7.3) as also observed by Katz [7]. Women
diagnosed after 30 years of age had a mean number of children comparable to the
Fig. 7.1 Factors contributing to reduced family size in women with rheumatoid arthritis and
spondyloarthropathy
Fig. 7.2 Mean number of children in all patients with chronic inflammatory arthritides (CIA) by
age at diagnosis. Red line = normal fertility rate. Lowess fit = regression line. Scatterplot = mean
number of children, size weighted for the number of patients diagnosed per year. Adapted from
Wallenius et al., Rheumatology (Oxford) 2011;50:1162–67
Fig. 7.3 Probability of a second child by the mother’s age at first delivery. Total number of fer-
tile patients (RA, OCA, and JIA) versus references. RA rheumatoid arthritis, OCA other chronic
arthritides, JIA juvenile idiopathic arthritis. Adapted from Wallenius et al., Scand J Rheum
2012;41:202–7
Table 7.2 Relative fertility rates (RFR) in patients from the NOR-DMARD registry versus
references, before and after diagnosis
Group Diagnosis RFR 95 % CI p-value
After diagnosis RA Crude 0.88 0.83, 0.93 <0.001
Adjusteda 0.88 0.84, 0.93 <0.001
OCA Crude 0.84 0.78, 0.90 <0.001
Adjusteda 0.84 0.78, 0.90 <0.001
JIA 0.84 0.77, 0.92 <0.001
Before diagnosis RA 0.99 0.96, 1.03 0.89
OCA 0.99 0.95, 1.04 0.78
Adapted from Wallenius et al., Rheumatology (Oxford) 2011;50:1162–67
RA rheumatoid arthritis, OCA other chronic arthritides JIA juvenile idiopathic arthritis
a
Adjusted for birth order
reference group, most probably because many women diagnosed in the fourth
decade of life have completed their family before disease onset [5]. The study did
not show any differences in relative fertility rates in RA and OCA patients com-
pared with references before disease onset. In agreement with several previous stud-
ies [7–9] RA and OCA women had significantly lower relative fertility rates after
diagnosis (Table 7.2) which may be due to the more severe disease of the study
population who all were on treatment with disease-modifying antirheumatic drug
(DMARDs) [5]. In addition, women with active rheumatic disease may voluntarily
limit their family size due to concerns in regard to problems encountered by the
disease and in fear of prognosis [8]. Another contributing explanation for lower
fertility rates in rheumatic patients compared with references may be a high occur-
rence of cesarean section (CS) in deliveries of patients [10–14]. A population-based
study from the Medical Birth Registry of Norway (MBRN) has reported that women
with CS at first delivery will have fewer children than women who start with a
vaginal birth [15].
The Norwegian study [5] observed an increased inter pregnancy (IP) interval for
RA and OCA patients diagnosed between first and second birth, which indicates
that women diagnosed after a first birth may postpone a second pregnancy until the
disease is controlled (Table 7.3). No difference in IP-intervals was observed for
women with births after diagnosis. This contrasts a previous study where an
increased interval after diagnosis was reported [9], possibly indicating that improved
treatment during the last decade results in better disease control and opportunity to
continue to a second pregnancy. Patients with RA and OCA continuing to a second
pregnancy were statistically significantly older than references at the time of the
first delivery, because they needed to complete their families within a shorter time
period given fewer remaining years of potential fertility. This observation is in
accordance with a Norwegian population-based cohort study of patients with RA,
JIA, and AS [9], but in contrast to observations in a Canadian case–control study of
women with recent onset RA [16]. Different study populations and study designs
may explain the different results. The Canadian study examined women with new
onset RA (within 3 years) and had a small sample size.
Table 7.3 Inter pregnancy intervala in relation to time of diagnosis, crude* and adjusted for
maternal age at first delivery**
Age at first Age at first Median Median
delivery delivery interval interval
patients references patients references
Group Diagnosis (mean) (mean) p-value (years) (years) p-value
First birth before RA (n = 22) 25.3 25.3 0.90 3.5 2.3 0.004*
diagnosis, 0.003**
second birth OCA (n = 16) 25.3 25.3 0.91 4.6 2.1 0.001*
after diagnosis 0.002**
First and second RA (n = 36) 28.1 25.2 <0.001 2.6 2.2 0.33*
birth after 0.82**
diagnosis OCA (n = 17) 26.9 25.2 0.09 1.9 2.2 0.64*
0.74**
JIA (n = 17) 25.0 25.2 0.94 2.5 2.3 0.56*
0.39**
Adapted from Wallenius et al., Rheumatology (Oxford) 2011;50:1162–67
RA rheumatoid arthritis, OCA other chronic arthritides (psoriatic arthritis, ankylosing spondylitis
and unspecified arthritis combined), JIA juvenile idiopathic arthritis
a
Analysis on single births
Contraception in RA and SpA
Unplanned pregnancies in RA and SpA carry risks for mother and child; therefore,
family planning should be discussed with every patient of fertile age. RA and SpA
patients have no restrictions in regard to method of birth control (see also Chap. 11).
A population-based study showed equal frequency of use of oral contraceptives in
women with RA and AS compared to age-matched healthy women [17]. Estrogens
and gestagens have no particular influence on the signs and symptoms of AS, and
probably not on other SpA either. By contrast, use of combination oral contracep-
tives (COC) containing estrogen and gestagen mitigates the severity of RA, though
COC do not prevent the onset of RA [18]. A recent study showed that use of COC
shortly before symptom onset and during RA or inflammatory polyarthritis had a
beneficial effect on functional outcome [19]. As in healthy women, use of COC in
RA and SpA women requires absence of antiphospholipid (aPL) antibodies, absence
of thrombophilia or a recent thrombosis, and no use of nicotine. Advice on contra-
ception must be given to all patients who start with possible teratogenic drugs,
which for RA and SpA mainly is treatment with methotrexate (MTX) either as
monotherapy or as combination therapy (see Chap. 11). Safe birth control has also
been recommended for leflunomide though controlled, prospective studies in
humans have shown neither an increase in the rate of congenital malformations nor
a specific pattern of anomalies after first trimester exposure [20, 21]. Information on
necessary contraception must be repeated during follow-up of patients to ensure
adherence to birth control [22].
Rheumatoid Arthritis
Pregnancy Outcome in RA
Previous studies have not shown any increased risk of spontaneous abortions among
RA patients [12, 23–26]. However, only one of these studies is from after year 2000.
New and still unpublished population-based data in the period 2000–2009
(Wallenius, Abstract EULAR 13–2595) have shown an increased relative risk of
spontaneous abortion among patients with RA both in early pregnancy ≤ week 12
(OR 1.36) and from gestational week 13–22 (OR 1.42).
Women with rheumatic diseases in general have been found to have higher risks
for adverse outcomes like preeclampsia, preterm delivery, cesarean section (CS),
and small for gestational age (SGA) infants [10–13, 27, 28]. An increased rate of
preeclampsia in RA varying between 1.28 [13], 2.2 [11], and 2.9 [29] was found in
population-based studies, but patient populations were different, and neither phar-
macotherapy or disease activity or comorbidities were known.
A population-based study with a specific focus on first birth examined possible
associations between chronic inflammatory arthritides (CIA) and pregnancy out-
comes with separate analyses of first and subsequent births before and after diagno-
sis [14]. Linkage of data from the Norwegian disease-modifying antirheumatic drug
(NOR-DMARD) Registry and the MBRN enabled comparison of pregnancy out-
comes in CIA and non-CIA-women. Outcomes of first and subsequent births before
and after diagnosis were analyzed separately. In the study, 128 first births in previous
nulliparous patients and 151 subsequent births were analyzed and compared with
reference deliveries from the general population. Also 286 first and 262 subsequent
births before the women were diagnosed with CIA were analyzed. Excess risks were
related to first birth in women diagnosed with CIA. No increased risk for preeclamp-
sia was detected. A twofold higher risk of vaginal bleeding occurred in patients
compared with references in pregnancies related to first birth. Few reports exist on a
possible relationship between use of nonsteroidal anti-inflammatory drugs (NSAIDs)
and bleeding in pregnancy. Use of NSAIDs is easily underestimated because patients
may report only prescribed drugs and not over-the-counter purchases.
Several population-based studies from different geographic areas have found a
1.5–2.0 increased risk for CS in patients with RA [10–12, 29]. The Norwegian
study, including patients with RA and other inflammatory arthritides, has examined
both acute and elective CS separately [14]. In the study based on the NOR-DMARD
registry, acute CS was not observed more often in patients than references, but the
rate of elective CS was doubled among patients both in first and subsequent preg-
nancies after a diagnosis of CIA. Placental dysfunction, cephalopelvic dispropor-
tion, and combined causes constituted each one third of the indications. Furthermore,
obstetricians may primarily choose CS in women with rheumatic disease because
they anticipate problems during delivery.
Prospective studies including RA women with well-defined disease activity
found that pregnancy outcome was similar to healthy women in patients entering
pregnancy with low disease activity and limited drug therapy [30]. This was also
supported by prospective studies including small numbers of RA pregnancies stud-
ied in parallel with healthy pregnant women [31, 32].
The Newborn
Several studies have reported a 1.2–1.8 increased risks of preterm delivery in

patients with inflammatory arthritic disease and RA, without relating this to birth
order [12, 27, 28]. In the NOR-DMARD study the risks of preterm delivery and
SGA were higher for first born children in mothers with CIA compared with refer-
ences [14]. Multiple regression analysis with covariates for maternal age at delivery,
gestational age, and gender of child showed small, but statistically significantly
lower mean birth weight in first born children of women with rheumatic disease
compared to references. The difference was no longer statistically significant in later
pregnancies. Birth weight is related to not only placenta function [33, 34] but also
other factors, i.e. genetics and drug use. Two prospective studies comprising 285
RA pregnancies found birth weight within normal range, but lower than in healthy
women, and even lower in infants of RA mothers with high disease activity [30, 35].
The Dutch prospective study found prematurity associated with the use of predni-
sone. In RA pregnancies with well-controlled disease activity and with no or mini-
mal use of prednisone, no increase in prematurity or SGA infants was found [30].
Perinatal morbidity and mortality has been found slightly increased in arthritic
study populations in which the majority of patients had RA [14, 28]. Three of four
children reported in the Norwegian NOR-DMARD study with perinatal deaths were
first born children of mothers diagnosed with inflammatory arthritis including RA.
The perinatal mortality rate was three times higher in children of patients than in
references [14]. In a retrospective study of women with RA, excess of perinatal
deaths were reported in infants of mothers who subsequently developed RA after
delivery [25].
Few studies have examined the risk of major congenital malformations in off-
spring of women with RA [14, 27–29]. In a population-based study based on data
from the MBRN a higher proportion of congenital malformations was reported
among children of patients with arthritis (RA, AS, JIA, and UA combined) com-
pared with references in the period 1967–1998 [28]. No other study has reported a
higher risk of birth defects in children born by RA patients or women with CIA.
Effect of Pregnancy on Rheumatoid Arthritis
Since the 1940s it has been known that about 75 % (range 54–86 %) of RA patients
experience spontaneous improvement of symptoms and signs of RA during preg-
nancy [36]. In a prospective study of RA patients’ perception of their general health
as measured by the SF36 during the second and third trimester of pregnancy, RA
patients experienced an improvement in physical well-being and pain, resulting in
scores on the SF36 comparable to healthy controls [37]. Compared with nonpreg-
nant RA patients, pregnant RA patients experienced significantly less pain and had
improved physical function. The need for analgesics or NSAIDs decreased through-
out pregnancy. The postpartum deterioration of the disease at week 12 and 24 was
reflected by significantly worse scores for bodily pain and for impairment of physi-
cal function [37].
Two large prospective studies using validated instruments to measure disease
activity found reduced or low disease activity in at least 50 % of RA patients in spite
of reduced or no drug therapy during pregnancy [38, 39]. Administration of DMARD
decreased significantly, and use of NSAIDs was only 4 % compared to 32 % before
conception indicating that pregnancy indeed has a beneficial effect on RA [39].
Patients with low disease activity remained stable throughout pregnancy [39].
Patients with high disease activity at conception did not improve during pregnancy,
a finding also confirmed by another study [40]. Complete remission indicating
absence of arthritis and no need for therapy is limited to a small proportion of preg-
nant RA patients [38, 39]. In a prospective study of 118 patients, 75 %
of patients negative for RF and CCP antibodies improved compared to only 39 % of
those positive for RF and CCP antibodies suggesting that antibody negativity is
predictive of pregnancy-induced disease amelioration [41]. Another study showed
that long-term functional outcome measured by HAQ was worse in ACPA and RF
positive patients who had been pregnant compared to autoantibody negative RA
patients with pregnancies [42]. Barret et al. found that the disease response to one
pregnancy was predictive of the response in a subsequent pregnancy [38].
Maternal Disease Activity Postpartum
Previous studies stated that the majority of RA patients have recurrent disease
within 3–4 months after delivery. Prospective studies from the last two decades
found a lower relapse rate which partly could be due to altered management of RA
patients during and after pregnancy [39, 43]. Barrett et al [43] found a significant
increase in the number of affected joints in 62 % of patients within the first 6 months
after delivery. At the same time, drug therapy was increased. Deterioration of dis-
ease symptoms after delivery was also found in about 50 % of patients in the Dutch
prospective study [39]. The simultaneous increase in drug therapy could indicate
that the postpartum relapse rate was probably even higher. Another prospective
study showed that entering pregnancy with low disease activity was a relevant factor
for stable low disease activity during gestation and even for a reduced risk for a
postpartum flare [40]. One study reported a correlation between lactation and
increased disease activity postpartum in women with RA, who were breastfeeding
for the first time [43]. However, earlier studies reported no correlation between a
disease flare and breastfeeding [36]. A prospective study evaluating women with a
12-year follow-up found no significant influence of pregnancy on long-term RA

outcome, but found a trend for patients with multiple pregnancies to have less radio-
graphic joint damage and a better functional level [44]
Etiology of the Pregnancy-Induced Amelioration of RA
A number of different factors have been considered in the pregnancy-induced ame-

lioration of RA [45]. Research through more than six decades indicates that not a
single but a combination of factors are involved in the improvement of RA during
pregnancy [46]. The crucial event is the presence of the semiallogeneic fetus in the
mother and the resulting hormonal, immunological, and biochemical alterations
which support pregnancy. One important factor recently described in association
with amelioration of RA during pregnancy is the reversal of abnormalities in the
percentage of IgG immunoglobulins lacking the terminal galactose [47]. The per-
centage of agalactosyl IgG exceeds age-related normal values in patients with RA.
In a prospective study of RA pregnancies, high galactosylation levels were associ-
ated with low disease activity of RA and vice versa. Interestingly, the increase of
galactosylation levels during pregnancy was more pronounced in the RA patients
who improved and resembled those of healthy women [47]. Autoantibody levels did
not change significantly during pregnancy [40], but the pathogenicity of autoanti-
bodies is modified by changes in glycosylation of IgG. This may have a role in the
pregnancy-induced remission of RA, because the glycosylation of IgG determines
its ability to bind to complement and to Fc receptors.
HLA-G which is produced by the placenta has anti-inflammatory and immuno-
suppressive properties and can mitigate inflammation in murine collagen-induced
arthritis [48]. Fetal DNA, soluble HLA molecules of fetal origin or peptides derived
from these molecules can also contribute to improvement, as could a shift in cytokine
production from a TH1 to TH2 profile during pregnancy [45]. The secretion of cyto-
kines and their receptors in peripheral blood lymphocytes and monocytes changes
during pregnancy. Proinflammatory cytokines TNF-α, IL-1β, and IL-6 decrease
whereas the anti-inflammatory cytokines IL-4 and IL-10 remain stable or increase.
Levels of TNF receptors (TNFR), IL-1 receptor antagonist, and IL-6 receptor increase
during pregnancy, thereby counteracting effects of TNF-α, IL-1β, and IL-6 [49].
In two studies of mother–child pairs for whom the mother experienced RA
improvement during pregnancy compared to those who did not, fetal–maternal dis-
parity in the HLA class II molecules HLA-DR and DQ was observed significantly
more often in the former compared to the latter [50, 51]. Regulatory T cells (Treg)
increase during pregnancy suppressing activated T effector cells and maternal auto-
immune responses [52]. In a prospective study numerical and functional changes of
CD4 + CD25high Treg were investigated in RA patients and healthy women during and
after pregnancy [53]. Expansion of Treg occurred to a similar degree during preg-
nancy in patients and healthy women. Numbers of CD4 + CD25high Treg inversely
correlated with disease activity of RA in the third trimester and postpartum.
In co-culture experiments of Treg and T effector cells, significantly higher amounts

of IL-10 and lowered levels of TNFα and IFNγ were found in supernatants of the
third trimester compared to postpartum samples. Postpartum TNFα and IFNγ levels
were higher in patients with disease flares than in RA patients with inactive disease
[53]. The results showed that amelioration of RA in the third trimester was associ-
ated with an increased number of Treg that induced a pronounced anti-inflammatory
cytokine milieu.
Ankylosing Spondylitis
Fertility in Ankylosing Spondylitis
A retrospective, international study of reproductive performance in 939 female,

Caucasian AS patients found on average 2.4 children per woman, not different from
the number of offspring in the healthy population [54]. One population study of
women aged 40–42 found normal fertility but diminished fecundity in women with
AS [17].
The mainstay of therapy in AS are NSAIDs. Prostaglandins are involved in ovu-
lation and implantation. Studies in animals and humans have shown that NSAIDs
inhibiting cyclooxygenase (COX) 1 and 2 can inhibit the rupture of the luteinized
follicle, and thereby cause transient infertility [55]. One study showed that NSAIDs
increase the risk of the luteinized unruptured follicle (LUF) syndrome, particularly
in patients with inactive disease [55]. Selective COX-2 inhibitors seem to be more
potent inductors of LUF syndrome than nonselective COX-inhibitors [55]. Patients
who take NSAIDs especially selective COX-2 inhibitors continuously, in high doses
or take agents with a long half-life are at particular risk for the LUF syndrome.
Continuous, periovulatory exposure to NSAIDs should be avoided when planning a
pregnancy in patients with rheumatic diseases.
Pregnancy and Ankylosing Spondylitis
Pregnancy Outcome in SpA
The retrospective and prospective studies including AS patients with mild, moder-
ate, and severe disease activity found no increase in adverse pregnancy outcomes
including miscarriage, premature labor, or preeclampsia compared to healthy
women [31, 32, 54, 56–58]. In all studies of pregnancy outcome in AS, at least 90 %
of the patients delivered at term [54, 57, 59]. Compared to healthy women, elective
CS is more frequently performed in patients with AS. In the Norwegian population-
based study, women with AS had the highest occurrence of elective CS (25 %)
among the different diagnostic groups [14], a finding also confirmed by a previous
study [54]. Inflammation or ankylosis of the sacroiliac joints is not a mechanical

hindrance for the progression of parturition nor is spinal disease. Anesthesiologists
often fear that neuraxial anesthesia is difficult to establish in patients with AS
because of ankylosis in the lumbar spine. However, ankylosis of the lumbar spine is
rare in female AS patients and occurs only after 3–4 decades of disease duration
[58, 60]. Iatrogenic reasons or the wish of the patient for surgical delivery may be
of more impact for elective CS than the severity of AS.
Retrospective and some prospective studies have investigated the effect of preg-
nancy on the course and severity of AS [31, 32, 56, 61]. In contrast to RA, preg-
nancy has no profound effect on the symptoms of AS. In the prospective studies
clinical and laboratory measurements showed active disease during the first and
early second trimester, sometimes accompanied by a flare around week 20 of preg-
nancy. Pain and stiffness did increase, nocturnal pain intensified, and occasionally
arthritis in the knee or the ankle joints occurred. In some patients, pain at the attach-
ment sites of ligaments or tendons and a feeling of tightness in the chest created
additional problems. Anterior uveitis could become active during this period. Need
for NSAIDs and analgesics was present in about 70 % of the patients [31, 57, 62].
Disease activity decreased again in the third trimester in most AS patients, but com-
plete subsidence of symptoms was not observed. In a prospective study assessing
general health perception by the SF 36 throughout pregnancy in patients with AS
and RA compared to healthy pregnant women, most patients with AS entered preg-
nancy with active disease and suffered the greatest impairment of health-related
quality of life with persistent active disease throughout pregnancy [37]. In contrast
to pregnant RA patients functional scores and bodily pain scores were not altered by
pregnancy in AS. Compared with healthy women, patients with AS had worse
scores for bodily pain, physical functioning, and general health perception, both
during pregnancy and in the postpartum period.
Some 20 % of AS patients improve from spinal and extraspinal symptoms during
pregnancy [31, 61]. These patients most often have a history of arthritis in joints
other than the spine, or psoriasis or IBD associated with their AS. In patients studied
during multiple pregnancies intensity of disease symptoms varied from one preg-
nancy to the other. No uniform pattern with regard to improvement or aggravation
emerged. However, complete remission of symptoms never occurred in any patient
with pure spinal disease [31, 56].
Maternal Disease Activity in AS Post Partum
Fifty to eighty percent of the AS patients experience aggravation of symptoms

4–12 weeks after delivery independent from the period of breastfeeding [31]. One
study found the flare correlated to active disease at conception, but not related to
disease activity during pregnancy [54]. Episodes of acute peripheral arthritis and
anterior uveitis occurred 1.5–3 times more often postpartum than during pregnancy
[54, 61]. Clinical signs were accompanied by elevations of acute phase reactants
[62]. Disease activity returned as a rule to the pre-pregnancy pattern during the year
following delivery [31].
Management of Pregnancy in Patients with RA and SpA
The patient with active RA or SpA who contemplates pregnancy or is already preg-
nant requires therapy compatible with pregnancy (reviewed in detail in Chap. 14).
This obviously limits the choice of DMARD considerably and requires more flexi-
bility as to the timing of certain drugs prior to pregnancy. For example, one could
decide for a combination of MTX and a TNFα inhibitor as a first line therapy in a
patient with early RA or SpA who plans a pregnancy within the near future. The
aim would be to achieve disease control within reasonable short time, then to dis-
continue MTX and to continue with a therapy compatible with pregnancy. The con-
tinuation of therapy with DMARD in RA patients who plan to become pregnant
may be beneficial. In a study of RA pregnancies, 75 % of patients with inactive
disease were on DMARD before conception of whom 38 % continued treatment
throughout pregnancy. By contrast, among patients with persistent active disease
only 33 % received immunosuppressive therapy before conception, and only 17 %
continued therapy during pregnancy [40]. This supports the notion that continuation
of compatible DMARD therapy during pregnancy, at least in RA, helps to suppress
flares of disease.
There are two reasons for drug therapy during pregnancy and lactation: one is to
prevent a flare with possible harmful effects on mother and fetus, the other is treat-
ment of a flare occurring during or after pregnancy. The goal of drug therapy in
pregnancy and lactation is to keep the patient at low disease activity or in remission
and to prevent progression of inflammation with structural damage. Regular moni-
toring of disease activity during and after pregnancy is a prerequisite to decide
whether drug treatment is necessary. The need for drug therapy in RA and AS dif-
fers significantly. The beneficial effect of pregnancy on the symptoms of RA reduces
the need for drug therapy and is present in only 15–25 % of pregnant RA patients.
The persistent active disease in AS most often requires symptomatic treatment [32].
Patients with SpA, especially with AS, frequently have active arthritis at some stage
of pregnancy. Start of DMARD for a disease flare during pregnancy is not ideal
since most of the DMARDs compatible with pregnancy all have a delay of
2–3 months in onset of effect. Corticosteroids with the advantage of a very fast
action are best suited for treatment of acute arthritis in pregnancy, although they
slightly increase the risk for cleft palate formation when used during the first trimes-
ter. Intraarticular injections of corticosteroids into one or a limited number of
actively inflamed joints can be given to both RA and SpA patients, and systemic
corticosteroids can be added for continuous suppression of inflammation if neces-
sary. This goal can as a rule be achieved by 10–20 mg prednisone daily in patients
with RA. To prevent corticosteroid-induced osteopenia supplementation with cal-
cium and vitamin D3 is important in patients on prolonged systemic therapy.
Frequent controls to detect an increase in blood pressure or the development of
gestational diabetes in the mother are necessary. When administrating systemic cor-
ticosteroids, the lowest effective dose of corticosteroids should be given for a lim-
ited time period to avoid intrauterine growth restriction and premature delivery.
Patients with AS generally do not respond as promptly to prednisone. They often

benefit more from NSAIDs although these medications need to be discontinued by
week 28–30 of pregnancy to circumvent the risk of premature closure of the ductus
arteriosus.
Patients with RA and SpA need more intensive prenatal care than healthy preg-
nant women. Type and frequency of appointments during pregnancy should be
agreed upon with the patient and contacts established between doctors involved in
follow-up. Good communication among specialist increases the chance for a suc-
cessful pregnancy and delivery. The schedule for follow-up visits depends on dis-
ease activity, and maternal and fetal risk factors present at conception. Monthly
evaluations throughout pregnancy may be sufficient in patients in remission, but
active disease demands more frequent visits. Lifestyle adjustments before preg-
nancy include stopping smoking, alcohol ingestion, and recreational drugs during
pregnancy and maintaining a healthy diet containing multiple vitamins [63].
Importance of folic acid supplementation during the early stages of pregnancy
needs to be emphasized [64]. The usual dose for healthy pregnant women as well as
patients with RA and SpA is 0.4 mg/day. Patients who have received therapy with
MTX and sulfasalazine previously should continue 1 mg daily before conception
and at least throughout the first trimester.
An aggravation of disease activity occurs in a majority of patients with RA and
SpA within the first 6 months after delivery [46]. Frequent visits postpartum are
therefore necessary in order to detect a flare and to start effective therapy right away.
The time of disease aggravation coincides with the period of lactation. Effective
disease control at this stage is of great importance in order to inhibit disease pro-
gression and to enable the mother to care for her baby. Unfortunately the available
literature on therapy with antirheumatic drugs during lactation is sparse, and many
patients will feel that they need to choose between disease control and lactation.
Many mothers would rather deprive themselves of therapy rather than deprive the
child of milk. Warnings given against breastfeeding when on therapy are often not
based on evidence for adverse effects in the child, but on lack of knowledge [65].
Special Problems in RA and AS
Involvement of the cervical spine with cervical instability in RA is rare, but when
atlanto-axial subluxation is present, cervical cord damage is a risk [66]. It is impor-
tant to know of this deformity before considering general anesthesia for a surgical
delivery. Cervical radiographs or MR examination before a planned pregnancy is
recommended to exclude atlanto-axial subluxation.
In pregnant women with AS sometimes the anesthesiologist will not give epi-
dural anesthesia because he/she fears problems with positioning the epidural cath-
eter in case of ankylosis of the lumbar spine. These concerns can be overcome when
doing an X-ray of the lumbar spine before a planned pregnancy. Sometimes calcifi-
cation of the posterior, longitudinal ligament inhibits spreading of the anesthetic
solution by the epidural route, then intrathecal anesthesia may be necessary [67].
Pre-conceptional Counseling for Patients with RA and SpA
At a pre-conceptional visit, the physician must identify possible risks of a future

pregnancy in regard to the stage and activity of the disease and to organize adequate
monitoring during pregnancy and postpartum. An early stage of disease implies that
the pattern of disease severity is not yet apparent and frequent changes of drug treat-
ment may be necessary. A patient with active rheumatic disease should postpone
pregnancy until remission or stable disease is achieved and has persisted for at least
6 months. In patients planning a pregnancy a clinical and laboratory work-up should
be performed for risk assessment. RA patients positive for rheumatoid factor or
ACPA and those with currently active disease have significantly less chance for
spontaneous improvement during pregnancy and are at higher risk for adverse out-
comes. RA patients without RF or ACPA and those with low disease activity or in
remission are the most likely to remain inactive during pregnancy. The rheumatolo-
gist should test a woman with RA for the presence of aPL and antibodies against
SS-A (anti-Ro) and SS-B (anti-La) since these autoantibodies can occur in 30 % RA
patients and these patients may require special monitoring.
An adjustment of therapy with discontinuation of fetotoxic drugs and switch to
pregnancy compatible drugs is necessary in patients desiring to become pregnant or
in those already pregnant. Therapy must be tailored for the individual patient
according to disease activity and secure effective maternal disease control as well as
safety of the fetus (see Chap. 14). It is important that the treating physician warns
against discontinuation of all therapy when an attempt of conception is made.
Withdrawal of drug therapy may result in a disease flare. Other physicians, espe-
cially the obstetrician involved in patient treatment, should be informed about nec-
essary antirheumatic therapy in order to avoid contradictory advice. At the end of
pregnancy, a discussion of breastfeeding and use of drugs during lactation is
recommended.
Before pregnancy, access to familial and social support should be evaluated.
Therefore it is advantageous to include the patient’s partner or a family member into
pre-conceptual counseling. In order to prepare for the task of child caring after
delivery, consulting an occupational therapist is advisable for the patient with
impaired function. A meeting with an interdisciplinary team including a physio-
therapist, an occupational therapist and a social worker can help to prepare the rheu-
matic mother for parenting.
Patients are often concerned in regard to heredity of rheumatic diseases. In gen-
eral genetic factors and environmental factors contribute to the development of
rheumatic diseases and only few of them have been recognized or been studied in
detail. The gene linked with rheumatoid arthritis is HLA-DR4. The disease rate in
first-degree family members of RA patients is only 0.8 % compared to 0.5 % in the
general population indicating that genes only modestly increase the risk for RA and
that the environment is likely to play a stronger role. The risk to inherit the disease
in a child with one RA parent is only 1–3 %. A recent study has indicated that smok-
ing increases the risk for RA in DR4 positive individuals [68]. This implies that
children of a RA parent should be warned against smoking.
More than 90 % of Caucasian AS patients have the HLA-B27 gene, compared to

the approximately 7 % of the general population who carry this gene. The chance of
a child inheriting AS is estimated at about one in six if one parent has the gene
HLA-B27, and about one in ten if not. On the other hand, first-degree family mem-
bers (parents, siblings, and children) of AS patients with the HLA-B27 gene have a
20 % chance of developing the disease. This is probably because they are exposed
to the same environmental factors as the patient and have inherited certain other
important genes in addition to the HLA-B27 gene like ARTS 1 and IL-23R, two
newly identified non-HLA B27 susceptibility genes for AS [69].
Patients with RA and SpA can be assured that there is no increased risk for giv-
ing birth to a child with congenital malformations except for patients who have been
exposed to teratogenic drugs during the first trimester.
Conclusion
The disease process, therapy, and disease burden contribute to a reduction in the num-
ber of children in women with RA and SpA after disease onset. Pregnancy has no
major effect on the symptoms of AS, but induces spontaneous improvement in most
patients with RA. An aggravation of disease activity within 6 months after delivery is
common in both RA and SpA. In RA active disease and therapy with corticosteroids
during pregnancy increases the risk for preterm birth and reduced birth weight of
neonates. The rate of CS is significantly higher in all women with rheumatic disease;
however, acute CS seems to be no more frequent than in healthy pregnant women.
The highest rate of elective CS has been found in women with AS, probably related
to anticipation of problems during delivery by obstetricians and anesthesiologists.
Management during pregnancy is based on risk assessment for mother and child
and depends on disease activity which must be carefully monitored during pregnancy.
In order to reduce unplanned and ill-timed pregnancies, pre-conceptional counseling
is suggested for all patients of fertile age and includes discussion of contraception and
adjustment of therapy. Most women with RA and SpA can have successful pregnan-
cies provided that pregnancy is planned and occurs in a stage of remission or low
disease activity and under therapy with drugs compatible with pregnancy.
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Chapter 8
Pregnancy in Patients with Systemic Sclerosis
Cecily A. Clark-Ganheart, Julia Timofeev, and Virginia D. Steen
Background
Scleroderma (also known as systemic sclerosis) is an autoimmune disease that is

encountered less frequently than other connective tissue disorders. The diagnosis
is more common in women vs. men, at a rate of 4:1. The prevalence of scleroderma
is approximately 0.025 % with average age of onset between 40 and 50 years of
age [1]. Manifestations of the disease can include involvement of the skin, lungs,
kidneys, heart, gastrointestinal tract, and musculoskeletal system.
Because many of the initial complaints of scleroderma mimic other illnesses, the
diagnosis is often difficult. Skin thickening proximal to the metacarpophalangeal
joints (i.e., legs, face, trunk, etc.) is a hallmark of the disease [2]. Limited cutaneous
scleroderma, also known as the CREST (Calcinosis, Raynaud’s phenomenon,
Esophageal dysmotility, Sclerodactyly, and Telangiectasias) syndrome represents a
subset of individuals with less skin thickening. While numerous antibodies have been
described in patients with systemic sclerosis, anti-centromere, anti-topoisomerase I,
and anti-RNA polymerase III antibodies are three of the more commonly encoun-
tered. These antibodies are associated with significant clinical features. For example,
renal crisis occurs more frequently in patients that express anti-RNA polymerase III,
and anti-topoisomerase I is associated with more severe interstitial lung disease [3].
C.A. Clark-Ganheart, M.D. • J. Timofeev, M.D.

Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine,
Medstar Washington Hospital Center, Medstar Georgetown
University Hospital, Washington, DC 20010, USA
V.D. Steen, M.D. (*)
Department of Medicine/Rheumatology, Medstar Georgetown University Hospital,
3800 Reservoir Road, PHC 3004, Washington, DC 20007, USA
e-mail: steenv@georgetown.edu
160 C.A. Clark-Ganheart et al.
Scleroderma is commonly classified into limited cutaneous and diffuse cutaneous

types, with greater morbidity and mortality associated with the latter. Patients with
skin changes on the trunk or proximal to the elbows and/or knees are said to have dif-
fuse scleroderma. Those with skin changes distal to the elbows and/or knees and
without trunk involvement are considered to have limited cutaneous disease. Some
patients do not have any skin changes, except on the face, and this is termed limited
scleroderma, or scleroderma sine scleroderma [2]. Disease progression and the extent
of internal organ involvement are typically related to the extent of skin disease as well
as the scleroderma-specific autoantibody. Patients with limited scleroderma typically
have less severe organ impairment compared to patients with diffuse disease, although
they can have significant gastrointestinal disturbance and pulmonary arterial hyper-
tension. The early identification of organ disease provides the clinician an opportu-
nity to institute treatment prior to the establishment of permanent damage.
The exact etiology of scleroderma is unknown. Multiple studies have demon-
strated adverse pregnancy outcomes in women that later developed scleroderma.
Fetal cells may remain in the maternal circulation for several years after delivery,
and one theory involves a type of chronic graft versus host disease developing due
to presence of fetal cells [4]. Increased rates of scleroderma development have been
linked to antecedent pregnancies complicated by hypertensive disease and intrauter-
ine growth restriction (IUGR) [4]. This theory, however, does not fully explain why
some women develop scleroderma and others do not, along with the appearance of
the disease in women who have never been pregnant or in men.
Scleroderma and Fertility
Early literature suggested the possibility of decreased fertility among women with
scleroderma [5]. Given the fact that disease onset occurs most often during the ages
of 40–50, many women with scleroderma diagnosed during this time period would
be expected to have decreased pregnancy rates as a function of age alone. However,
in a retrospective study of scleroderma patients compared to rheumatoid arthritis
and neighborhood controls, there was no significant difference in the fertility rates
in scleroderma when adjusted for patients who were sexually active [6].
Impact of Scleroderma on Pregnancy Outcomes
Miscarriage
Miscarriages in other connective tissue diseases are often a major problem. Early
studies suggested that there was also an increased frequency of miscarriage in sclero-
derma and even in women prior to onset of scleroderma, but more recent studies
have shown that miscarriage rates are generally not significantly increased [5, 7].
A prospective study by Steen and colleagues looked at 59 women and 91 pregnancies.
8 Pregnancy in Patients with Systemic Sclerosis 161
Patients were divided by subset of disease and by stage of their illness. Miscarriage
occurred with similar frequency to the historical controls except in the subgroup of
patients with late diffuse scleroderma. These patients had a surprisingly high fre-
quency of miscarriages, 42 % of the 15 women with late diffuse disease compared to
13 % in all of the other groups. Renal insufficiency and severe gastrointestinal
malabsorption were present in two of the seven women who had miscarriages and
several others had some interstitial lung disease [8]. Women with late, diffuse sclero-
derma were three times more likely to experience miscarriage compared to their
peers [8]. Recently, an observational Italian study compared ninety-nine women
with systemic sclerosis (SSc) receiving high risk pregnancy management, to the gen-
eral Italian obstetric population and did not find an increase in miscarriage in these
patients [9]. The series included 109 pregnancies resulting in 101 newborns.
Miscarriages (<10 weeks) occurred in 4 % of women, fetal deaths (>10 weeks) in
2 %, and voluntary and therapeutic abortions in 4 % which was not different than
the general Italian population. In all, the rate of spontaneous losses in SSc women
regularly followed as high risk pregnancy seems comparable to that expected in the
general population.
IUGR is classically defined as a fetus who fails to reach their maximum growth
potential in utero, with estimated fetal weight less than the tenth percentile. Etiologies
of IUGR can result from either maternal or fetal factors. Several retrospective studies
suggest that systemic sclerosis confers an increased risk of delivering a growth-
restricted fetus. Based on available data, women with a diagnosis of scleroderma
have a 3.7-fold increase of IUGR compared to women without the disease [10].
Though small in number, various studies have examined placental pathology in
women with systemic sclerosis [11]. Findings of fibrosis and abnormal vascular
remodeling may predispose women with systemic sclerosis to having small for ges-
tational age infants.
In a recent prospective study that examined pregnancy outcomes in 59 women
with scleroderma, none of the pregnancies were complicated by IUGR. Thirty-three
patients had diffuse disease, while 26 patients had limited scleroderma [8]. These
findings raise the question on the degree of impact that systemic sclerosis has on fetal
growth. However, in an Italian study which reviewed data on 109 pregnancies in
women with scleroderma, the rate of IUGR was 6 vs. 1 % in controls [9]. Given this,
it is reasonable to perform serial growth ultrasounds in women with scleroderma.
Preterm Delivery
Preterm delivery occurs at a greater frequency in women affected by systemic scle-

rosis. Both retrospective and prospective studies have demonstrated an increase in
the number of women delivering prematurely compared with controls. Patients with
early diffuse scleroderma are a subset that has a particularly high rate of preterm
birth. In a series of 91 pregnancies in 59 women, 65 % of pregnancies in women
with early diffuse disease delivered prior to 37 weeks [12]. The overall rate of pre-
term delivery for women with systemic sclerosis in this series was 29 %, which is a
5.8-fold risk compared to controls. The average gestational age at birth was
34.9 weeks, with the majority of neonates having positive outcomes.
A retrospective study by Taraborelli et al. also reported an increased incidence of
preterm delivery compared with controls (25 vs. 12 %) [9]. Interestingly, in this
study 72 % of the preterm deliveries were iatrogenic which suggests that the obste-
trician made the decision to deliver the baby early and therefore the reasons of
prematurity might be related more to other pregnancy complications than to sclero-
derma itself. However, given that the indications for preterm delivery are not always
clear, regardless of etiology, the patients with scleroderma should be aware of the
increased risk of preterm birth.
Fetal Death
Infant deaths were quite common in the individual case reports and many cases
were associated with the acute exacerbation of scleroderma complications in the
mother, particularly renal crisis. Neonatal deaths are occasionally noted in the series
and case–control studies, but none found a statistically or clinically excessive num-
ber compared with controls [6].
Pregnancy Complications
Renal Crisis
Ten to twenty percent of women with diffuse systemic sclerosis will experience a
renal crisis at some point in their disease course [12]. Although early literature
described many cases of renal crisis during pregnancy, cohort studies were unable
to confirm this [6]. It is unlikely that pregnancy increases the risk of developing
renal crisis; however, literature on this specific subject is lacking. The risk is great-
est in those with recent disease onset or diffuse systemic sclerosis; therefore, it is
important that women in these categories have stabilization of their condition prior
to conception [13]. This life-threatening condition is characterized by malignant
hypertension, acute renal failure, proteinuria, and microangiopathic hemolytic ane-
mia, and “onion skin” appearance of the renal arteries on histology [14]. Angiotensin-
converting-enzyme (ACE)-inhibitors are the cornerstone of treatment in renal crisis
during the nonpregnant state. Unfortunately, treatment with ACE-inhibitors is gen-
erally avoided in pregnancy due to potential adverse fetal effects. Early data sug-
gested a possible link between fetal malformations and first trimester exposure to
ACE-inhibitors; however, recent studies seem to dispel these findings [14].
However, during the second and third trimesters, this class of medications has
been associated with decreased fetal blood volume, oligohydramnios, renal failure,
IUGR, and hypocalvaria [14, 15]. More importantly, some of the in utero effects are
not completely reversed after drug discontinuation. A systematic review of the lit-
erature by Bullo et al. provided postnatal follow-up of children with prenatal expo-
sure to ACE-inhibitors and angiotensin receptor blockers (ARBs). Twenty-two
children were exposed during the second and third trimesters or for the duration of
the entire pregnancy. Of these children, ten had no long-term sequelae, ten had mild
impairment (i.e., mild renal insufficiency, arterial hypertension, proteinuria, or
developmental delay), while two children had end-stage renal disease, requiring
dialysis or transplantation [15]. Due to these findings, ACE-inhibitors and ARBs are
generally not used during the second and third trimesters of pregnancy.
Although typically contraindicated during pregnancy, treatment of renal crisis
with ACE-inhibitors may prove lifesaving to the mother despite the risks to the
fetus. Prior to the initiation of ACE-inhibitor therapy for the treatment of renal cri-
sis, the overwhelming majority of patients with disease died within the first year
[12]. Therefore, ACE-inhibitors are indicated for the management of renal crisis
given the substantial mortality risk if treatment is withheld.
Another complexity of renal crisis in pregnancy is differentiating it from pre-
eclampsia which has a similar presentation, thus possibly delaying the diagnosis
and treatment. While delivery is curative for preeclampsia, it will not address the
pathology underlying renal crisis in scleroderma. Preeclampsia and renal crisis
share several features, which makes differentiating between the two pathologies
difficult. Renal crisis is most likely to develop in women with early, rapidly progres-
sive, diffuse scleroderma [13]. Again, women with this disease subtype are strongly
advised to delay pregnancy until stabilization of their disease.
Baseline antibody profiles in women with systemic sclerosis may assist clini-
cians in making the diagnosis of renal crisis. In a study by Nikpour et al., patients
presenting with renal crisis had a significantly increased prevalence of anti-RNA
polymerase III compared to patients with other antibody profiles. In patients with
anti-RNA polymerase III antibodies, 24.6 % developed renal crisis compared to
only 1.8 % in individuals in which anti-RNA antibodies were absent [16]. Diffuse
scleroderma patients with anti-topoisomerase (anti-Scl 70) antibody are also at sig-
nificant increased risk for renal crisis but patients with anti-centromere antibody
rarely if ever get this complication. Antibody titers do not correlate with the likeli-
hood of disease development, nor the severity of renal crisis, therefore the presence
of anti-RNA antibodies even in low titers should alert the clinician to the possibility
of renal crisis [16].
Both complications are associated with severe hypertension and early onset of
renal insufficiency. Even just a 50 % change in serum creatinine from baseline
should raise major concern for renal crisis. The serum creatinine may increase rap-
idly if blood pressure is not controlled promptly. Finally, measurement of liver
transaminase can also assist in making a diagnosis. Elevation of aspartate amino-
transferase (AST) and alanine aminotransferase (ALT) is more characteristic of pre-
eclampsia, though it is important to note that normal liver function tests do not rule
out the disease. A 24 h urine protein in the beginning of pregnancy will help to
establish baseline renal function and may aid the clinician in differentiating between
new onset and preexisting proteinuria later in pregnancy, although increased pro-
teinuria prior to renal crisis is not common. Serum renin levels are usually markedly
elevated during renal crisis and are typically within the normal or low range in
preeclampsia although these results often take several weeks and clinically are not
very useful [13].
Although distinguishing renal crisis from preeclampsia is difficult, ACE-inhibitor
therapy should be instituted immediately as this could prove to be lifesaving.
A reasonable approach in women with scleroderma presenting with new onset
malignant hypertension and proteinuria would be an immediate trial of ACE-
inhibitors, while administering steroids for fetal lung maturity at gestational ages
less than 34 weeks, and magnesium sulfate for seizure prophylaxis. Failure to
control blood pressure within 36–48 h of initiation of ACE-inhibitors should alert
the clinician to the possibility of severe preeclampsia and delivery. ACE-inhibitor
therapy should continue postpartum, until it is determined that the etiology of
hypertension was not due to renal crisis [13, 17].
Impact of Pregnancy on Scleroderma
Concern of the impact of pregnancy on the disease is a common question among

clinicians and patients. Ten-year survival appears equivalent in women with a previ-
ous pregnancy compared to those who are nulliparous [13]. In a retrospective study
of 99 pregnant women with scleroderma, the authors found no evidence of signifi-
cant disease progression during pregnancy. A prospective study of pregnant women
with scleroderma demonstrated that the majority of women reported no change in
symptoms throughout the gestation. In the 16 pregnancies that did indicate worsen-
ing of symptoms, the majority of complaints were related to esophageal reflux [8].
However, gastroesophageal reflux disease (GERD) is common among gravidas in
the general population, and it is likely that this finding has more to do with the
physiologic changes of pregnancy than from the worsening of scleroderma itself.
Women with scleroderma do not seem to have greater adverse outcomes from car-
diopulmonary problems than one would expect from other pregnant patient with
similar cardiopulmonary disease. All are at high risk. Other than increased short-
ness of breath (typical in most pregnant women due to increased basal oxygen con-
sumption and alveolar ventilation), there is no evidence that pregnancy increases the
severity of scleroderma pulmonary fibrosis. Scleroderma patients may have unde-
tected myocardial damage and this could in theory cause cardiac dysfunction and
compromise during the cardiovascular stress of pregnancy. Pregnancy in patients
with pulmonary arterial hypertension (PAH) is strongly discouraged. Any woman
with PAH who becomes pregnant is at extremely high risk for severe hemodynamic
complications during pregnancy and especially in the peripartum state. Reports esti-
mate a 36–50 % maternal death rate in women with PAH, with the most vulnerable
period occurring with the delivery and the first 2 weeks postpartum [18].
If improvements in scleroderma symptoms are noted during pregnancy, it is most

likely with respect to Raynaud’s phenomenon and digital ulcers. It is thought that the
natural decrease in peripheral vascular resistance is responsible for this improve-
ment. Unfortunately, this improvement is lost postpartum, as Raynaud’s phenome-
non is the most common symptom noted in postpartum women experiencing
aggravation of their condition [8]. Overall, current published literature indicates that
pregnancy has little impact on systemic sclerosis or disease progression.
Management
Preconception and Antepartum Management
With advances in the care of women with rheumatologic disease, providers are more
likely to encounter pregnant women with autoimmune conditions. Though precon-
ception counseling is underutilized, understanding of the unique considerations
brought to pregnancy by scleroderma is the key to successful management (Table 8.1).
Successful pregnancy outcomes are possible for women with systemic sclerosis,
however, prior to becoming pregnant consultations with Maternal-Fetal Medicine
and Rheumatology specialists are highly recommended. Women with diffuse sys-
temic sclerosis or disease duration of less than 4 years are more likely to experience
adverse neonatal outcomes. This is likely due to the fact that women with these
characteristics are more likely to experience active disease. In this group of women,
pregnancy can be attempted after stabilization of disease. Patients should be aware
of the increased risk of preterm delivery and IUGR, and possible long-term neonatal
risks if treatment with an ACE-inhibitor is indicated given the potential of renal
crisis occurring during this time period.
An antibody profile of women desiring pregnancy should be obtained. This
includes an investigation for the presence of anti-topoisomerase (scl 70), anti-RNA
Table 8.1 Recommended evaluations for women with scleroderma prior to pregnancy
Manifestation Study
Overall Disease duration, disease subtype, autoantibodies, evaluate medications
Cardiovascular diseaseb CBC, LFTs, echocardiogram, electrocardiography, blood pressure
Pulmonary diseaseb Pulmonary function tests, chest X-ray or high resolution CT scan to
evaluate for fibrosisa
Renal diseaseb Blood pressure, urinalysis, BUN/creatinine, electrolytes, 24 h UTP
Miscellaneous Evaluation of esophageal disease, assessment of airway, range
of neck motion, mucosal telangiectasia, examination of extremities
including pulses, sites for IV access, and gangrene of digits
LFT liver function tests, UTP urinary total protein, BUN blood urea nitrogen, 24 h UTP 24 h urine
protein
a
Perform prior to pregnancy unless patient is already pregnant, then perform as clinically indicated
b
Appropriate for preconception evaluation and/or at first prenatal visit to establish baseline risk
polymerase III, anti-centromere, anti-Ro/SSA and anti-La/SSB antibody titers [13].

Women with anti-topoisomerase are more likely to have severe pulmonary fibrosis
and those with anti-RNA polymerase III are more likely to get renal crisis. Both
groups experience a more aggressive and active disease course. Additionally, the
presence of anti-Ro and anti-La, although more common in systemic lupus erythe-
matosus, is associated with the development of congenital heart block and therefore
the presence of these antibodies should alert the clinician to this complication
(detailed in Chap. 4).
The degree of organ involvement should also be assessed, ideally prior to con-
ception. Depending on the degree of underlying organ dysfunction, pregnancy may
be contraindicated. Patients with PAH are strongly discouraged from becoming
pregnant because of the high mortality for these mothers. Also, it is a widely held
consensus that women with cardiac ejection fraction less than 40 % should not
become pregnant. In fact, pregnancy termination is recommended due to the one in
five risk of maternal mortality during or immediately postpartum [19]. Likewise, the
degree of renal impairment should be evaluated prior to conception. Women with
serum creatinine above 1.4 gm/dL are at increased risk for pregnancy complications
and renal deterioration irrespective of their scleroderma; for example, there is a
40 % risk of IUGR and preeclampsia, 5 % risk of perinatal death, and a 20 % risk
of further deterioration of renal function persisting postpartum, with up to 2 % risk
of end-stage renal disease within 1 year [20].
With respect to the restrictive lung disease, limited datum exists of the impact on
pregnancy. A series of nine patients with restrictive lung disease resulted in favor-
able neonatal outcomes. Five mothers developed exercise-induced desaturation
with four patients requiring supplemental oxygen. One patient was delivered at
31 weeks via general anesthesia and subsequently required mechanical ventilation
for 3 days [21]. Consultation with pulmonology is recommended to assess the
decrease of lung involvement prior to and during pregnancy. The clinician should
keep in mind that underlying restrictive lung disease may present without alveolitis
and therefore pulmonary function tests are recommended in the first trimester and
should be repeated as clinically indicated thereafter [13].
Review of medications prior to pregnancy is extremely important since immuno-
suppressive medications such as methotrexate and mycophenolate are frequently
used for treatment of skin, muscle, joint and lung disease in early scleroderma.
These medications must be discontinued before conception. Azathioprine and
plaquenil, which have been used throughout pregnancy in lupus patients, have not
been particularly useful for management of skin or lung problems in scleroderma
although they may be helpful in maintenance of prior improvement of skin, joint,
muscle, or lung problems (medication safety in pregnancy is detailed in Chap. 14).
Women who have experienced a prior renal crisis require ACE-inhibitors as part
of the management of the disease. A trial off ACE-inhibitors can be considered prior
to pregnancy to see whether there is even the potential of managing the blood pres-
sure without ACE-inhibitors. However, prompt resumption of therapy must occur if
even the slightest blood pressure elevation occurs. Discontinuation of this class of
medicine could prove fatal; therefore, the patient must have clear understanding of
the potential fetal risks associated with ACE-inhibitor use and the implications on
her health if the medication is discontinued. It appears that captopril may have the
most favorable side effect profile regarding fetal complications of the available
ACE-inhibitors. The use of enalapril was associated with a higher percentage of
fetal complications than was noted with use of captopril. This is potentially related
to the shorter half-life of captopril [15]. Therefore, in women with a prior renal
crisis who require the use of ACE-inhibitors to maintain their health, consideration
can be given to using captopril during the pregnancy.
Because ACE-inhibitor use in the second and third trimesters is associated with
fetal complications, it would be reasonable to increase fetal surveillance during this
time. Serial growth sonograms beginning in the second trimester are indicated given
the association with growth restriction. Modified biophysical profile (non-stress test
combined with measurement of the amniotic fluid index) could be instituted in the
third trimester given the risk of oligohydramnios. Testing should be initiated earlier
in pregnancy or at an increased frequency depending on the clinical scenario and at
the provider’s discretion.
Intrapartum Management
Women with systemic sclerosis require special considerations during the intrapar-
tum course (Table 8.2). Consultation with an anesthesiologist should be considered
prior to the labor process. Scleroderma presents several unique considerations to
both the anesthesiologist and obstetrician. Systemic sclerosis in general is not a
contraindication for vaginal delivery. Contractures may provide limitations in range
of motion, which the clinician should take into consideration. The presence of
severe pulmonary or cardiac disease may necessitate an assisted second stage of
labor (with forceps or vacuum delivery) or cesarean delivery depending on the
degree of compromise.
Furthermore, features of the disease such as vasoconstriction, anatomic deformi-
ties of the airway, and skin changes may present additional challenges for the anes-
thesiologist. Prolonged sensory blockade has been reported with the use of regional
anesthesia [22]. Spinal anesthesia can be associated with profound hypotension that
is refractory to treatment with vasopressors. Even more challenging, vasodilatation
below the level of the spinal block may not respond to vasopressors, thus predispos-
ing to worsening of the patient’s upper extremity vasoconstriction. Aggressive fluid
management may be required to address hypotension; therefore, epidural anesthesia
may be a better choice in patients with scleroderma if feasible [22].
Anatomic deformities of the upper airway including fibrosis of the temporoman-
dibular joint, poor mouth opening, skin tightening of the face with reduced mobility,
etc. can result in difficult intubation for patients with scleroderma. Likewise, esoph-
ageal dysmotility in addition to the intrinsic relaxation of the lower esophageal
sphincter during pregnancy may increase the risk of aspiration. Ventilation may also
prove difficult in the setting of underlying restrictive lung disease, which is not
always apparent prior to conception or during the antepartum period. In general, if
a cesarean section is indicated, it would be best to avoid general anesthesia.
Table 8.2 Intrapartum considerations for patients with scleroderma

Specialty Consideration
Obstetrics Route of delivery
– Lower extremity range of motion
Degree of pulmonary disease
– Assisted second stage for severe disease
Degree of cardiac disease
– Assisted second stage for severe disease
Anesthesia Airway
– Mandibular range of motion
Ventilation
– Pulmonary fibrosis and/or restrictive lung disease
Regional anesthesia
– Skin thickening
– Vasoconstriction
– Hypotension
– Prolonged sensory blockade
– Cardiac disease
Nursing Positioning
– Contractures
Temperature
– Raynaud’s phenomena/vasoconstriction in cold environment
Skin thickening
– IV access and blood draws
Contraceptive Options
Given that up to 50 % of pregnancies are unplanned, an understanding of contracep-

tive options for women with scleroderma, particularly for women with very early
diffuse scleroderma and those with concomitant use of teratogenic medications, is
key. Literature specifically addressing contraception in patients with scleroderma is
lacking, but there is nothing to suggest that hormones are a problem in scleroderma.
Thus, the principles of contraception management in women with other autoimmune
diseases may be applied to patients with systemic sclerosis. It is important to note
that women with rheumatologic conditions have contraceptive options, and contra-
ception should not be withheld solely based on the presence of autoimmune disease
(contraception in rheumatic disease patients is reviewed in detail in Chap. 11).
Barrier methods, intrauterine devices, and progestin-only methods are options for
women with scleroderma. As in women without rheumatologic disease, the etono-
gestrel single-rod implant and intrauterine devices have the lowest rate of unintended
pregnancy. Rates of unintended pregnancy per 100 women during the first year of
typical use for the implant, levonorgestrel intrauterine system, and the Copper T
intrauterine devices are 0.05, 0.2, and 0.8, respectively [23]. Devices containing pro-
gestin do not appear to alter immunogenicity in patients with rheumatologic disease
nor do they increase the risk of thrombosis [24]. Medroxyprogesterone acetate is
another option for women seeking a reliable form of contraception with an unin-
tended pregnancy rate of 3 % during the first year with typical use.
The use of barrier methods should be encouraged for the prevention of sexually
transmitted diseases and as a contraceptive adjunct to the methods listed above.
Patients should be aware that natural skin condoms do not prevent disease transmis-
sion. Rates of unintended pregnancy are greater with the use of male or female
condoms compared to the other contraceptive options. Thus, in patients where
avoidance of pregnancy is preferred, use of a more reliable form of contraception
should be advocated (for example, intrauterine device). Additionally, if childbear-
ing is complete, consideration of a permanent sterilization procedure is reasonable.
Summary
Despite the fact that early literature suggested an increased risk of infertility and
poor pregnancy complications, positive pregnancy and neonatal outcomes in
patients with scleroderma are generally the rule and not the exception. Most of the
adverse pregnancy outcomes occur in women with early, diffuse systemic sclerosis.
In this group, childbearing should be deferred until disease stabilization. The most
commonly reported complications in pregnancies with systemic sclerosis are pre-
maturity and IUGR. In the absence of other risk factors, the rates of intrauterine
fetal demise are not increased [12]. Ideally, patients should undergo preconception
counseling to determine if multi-organ involvement precludes pregnancy.
A multidisciplinary approach including consultation with Maternal-Fetal
Medicine, Rheumatology, and Anesthesiology are important to classify the patient’s
disease and provide recommendations for antepartum, intrapartum, and postpartum
management. While successful pregnancies have been reported in women with a
history of renal crisis, generally pregnancy is not advised in these patients. For
women with renal crisis, a trial off ACE-inhibitors can be considered; however,
prompt resumption of therapy must occur if even the slightest blood pressure eleva-
tion occurs. If renal crisis is suspected during pregnancy, immediate treatment with
ACE-inhibitors is indicated. With appropriate preconception counseling and man-
agement with a multidisciplinary team, women with systemic sclerosis can achieve
successful pregnancy outcomes.
References
1. Hummers LK, Wigley FM. Scleroderma. In: Imboden JB HD, Stone JH, editors. Current rheu-
matology diagnosis & treatment. 2nd ed. New York: McGraw-Hill; 2007. http://www.access-
medicine.com.proxy1.cl.msu.edu/content.aspx?aID=2725959 (Cited: 16 March 2013).
2. Boin F, Wigley FM. Clinical features and treatment of scleroderma. In: Firestein GS, Budd
RC, Gabriel SE, Mcinnes IB, O’Dell JR, editors. Firestein: Kelley’s textbook of rheumatology.
9th ed. Philedelphia: Elsevier/Saunders; 2013. p. 1368–70.
3. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35(1):35–42.

4. van Wyk L, van der Marel J, Schuerwegh AJ, Schouffoer AA, Voskuyl AE, Huizinga TW,
et al. Increased incidence of pregnancy complications in women who later develop sclero-
derma: a case control study. Arthritis Res Ther. 2011;13(6):R183.
5. Silman AJ, Black C. Increased incidence of spontaneous abortion and infertility in women with
scleroderma before disease onset: a controlled study. Ann Rheum Dis. 1988;47(6):441–4.
6. Steen VD, Medsger Jr TA. Fertility and pregnancy outcome in women with systemic sclerosis.
Arthritis Rheum. 1999;42(4):763–8.
Rheum Dis. 1988;47(12):982–7.
8. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol. 1999;94(1):15–20.
9. Taraborelli M, Ramoni V, Brucato A, Airo P, Bajocchi G, Bellisai F, et al. Brief report:
Successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis:
an Italian multicenter study. Arthritis Rheum. 2012;64(6):1970–7.
10. Chakravarty EF, Khanna D, Chung L. Pregnancy outcomes in systemic sclerosis, primary pul-
monary hypertension, and sickle cell disease. Obstet Gynecol. 2008;111(4):927–34.
11. Ibba-Manneschi L, Manetti M, Milia AF, Miniati I, Benelli G, Guiducci S, et al. Severe fibrotic
changes and altered expression of angiogenic factors in maternal scleroderma: placental find-
ings. Ann Rheum Dis. 2010;69(2):458–61.
12. Steen VD. Pregnancy in scleroderma. Rheum Dis Clin North Am. 2007;33(2):345–58, vii.
13. Lidar M, Langevitz P. Pregnancy issues in scleroderma. Autoimmun Rev. 2012;11(6–7):
A515–9.
14. Al-Maawali A, Walfisch A, Koren G. Taking angiotensin-converting enzyme inhibitors during
pregnancy: is it safe? Can Fam Physician . 2012;58(1):49–51.
15. Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD. Pregnancy outcome follow-
ing exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists:
a systematic review. Hypertension. 2012;60(2):444–50.
16. Nikpour M, Hissaria P, Byron J, Sahhar J, Micallef M, Paspaliaris W, et al. Prevalence, corre-
lates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a
cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther. 2011;13(6):R211.
17. Chakravarty EF. Vascular complications of systemic sclerosis during pregnancy. Int J
Rheumatol. 2010;2010, p. 1–5.
18. Hsu CH, Gomberg-Maitland M, Glassner C, Chen JH. The management of pregnancy and
pregnancy-related medical conditions in pulmonary arterial hypertension patients. Int J Clin
Pract Suppl. 2011;172:6–14.
19. Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective
multicenter study of pregnancy outcomes in women with heart disease. Circulation.
2001;104(5):515–21.
20. Williams D DJ. Chapter 44: Renal Disorders. 6th ed. Creasy and Rosnik’s Maternal-Fetal
Medicine. Principles and Practice, 2009. Philadelphia: Elsevier/Saunders. 19103–2899.
21. Boggess KA, Easterling TR, Raghu G. Management and outcome of pregnant women with
interstitial and restrictive lung disease. Am J Obstet Gynecol. 1995;173(4):1007–14.
22. Dempsey ZS, Rowell S, McRobert R. The role of regional and neuroaxial anesthesia in patients
with systemic sclerosis. Local Reg Anesth. 2011;4:47–56.
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Res Clin Rheumatol. 2010;24(3):373–85.
Chapter 9
Vasculitis and Pregnancy
Lindsay Lally and Robert F. Spiera
Introduction
The primary systemic vasculitides are a heterogeneous group of disorders that are
generally classified according to the size of the blood vessels involved and the organ
systems affected. Several forms of primary systemic vasculitis may affect women of
childbearing age. Data on pregnancy outcomes, neonatal outcomes, and effect of
pregnancy on vasculitis disease activity remain limited and are predominantly
reported in small case reports and series. A recent survey of a large cohort of women
with several types of systemic vasculitis reported that women who conceived fol-
lowing a diagnosis of vasculitis had higher rates of pregnancy loss and preterm
delivery compared to those who conceived prior to vasculitis diagnosis; however,
vasculitis activity reportedly increased during pregnancy in fewer than 20 % of
cases [1]. Vasculitis activity, end-organ damage from previous disease activity, and
effects of immunosuppressive therapy all must be taken into consideration when
approaching pregnancy in a woman with a systemic vasculitis. This chapter will
explore the relationship between pregnancy and several primary systemic vasculiti-
des, affecting large, medium, and small blood vessels.
Irrespective of the form of systemic vasculitis encountered, some general prin-
ciples regarding pregnancy and vasculitis can be applied. As many of the systemic
vasculitides are characterized by relapsing disease course, pregnancy should ideally
be attempted when the disease is in remission. Maternal and neonatal outcomes are
better in all forms of vasculitis when the mother enters pregnancy in remission.
Similarly, because most of the vasculitides can result in accrual of permanent
damage such as hypertension and renal insufficiency, thorough assessment of
L. Lally, M.D. (*) • R.F. Spiera, M.D.

Division of Rheumatology, Hospital for Special Surgery,
535 E. 70th Street, New York, NY 10021, USA
e-mail: lallyl@hss.edu; spierar@hss.edu
172 L. Lally and R.F. Spiera
both vasculitis activity and damage should be performed prior to pregnancy and
monitored meticulously throughout the peri-partum period. Lastly, the therapeutic
armamentarium relied upon to treat many of the systemic vasculitides includes
immunosuppressive agents, such as cyclophosphamide and methotrexate, that can
result in reduced fertility and/or direct fetal toxicity. The teratogenic potential of
these medications should be discussed with patients prior to initiation and, when
possible, discontinued several months before contemplation of pregnancy.
Vasculitis can occur in the context of many autoimmune diseases including rheu-
matoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome
(SS). In these cases, the vasculitis is considered secondary. As such, treatment is
generally aimed at the underlying disease process, though the concurrence of vascu-
litis may prompt more aggressive therapy. Vasculitis in RA typically occurs late in
the disease course in patients with rheumatoid nodules and erosive joint disease.
Rheumatoid vasculitis can affect medium and small blood vessels with involvement
of skin, peripheral nervous system (mononeuritis or symmetric polyneuropathy),
eye and heart being most common [2].
Vasculitis occurs in approximately 10–20 % of SLE patients. Immune-complex-
mediated small vessel cutaneous vasculitis, including urticarial vasculitis, accounts
for over 80 % of the vasculitic presentations in SLE [3]. Though less common, SLE
patients can develop medium-vessel vasculitis, typically affecting peripheral nerves
or visceral organs like the gastrointestinal tract.
Cutaneous vasculitis occurs in approximately 10 % of SS patients and is associ-
ated with extraglandular manifestations of disease, cryoglobulinemia, and poor
prognosis [4]. A broad range of neuropathies are associated with SS ranging from
small fiber sensory polyneuropathy, to mixed sensory-motor radiculoneuropathy to
mononeuritis multiplex. Vasculitic involvement of the nervous system is implicated
in several of these neuropathic manifestations [5]. Specifics regarding presentation,
treatment, and relationship to pregnancy of these connective tissue diseases will be
discussed elsewhere in the text in the chapters addressing those specific diseases.
Large Vessel Vasculitis
Takayasu’s Arteritis
Takayasu arteritis (TAK) is a granulomatous large vessel vasculitis predominantly

affecting the aorta and its branches. TAK is generally a disease of young women,
with a female to male ratio of 8.5–1 and the vast majority of cases presenting
between 10 and 30 years of age [6]. While most prevalent in Japan, India, and
Mexico, TAK can occur worldwide in a variety of ethnic populations [7].
The large vessel inflammation in TAK can result in aneurysm formation, wide-
spread stenosis, and end-organ ischemia. Constitutional symptoms such as fever,
night sweats, weight loss, and myalgia are common at presentation. As the disease
9 Vasculitis and Pregnancy 173
progresses, vascular manifestations such as claudication, discordant blood pressures

in limbs and absent pulses become more prominent. Hypertension, arterial bruits,
and decreased upper extremity pulses are frequent physical exam findings.
Laboratory abnormalities reflect the pro-inflammatory state with nonspecific eleva-
tions in acute phase reactants like the erythrocyte sedimentation rate and C reactive
protein, anemia, and thrombocytosis. There is no specific autoantibody associated
with TAK. While TAK is a clinical diagnosis, angiographic demonstration of abnor-
mal vasculature whether by conventional arteriography or noninvasive cross-
sectional imaging (CT, MRI, or PET scan) supports the diagnosis.
As TAK is most prevalent in women of reproductive age, there are many pub-
lished case reports and retrospective reviews of pregnancy in TAK patients.
Generally, maternal and neonatal outcomes were more favorable in patients with
fewer damaged vessels and less severe disease prior to becoming pregnant [8].
Aortic aneurysms and severe valvular disease are considered contraindications for
pregnancy. A systematic review of pregnancy and vasculitis published in 2012 iden-
tified 214 TAK pregnancies in the literature [9]. Preeclampsia complicated 45 % of
reported TAK pregnancies and preterm delivery occurred in 16 % of cases. Low-
birth weight and IUGR were noted in 20 % of newborns born to mothers with TAK.
Thirty cases of fetal loss and one neonatal death in a premature infant have been
reported. TAK patients with abdominal aortic and renal artery involvement are at
particular risk for hypertensive-related maternal and fetal complications.
Pregnancy does not commonly alter disease activity in TAK. Disease flare or
relapse during pregnancy is rare, occurring in <5 % of pregnancies. Active disease
during pregnancy can usually be managed with corticosteroids. There are case
reports of aortic dissection, aneurysm formation, progressive renal insufficiency,
congestive heart failure, cerebral hemorrhage, and stroke occurring in pregnant
patients with TAK; however, these vascular complications are usually related to
sequelae of previous disease coupled with the hemodynamic changes that accom-
pany pregnancy and not to active inflammatory disease [10, 11].
Worsening of preexistent hypertension during pregnancy accounts for the major-
ity of pregnancy morbidity experienced by TAK patients. Thus, aggressive blood
pressure control is necessary in the management of TAK patients during pregnancy
and delivery. An anti-hypertensive regimen without the potential for fetal toxicity
should be employed and may include calcium channel blockers, methyldopa or
hydralazine. There are case reports of women who had renal artery angioplasty
prior to conception and subsequently had uncomplicated pregnancy, causing the
authors to speculate that pre-pregnancy renal artery angioplasty may play a protec-
tive role against hypertension-related pregnancy complications in TAK [12].
Stenosis and occlusion in the arteries of the upper extremities may make nonin-
vasive blood pressure measurement from the arms difficult and necessitate measure-
ment in an uninvolved lower extremity with an adequate sized cuff. Invasive
intra-arterial blood pressure measurement may be used during delivery when scru-
pulous hemodynamic monitoring is critical [13]. Use of regional anesthesia, either
epidural or spinal, is generally recommended during delivery to avoid fluctuations
in blood pressure that may occur during active labor [14, 15]. Hyper- and
hypo-tension should both be avoided. Cesarean section was performed in 36 % of

reported TAK pregnancies, mostly for obstetric complications [5]. A case series of
33 TAK pregnancies from Japan suggest that, in addition to obstetric indications,
cesarean section should be considered in patients with high systolic blood pressure
at time of labor, severe disease, or aortic insufficiency or aneurysm [16]. Blood
pressure must continue to be closely monitored in the days following delivery as
post-partum hemodynamic changes may result in further vascular damage (e.g.,
aortic dissection) or regional hypoperfusion (e.g., cerebral ischemia). With careful
monitoring and close collaboration between medical, obstetrical, and anesthesia
providers successful maternal and fetal outcomes are possible in TAK.
Giant Cell Arteritis
Giant cell arteritis (GCA) is a systemic large vessel vasculitis affecting adults over
50 years of age. Given the population of affected patients, there are no reports of
pregnancy in women with GCA. One study suggested a possible protective effect of
multiparity on subsequent development of GCA. The mechanism of this proposed
relationship is unknown though the authors conjecture there might be a protective
effect of the high estrogen state on the vasculature [17].
Medium-Vessel Vasculitis
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to medium-sized

arteries. Cutaneous, nerve, gastrointestinal, and renal involvement are common in
PAN. Presentation varies depending on organ system involved; many patients pres-
ent with constitutional symptoms, rash, arthralgia, and myalgia. Peripheral nerve
involvement usually manifests as a mononeuritis multiplex with sudden foot or
wrist drop. Symptoms of mesenteric ischemia herald gastrointestinal involvement.
Hypertension and renal insufficiency accompany vascular renal involvement in
PAN. Patients typically have elevated acute phase reactants during active disease;
there are no specific autoantibodies associated with PAN. There is a known associa-
tion between active hepatitis B virus (HBV) and PAN. While effective vaccine pro-
grams in the developed world have dramatically reduced the rates of acute HBV,
large cohort studies have found an association between HBV and PAN in one-third
of cases, thus all patients with PAN should be tested for HBV [18]. A focal, segmen-
tal necrotizing vasculitis of medium-sized arteries is the characteristic pathologic
lesion of PAN on biopsy and can confirm the clinical diagnosis. Angiographic dem-
onstration of microaneurysms can be an acceptable surrogate of histopathologic
confirmation when tissue cannot be readily obtained [19]. In 50 % of cases, PAN

can be cured with corticosteroids without additional immunosuppressive therapy, in
addition to anti-viral therapy in patients with HBV-associated disease [20].
There are few case reports of pregnancy in patients with PAN as there is a slight
male predominance and peak incidence is in the sixth decade of life. In general,
PAN patients in remission at the time of conception experienced uncomplicated
pregnancies [21, 22]. Three of 19 reported pregnant PAN patients developed prema-
ture membrane rupture resulting in preterm delivery without any negative long-term
consequences on the mother or the infant [5]. In women with established disease
prior to pregnancy, vasculitis did not flare during pregnancy. Conversely, women
diagnosed with new-onset PAN during pregnancy had catastrophic outcomes [23,
24]. High rates of maternal mortality have been reported in de novo PAN during
pregnancy with uncontrolled hypertension, renal failure, and aneurysm rupture
resulting in maternal death. Nagey et al. suggested therapeutic abortion for new-
onset PAN during early pregnancy given the high risk of maternal mortality.
Small Vessel Vasculitis
Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and

eosinophilic granulomatosis with polyangiitis (EGPA) comprise the antineutrophil
cytoplasmic antibody (ANCA)-associated vasculitides (AAV), a group of small-
vessel vasculitides characterized by pauci-immune necrotizing inflammation. AAV
affects multiple organ systems with glomerulonephritis and pulmonary involvement
being frequent manifestations. Women and men are affected equally. As the nomen-
clature suggests, these vasculitides are associated with serologically detectable
ANCA. ANCAs directed against proteinase-3 (PR3) or myeloperoxidase (MPO)
are associated with GPA and MPA, respectively, in the vast majority of patients;
only about 30–40 % of patients with EGPA have detectable ANCA.
Before the approval of rituximab in 2010 for induction therapy in severe AAV,
the cornerstone of therapy was cyclophosphamide, which is well known to cause
premature ovarian failure and infertility in women of childbearing age [25]. Not
surprisingly, women with GPA treated with daily oral cyclophosphamide for
6 months or less had significant loss of ovarian reserve as measured by anti-
Müllerian hormone level [26]. Increased overall survival rates in AAV and the use
of rituximab as a therapeutic alternative to cyclophosphamide likely account for
increasing reports of pregnancy in women with a history of AAV [1].
GPA (formerly known as Wegener’s Granulomatosis) commonly involves the
upper and lower respiratory tracts and the kidneys. Relapsing disease occurs in half
of the patients with GPA following remission induction [27, 28]. The small body of
literature on pregnancy in GPA includes roughly equal numbers of patients with
newly diagnosed GPA during pregnancy, GPA flare during pregnancy, and women
whose GPA remained in remission throughout pregnancy [29]. Both maternal and
neonatal outcomes are linked to disease activity during gestation with favorable
outcomes generally achieved when vasculitis remains in remission. In addition to
the effect of previous cyclophosphamide on fertility, concerns regarding pregnancy
in GPA involve end-organ damage from vasculitis damage such as renal insuffi-
ciency, hypertension, and subglottic stenosis.
In a recent single-center retrospective study, Tuin et al. [30] report 22 pregnan-
cies in a cohort of 14 women with AAV (13 with GPA). All women were in remis-
sion at time of conception and all but one remained in remission throughout the
pregnancy. All pregnancies resulted in live births; two pregnancies were compli-
cated by preeclampsia and two were associated with preterm delivery. Differentiating
preeclampsia from renal GPA flare during pregnancy can be difficult as hyperten-
sion, proteinuria, and elevated inflammatory markers are characteristic of both enti-
ties. ANCA titers do not reliably correlate with disease activity in the gravid or
non-gravid state. Active urine sediment may suggest glomerulonephritis. Other
series report higher rates of premature delivery in GPA (35 %), particularly in those
with active vasculitis during gestation [5]. Women with active disease at conception
historically have poor outcome with pregnancy resulting in intrauterine fetal demise,
therapeutic abortion, or maternal death in one case [31].
The effect of pregnancy on vasculitis activity in GPA is variable. In women enter-
ing pregnancy in remission, a flare rate during pregnancy of 20–25 % has been
reported [26, 27]. The rate of flare in patients entering pregnancy with active disease
approached 100 %. Given high rates of relapse in the overall GPA population, it is
unknown whether pregnancy itself increases risk of relapse. There are a dozen
reported cases of de novo GPA diagnosed during pregnancy; a new GPA diagnosis
occurred most frequently during the second or third trimester of pregnancy [32]. The
severity of GPA manifestations and the gestational age of the fetus dictate therapy
during pregnancy. Many GPA flares are characterized by exacerbation of otolargy-
nogolic disease, which can typically be managed with low to moderate doses of
corticosteroids. Worsening of subglottic stenosis, which may present with progres-
sive dyspnea or stridor, can occur during pregnancy. It is advisable that in women
with known or suspected subglottic disease, the airway be assessed by an otolaryn-
gologist with expertise in GPA prior to conception and pregnancy planning; if inter-
vention is necessary, it is of course optimal to do so prior to pregnancy. The cicatricial
nature of these lesions makes them minimally responsive to immunosuppressive
therapy and surgical intervention is often required [33]. Endoscopic intratracheal
dilation with glucocorticoid injection has been successfully performed in pregnant
patients with airway compromise. During delivery, the anesthesiologist should know
the extent and diameter of a patient’s subglottic disease so appropriate equipment for
endotracheal intubation is available should that be required to maintain the airway.
Severe disease, defined as organ or life-threatening disease, in the first trimester
resulted in medical termination in all cases. Later in pregnancy, severe disease has
been treated successfully with high-dose corticosteroids and cyclophosphamide,
which may be safe in the third trimester, or intravenous immunoglobulin (IVIg) [34].
Azathioprine in combination with corticosteroids is safe in pregnancy and has also
been utilized for active disease. While there is limited transmission of rituximab
across the placenta, a case report of woman with GPA who received rituximab
during their first trimester reported no observed adverse effect on the pregnancy or
fetal development [35].
Compared to GPA, MPA is generally characterized by fewer relapses and less
frequent involvement of the upper respiratory tract. There are very few pregnancies
reported in MPA, which may be explained by now outdated classification criteria
which categorized many of these patients as having PAN. There are three reports of
de novo MPA diagnosed in late pregnancy all presenting with pulmonary–renal syn-
drome [36–38]. Conventional therapy with cyclophosphamide and high-dose corti-
costeroids plus plasma exchange in one case was used with variable results; two
women delivered preterm, low-birth weight infants while one woman suffered spon-
taneous abortion and died from sepsis. While most cases of AAV are idiopathic,
some drugs can induce ANCAs and a secondary vasculitis. Propylthiouracil, which
is commonly used for management of hyperthyroidism in pregnant patients due to
favorable safety profile, is known to induce MPO autoantibodies [39, 40]. Cessation
of the drug has resulted in resolution of symptoms and good maternal and neonatal
outcomes were reported. Thus, in pregnant women with a suspected new diagnosis of
MPA during pregnancy, careful history including medication history is important.
There is a reported case of a woman with quiescent MPA and persistently posi-
tive MPO autoantibody who relapsed at 33 weeks gestation, underwent emergent
cesarean section and delivered a healthy infant [41]. Within 24 h of delivery, the
infant developed pulmonary-renal syndrome and demonstrated high-titer MPO anti-
bodies from presumed placental transfer of maternal antibody. The infant was suc-
cessfully treated with corticosteroids and supportive care. There is a subsequent
report of a woman with a history of MPA and persistent MPO positivity who main-
tained remission throughout pregnancy and delivered a healthy newborn with no
evidence of vasculitis despite detectable MPO in the neonate [42].
Eosinophilic Granulomatosis with Polyangiitis
EGPA (formerly known as Churg–Strauss Syndrome) is a multi-system necrotizing

vasculitis with granulomatosus inflammation and peripheral and tissue eosinophilia.
Allergic rhinitis, asthma, skin lesions, and peripheral neuropathy are common man-
ifestations of EGPA. Cardiac, gastrointestinal, and central nervous system involve-
ment portend poor prognosis [43]. Asthma is the fundamental feature of EGPA and
development of asthma and atopy often precede frank vasculitic manifestations
by several years.
There are approximately 25 reports in the literature of pregnancy in women with
EGPA [44–46]. The vast majority of EGPA pregnancies resulted in uncomplicated
pregnancy with good maternal and neonatal outcome. The majority of cases reported
are in women with EGPA prior to pregnancy and inactive disease at the time of
conception; however, in about 7 % of cases, EGPA was diagnosed during preg-
nancy. Premature delivery occurred in about 25 % of pregnancies, including two
twin gestations [47, 48]. Low-birth weight was reported in fewer than 10 % of
neonates. Few cases of fetal loss have been reported [42].
EGPA flare during pregnancy seems to occur in less than one quarter of women
in remission at the time of conception. Worsening of asthma is a common manifes-
tation of EGPA during pregnancy and can usually be managed with corticosteroids.
Discontinuation of inhaled steroids for asthma during pregnancy has been suggested
as a trigger for diagnosis of de novo EGPA [49]. More severe disease manifestations
such as mononeuritis multiplex and cardiac involvement have been reported during
pregnancy. Women with severe disease have been treated with cyclophosphamide,
IVIg, and azathioprine [48, 50]. As with EGPA not related to pregnancy, cardiac
involvement is the greatest cause of mortality in these patients. There are two reports
of maternal death in the peri-partum period both related to cardiac involvement as
well as one report of a woman undergoing successful heart transplant after develop-
ment of severe post-partum cardiomyopathy with histopathologic confirmation of
EGPA [51, 52].
Cryoglobulinemic Vasculitis
Cryoglobulins are monoclonal or polyclonal immunoglobulins that precipitate at

temperatures lower than 37 °C and dissolve with rewarming. Cryoglobulinemia
refers to the vasculitic syndrome resulting from deposition of cryoglobulin-
containing immune-complexes in skin, joints, kidney, or other organs throughout
the body. Cryoglobulinemia is classified according to the composition of the immu-
noglobulins with type I referring to monoclonal IgG cryoglobulins and type II and
III (mixed cryoglobulinemia) referring to presence of polyclonal IgG and IgM.
Mixed cryoglobulinemia is associated with hepatitis C virus (HCV) in 80–90 % of
cases [53]. Other causes of mixed cryoglobulinemia are autoimmune diseases such
as SS or SLE or viral infection other than HCV.
A triad of palpable purpura, arthralgia and weakness is present in the majority of
patients with cryoglobulinemic vasculitis at diagnosis. Renal involvement, a glo-
merulonephritis, occurs in approximately 20 % of patients. Cryoglobulins can be
measured and quantified from the serum of patients; however, these samples must
be kept warm to avoid precipitation of cryoglobulins prior to analysis in the lab.
These patients often have positive Rheumatoid Factor (RF), as the IgM component
of the cryoglobulin is an RF. Hypocomplementemia with low C4 is also common,
as complement components are consumed as part of the immune-complexes. Testing
for HCV should be done in all patients with suspected mixed cryoglobulinemia.
There are reports of six pregnancies in four women with cryoglobulinemia in the
literature. One report of a woman with chronic HCV and cryoglobulinemia in remis-
sion at time of pregnancy reported a flare during pregnancy with arthralgia, hyper-
tension, and proteinuria necessitating delivery via cesarean section at 31 weeks; the
method by which cryoglobulinemia was differentiated from pregnancy complica-
tions like preeclampsia is not discussed [54]. Two other case reports describe
women diagnosed with mixed cryoglobulinemia during pregnancy [55, 56]. While
both women presented with palpable purpura and one had evidence of renal involve-
ment, neither had detectable HCV or evidence of systemic autoimmune disease.
Both women delivered full-term healthy neonates with no other reported pregnancy-
related complications. Plasma exchange and corticosteroids were used to manage
disease during pregnancy. Sibilia et al. [57] describe a woman with type I cryo-
globulinemia in remission at the time of conception who remained in remission
throughout pregnancy and delivered twins vaginally at 39 weeks. One twin subse-
quently developed a macular rash upon removal from the incubator with serologic
demonstration of positive cryoglobulins which resolved with rewarming, suggest-
ing maternal transplacental transfer of cryoglobulins [58].
Variable Vessel Vasculitis
Behçet’s Disease
Behçet’s disease (BD) is a systemic vasculitis that can involve small, medium, or
large vessels in the arterial or venous system. Recurrent oral and genital ulcers are
a hallmark of BD. Other manifestations can include skin lesions, arthritis, uveitis,
gastrointestinal ulceration, and thrombosis. BD is most prevalent in persons of
Mediterranean or east Asian decent. Usually diagnosed in young adults aged 20–40,
Behçet’s has equal prevalence in men and women in endemic areas, but women are
affected more commonly in reports from the USA and northern Europe [59]. BD is
a clinical diagnosis that requires presence of recurrent oral ulcers in combination
with other systemic manifestations including skin lesions, pathergy, genital ulcers,
or eye disease. There is an association of BD with human leukocyte antigen (HLA)
B51; however, there are no serologic tests specific for the diagnosis.
As BD often presents in women of childbearing age, there are multiple series
reporting pregnancies in women with BD. Generally few maternal and fetal compli-
cations are reported with rates of preeclampsia, premature delivery, growth restric-
tion, and fetal loss paralleling that of the general population [60]. One case–control
study matching 135 pregnancies from 31 BD patients with age- and parity-matched
healthy controls found complications, including hypertension, gestational diabetes,
and premature delivery, in 26 % of BD pregnancies compared to 2 % of control
pregnancies [61]. They also reported significantly higher rates of miscarriage (20 vs
6 %) and cesarean section (15 vs 5 %) in BD compared to controls. Similar results
have not been echoed in other sizable cohorts of BD pregnancies.
Several studies suggest a protective effect of pregnancy on BD with improved or
stable disease in 70 % of patients, even amongst those with active disease entering
pregnancy [60, 61]. In the approximately 20 % of patients who flared during preg-
nancy, genital ulcers, rash, arthritis, and uveitis were the commonest manifestations.
There is a case report of colonic perforation from active BD of the gastrointestinal
tract during pregnancy [62]. Active disease during pregnancy can usually be managed
with corticosteroids. Colchicine, which can be helpful for the mucocutaneous mani-
festations of BD, was recently shown to be safe and non-teratogenic during preg-
nancy in a cohort of women that included those with BD [63]. Azathioprine, which is
often the immunosuppressive agent of choice for ocular BD, can also be safely uti-
lized during pregnancy. Infliximab, a tumor necrosis factor (anti-TNF) alpha inhibi-
tor, has been used for refractory uveitis during pregnancy with no reported adverse
maternal or neonatal events [64]. Though there are limited observational data, use of
anti-TNF therapy appears to be safe for both mother and fetus during pregnancy [65].
BD and pregnancy both increase propensity for thrombosis; as such, there are
several reports of thrombotic events during pregnancy and the post-partum period
[66]. In the setting of thromboembolism, anticoagulation with heparin is usually
administered in combination with immunosuppressive therapy. Some experts advo-
cate for prophylactic anticoagulation in the peri-partum period for those patients
with history of previous thrombosis given the risk for massive and potentially fatal
thromboembolism during this critical period. Others have suggested IVC filter
placement, as this may also mitigate risk of fatal thromboemboli [66, 67].
Rare cases of neonatal BD, born to mothers with active BD during pregnancy,
have been described [68, 69]. All of the neonates had transient oral ulcers and pus-
tular skin lesions noted shortly after birth which resolved with supportive care.
There are also several reported cases of gastrointestinal BD in neonates, including
one from a mother who had no history of BD [70, 71]. Corticosteroids have been
used to successfully treat infants with severe colonic ulcerations attributable to BD.
Examination of placental pathology from two women with BD showed necrotizing
villitis and decidual vasculitis with a neutrophil predominant infiltration, which is
similar to histology of BD in other organ systems [72]. The authors speculate that
placental involvement may account for both intrauterine transmission of BD and
high rates of fetal loss described in some cohorts.
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Chapter 10
Myositis and Pregnancy
Stephen J. Di Martino
Introduction
The idiopathic inflammatory myopathies (IIM) are a group of rare autoimmune

conditions that share the common theme of an immune-mediated attack on skeletal
muscle with resulting clinical weakness. The group includes dermatomyositis
(DM), polymyositis (PM), juvenile myositis (JM), inclusion body myositis (IBM),
cancer-associated myositis, overlap myositis, and necrotizing autoimmune myopa-
thy (NAM). Women are affected at three times the rate of men with the exceptions
of overlap myositis (myositis patients that also meet criteria for or share features of
other autoimmune conditions) in which the ratio is higher at 9:1, and IBM, which
affects men more than women at a ratio of 3:1.
In general, studies performed in patients with inflammatory myopathy are sub-
ject to several challenges at the onset. First, the incidence of IIM is estimated to be
between five and ten cases per million people; because these conditions are so rare,
most reports only include small numbers of patients. Indeed, most of the therapeutic
trials on which current treatment is based have included less than 30 patients, mak-
ing it difficult to extrapolate findings to individual patients. Second, the differential
diagnosis is broad for these entities and includes muscular dystrophies, metabolic
myopathies and toxic myopathies, all of which can present with the same clinical
features as IIM, and some of which may even exhibit inflammation on muscle
biopsy. Therefore, it is impossible to be certain that a group of myositis patients in
a given study does not include some patients with non-inflammatory myopathy. The
presence of myositis-specific autoantibodies (MSA’s) can be helpful in establishing
the diagnosis of a true inflammatory myopathy; however, because there are so many
S.J. Di Martino, M.D., Ph.D. (*)

Division of Rheumatology, Hospital for Special Surgery, 535 East 70th Street,
New York, NY 10021, USA
e-mail: dimartinoS@hss.edu
186 S.J. Di Martino
MSA’s, they also serve to further subdivide these rare entities, again making it
difficult to extrapolate study results to individual patients.
It has been estimated that only 14 % of patients with inflammatory myopathy
develop disease before or during childbearing years [1]. Therefore, because IIM’s
are already rare, diverse, and have a broad differential, the challenges described
above are amplified for investigators seeking to understand the association of preg-
nancy with inflammatory myopathy. The vast majority of literature concerning IIM
and pregnancy are single cases or reports of two or three patients. Despite the lim-
ited numbers, there are several clinical scenarios that have been described in articles
discussing myositis and pregnancy: (1) new onset of disease during pregnancy (2)
pregnancy in a patient with preexisting disease (with or without flare), and (3) new
disease onset after pregnancy.
In this chapter, we review 36 publications that, in total, describe 78 pregnancies
of 59 women. Overall, there were 31 women with DM, 21 women with PM, 5
women with JM or JDM (juvenile dermatomyositis), and one woman with PM/DM.
Six patients were known to be Jo-1 positive and one PL-7 positive; however, most
were not tested. These cases include 27 pregnancies where there was no flare of
preexisting disease, 21 cases in which preexisting disease flared during pregnancy,
20 cases of new onset disease during pregnancy, and 10 cases of new onset disease
shortly after pregnancy. In these published cases, three women had three reported
pregnancies each and 12 women had two reported pregnancies each. Many patients
had pregnancies before the diagnosis of inflammatory myopathy, but there was no
clear indication that there was a higher rate of complications before the onset of
disease; however, this issue has not been examined in detail. There are no reported
cases of malignancy-associated inflammatory myopathy during pregnancy. There
are several important concerns when looking at this group of publications. First, it
seems reasonable to suspect that pregnancies in women with preexisting inflamma-
tory myopathy who had uneventful outcomes would be less likely to be reported,
meaning that the existing literature may over-represent negative outcomes. Second,
these conditions can be difficult to diagnose, therefore, cases of new onset during
pregnancy, especially those with poor outcomes, may not be reported due to lack of
a definitive diagnosis.
Fertility in Women with Inflammatory Myopathies
The issue of fertility in patients with inflammatory myopathy has been addressed in
two publications [2, 3] to date. Both reports looked at very small groups of patients
who developed IIM before or during their childbearing years. One concluded that
there was an incidence of nulliparity comparable to the general population [2] while
the other concluded that there was a reduction in the fertility rate [3]. The small
sample sizes make it impossible to have confidence in either conclusion.
10 Myositis and Pregnancy 187
Pregnancy Outcome in Women with Inflammatory

Myopathies
Pregnancy Outcome with Disease Onset During Pregnancy
Twenty cases of new onset inflammatory myopathy during pregnancy have been
described; these are summarized in Table 10.1 [3–19]: eleven patients had DM,
seven patients had PM, one had JDM, and one had PM/DM. Cases were reported
with onset during each of the three trimesters: nine cases presented before 15 weeks,
four cases presented at 18–24 weeks, and seven cases presented after 28 weeks.
Ages of the patients at pregnancy ranged from 14 to 42 years old. It was the first
pregnancy for 7 of the 20 patients. Eleven patients had previous pregnancies before
the diagnosis of myositis. Three of those 11 previous pregnancies did not end with
a live birth; reasons for this were not discussed.
Of the seven patients who presented with disease late in pregnancy (after 28
weeks), all pregnancies produced healthy babies, although one was small for gesta-
tional age (SGA). Four of those seven patients were treated with corticosteroids and
three were untreated. One of the treated patients was induced at 34 weeks due to
disease activity and was noted to respond better to therapy after delivery [11], and
two patients had Cesarean sections at 37 weeks [9, 19]. In at least three of the cases,
there was the suggestion of active disease as manifested by descriptions of proximal
weakness and dysphagia. This suggests that healthy babies were born despite sig-
nificant disease activity when disease onset was late in pregnancy.
There were four cases of disease onset between 18 and 24 weeks: two pregnan-
cies resulted in healthy babies, one was an intrauterine death, and the other was an
elective abortion. The two patients with successful pregnancies were treated with
high-dose steroids (one of these patients also received monthly IVIG) and had
Cesarean sections after 35 weeks: both babies were healthy, although one was SGA
[15, 17]. The patient who had an intrauterine death presented with myositis at 23
weeks and lost the baby at 24 weeks [14]. The fourth patient, who was Jo-1 positive,
had interstitial lung disease and chose to have an elective abortion [16]. Nine cases
presented early in pregnancy, during the first trimester: six of those nine pregnancies
ended in intrauterine or neonatal death. Seven of the nine pregnancies were treated
with high-dose corticosteroids. One of the patients who was not treated had a his-
tory of tuberculosis and histoplasmosis [4] and although this patient had a live birth
at 39 weeks, the infant died shortly thereafter; there were no noted placental abnor-
malities. The other patient who was not treated did not have inflammation observed
on muscle biopsy: she went into rapid remission shortly after birth after delivering
a healthy baby at 36 weeks following artificial rupture of membranes [6]. In the two
other cases that resulted in a healthy baby, one was treated with high doses of corti-
costeroids starting at 15 weeks [7] and one was treated with both high doses of
corticosteroids and monthly IVIG starting at 21 weeks [18].
188
Table 10.1 Treatment and outcome of pregnancy in inflammatory myopathy with onset during pregnancy
Time of
Reference Diagnosis disease onset Therapy Fetal/neonatal outcome
Tsai et al. [4] DM 10 weeks Topical steroid Neonatal death (39 weeks)
Bauer et al. [5] PM 3 months Prednisone 60–160 mg/day IUFD (8 months)
Katz [6] PM 3 months None Induced 36 weeks, healthy
Gutierrez et al. [3] Pt 1: DM First trimester Prednisone IUFD < 20 weeks
Pt 2: DM First trimester Prednisone IUFD > 21 weeks
Pt 4: PM First trimester Prednisone Neonatal death (premature birth)
England et al. [7] DM 15 weeks Corticosteroid IUGR
Emy et al. [9] DM/PM 30 weeks Corticosteroid IUGR (C/S 37 weeks)
Ishii et al. [12] DM (first pregnancy) 32 weeks None Delivered 38 weeks, healthy
Pinheiro et al. [8] JDM 35 weeks Corticosteroid Emergency C/S 37 weeks, healthy
Age 14
Satoh et al. [14] PM 23 weeks Not stated IUFD 24 weeks
Harris et al. [10] DM 36 weeks None Induced 38 weeks, healthy
Solomon and D’Alton [11] DM 29 weeks Prednisone 80 mg/day Induced 34 weeks, healthy
Kofteridis et al. [13] DM 13 weeks Prednisone 1 mg/kg IUFD 14 weeks
Messina et al. [15] Pt 1: PM Third trimester None Healthy
Pt 2: PM 6 month Prednisone 60 mg/day, tapered Healthy
Vancsa et al. [19] Pt 7: DM 28 weeks High-dose IV corticosteroid with po taper 37 weeks, healthy
Nozaki et al. [17] DM 18 weeks Prednisone 60 mg/day, tapered (IVIG after delivery) IUGR, Emergency C/S 35 weeks
Okada et al. [16] PM 20 weeks None (Prednisone, tacrolimus, cyclophosphamide after TOP) Elective termination pregnancy
Linardaki et al. [18] DM 15 weeks Methylprednisolone 24 mg/day, IVIG monthly Planned C/S 37 weeks, healthy
DM dermatomyositis, PM polymyositis, JM juvenile myositis, JDM juvenile dermatomyositis, IUFD intrauterine fetal demise, IUGR intrauterine growth restriction, C/S
Cesarean section, IVIG intravenous immunoglobulin, TOP termination of pregnancy
S.J. Di Martino
While the interpretation of the above information is subject to concerns men-

tioned earlier, it seems reasonable to conclude that the earlier the disease presents
during pregnancy, the greater the likelihood of a poor outcome. Whether or not this
is a consequence of disease activity, therapy, or both is not clear. However, in 7 of
the 12 successful pregnancies, the patients were treated with high-dose corticoste-
roids (four of these patients were started on corticosteroids in the first or second
trimester). All of the losses occurred in pregnancies with disease onset prior to the
third trimester: eight fetal or neonatal deaths in total of the 20 cases reported where
disease onset occurred during pregnancy. However, it is important to note that five
of these eight losses were reported in 1986 or earlier, two were reported in the
1990s, and the one published in 2012 was an elective abortion. Therefore, given
advances in maternal–fetal medicine, one can question whether these numbers are
applicable to modern-day pregnancies.
Pregnancy Outcome in Which Disease Was in Remission During

Gestation
There have been 27 reported pregnancies in 22 women with preexisting inflamma-

tory myopathy that remained quiescent during pregnancy [1–3, 12, 19–25]. Fourteen
patients had DM, two had JDM, and six had PM. Ages at pregnancy ranged from 22
to 42 years. It was the first pregnancy for 4 of the 22 women. The duration of remis-
sion prior to the beginning of pregnancy was only reported in about one third of
cases and ranged from less than 1 to 5 years. Nine patients were treated with low
doses of steroids, ranging from a low of 5 mg prednisone (4 mg methylprednisone)
to a high of 12 mg of methylprednisone, possibly suggesting that in these patients
disease remission was medication-dependent. Seven of the nine pregnancies in
which steroids were used resulted in healthy babies at term. In the other two preg-
nancies, one required an emergency Cesarean section at 32 weeks (the baby was
healthy, and the placenta exhibited borderline massive fibrin deposition) [22], and
the other was a spontaneous abortion in the second trimester reported in 1962 [20].
In the remaining 18 pregnancies that were not treated with steroids, two patients had
elective abortions [19], there were two intrauterine deaths [3, 20] and one neonatal
death in a twin pregnancy [3]. The two spontaneous abortions and neonatal death
were all reported in 1984 or earlier. Three of the women had a flare of disease
postpartum (mild in two of the three cases) [3, 24, 25].
As one might expect, the absence of disease activity during pregnancy appears to
be associated with a higher percentage of favorable outcomes. This was the case
whether or not steroids were employed to keep the disease under control. Because
one cannot differentiate between a patient in complete, permanent remission and
one who has the potential for disease activity, it may be that the group maintained
on steroid to prevent disease activity may be the most instructive. The favorable
outcomes seen in this group provide compelling information to suggest keeping a
patient in remission on therapy into pregnancy.
190 S.J. Di Martino
Pregnancy Outcomes in Which Disease Flares During Pregnancy
There are reports of 21 pregnancies in 17 patients with known inflammatory myopa-

thy that flared during pregnancy, with treatment and clinical outcomes summarized in
Table 10.2 [1–3, 19–22, 26–32]. Ages of patients ranged from 20 to 40 years. Seven
patients had DM, seven patients had PM, and three patients had juvenile myositis.
This was the first pregnancy for 6 of the 17 patients. Four of the remaining eleven
patients had previous unsuccessful pregnancies for unclear reasons. A number of the
patients were in remission at the beginning of pregnancy, although this was often not
commented upon. In the few reports where the information was available, time of
remission before pregnancy ranged from less than 3 months to greater than 5 years.
Seven pregnancies have been reported in which the disease was active going into
pregnancy; three of these cases were in a single patient who had a diagnosis of juvenile
myositis at 10 years old and became pregnant in three successive years starting at age
25 [19]. Her disease was active going into all three pregnancies, although the severity
of the symptoms was not discussed. The patient was treated with high doses of corti-
costeroids during each pregnancy and had a spontaneous abortion in the first trimester
of both the first and second pregnancies. The third pregnancy resulted in a healthy
baby at term; during this time, the patient was maintained on 12 mg methylprednisone.
In the four remaining cases [19, 30–32], the onset of disease occurred just prior to
pregnancy and the patients were flaring while entering pregnancy. One of these patients
had an elective abortion and responded to IVIG after the termination of pregnancy
(TOP) [30]. Two other cases were reported in 2005 [31] and 2007 [32]; each patient
was treated with IVIG, although the case presented in Mosca et al. [31] was also
treated with high doses of corticosteroid. Each mother delivered a healthy baby: the
patient treated with steroids had a Cesarean section at 35 weeks, the other had a spon-
taneous vaginal delivery at term. The last case developed anti-synthetase syndrome 3
months before pregnancy and was on high doses of steroids going into pregnancy;
remission was achieved by 6 months and a healthy premature baby was delivered [19].
Five pregnancies have been reported in which there was a myositis flare in the
second trimester. One patient had an elective TOP with subsequent good response
to therapy [21]. Another patient had an intrauterine death at 22 weeks gestation (this
patient started the pregnancy on 10 mg of prednisone and was tapered off by the
third month) [27]. Each of the three remaining patients was treated with high-dose
corticosteroid and each delivered a healthy baby.
Three pregnancies (including one twin pregnancy) in which preexisting disease
flared in the third trimester have been reported [3, 28]. Severity of disease was not
discussed but all patients were treated with standard doses of corticosteroid. All
three pregnancies produced healthy babies although two infants were premature and
the twins were small for age.
In the remaining six reported cases with disease flare during pregnancy, it is
unclear exactly when during the pregnancy the patient’s disease became active. Four
of the six ended with intrauterine death or abortion, and two had healthy babies. In
the two cases with healthy babies, both patients were treated with steroids and both
were reported before 1965 [20, 26]. Two of the four pregnancy losses were in the
10
Table 10.2 Treatment and outcome of pregnancy in inflammatory myopathy with flare during pregnancy
Reference Diagnosis Time of disease flare Treatment Fetal/neonatal outcome
Glickman [26] DM Duration of pregnancy Prednisone 20 mg/day Healthy, term
Massé [20] DM (first pregnancy) Unknown Corticosteroid Healthy
Gutierrez et al. [3] Pt 3 (second pregnancy): JDM Third trimester Prednisone Premature, C/S
Pt 7 (first pregnancy): DM Third trimester Prednisone Premature
Myositis and Pregnancy
King and Chow [2] Pt 3: DM 18 weeks Prednisone 60 mg/day taper Healthy, term
Houck et al. [27] JM (first pregnancy) 17 weeks None IUFD 22 weeks
JM (second pregnancy) Second trimester Prednisone 20 mg/day Induced 37 weeks, healthy
Le Thi Huong et al. [28] PM 37 weeks Corticosteroid IUGR
Rosenweig et al. [29] PM 26 weeks Prednisone 60 mg/day Emergency C/S 27 weeks
Papapetropoulos et al. [21] PM (second pregnancy) 10 weeks Prednisone 60 mg/day Termination of pregnancy 16 weeks
Silva et al. [1] PM Unknown None IUFD 34 weeks
Park et al. [30] DM Time of conception Unknown Termination of pregnancy
Mosca et al. [31] DM Time of conception Prednisone 40–60 mg/day, IVIG C/S for PPROM 35 weeks, healthy
Williams et al. [32] 2 months prior to conception IVIG Healthy, term
Vancsa et al. [19] Pt 1 (first pregnancy): PM Prior to conception Methylprednisolone high dose, taper Premature at 35 weeks, healthy
Pt 5 (first pregnancy): JM Prior to conception Corticosteroid Spontaneous abortion, first trimester
Pt 5 (second pregnancy): JM Prior to conception Corticosteroid Spontaneous abortion, first trimester
Pt 5 (third pregnancy): JM Prior to conception Prednisone high dose, taper Healthy, term
Pt 9 (first pregnancy): PM Unknown Corticosteroid IUFD
Pt 9 (second pregnancy): PM Unknown Corticosteroid IUFD
Al-Adnani et al. [22] PM (first pregnancy) Unknown None IUFD, 34 weeks
DM dermatomyositis, PM polymyositis, JM juvenile myositis, JDM juvenile dermatomyositis, IUFD intrauterine fetal demise, IUGR intrauterine growth restriction, C/S
Cesarean section, PPROM preterm premature rupture of membranes, IVIG intravenous immunoglobulin
191
192 S.J. Di Martino
same patient, who was treated with steroid during both pregnancies [19]. The other
two losses were in patients who were not treated because they had high creatine
kinase (CK) but no clinical weakness: these intrauterine deaths were in the third
trimester and were associated with massive amounts of fibrin in the placentas [1, 22].
It is difficult to draw conclusions regarding several important questions because
many of the reports are missing critical information including the time during preg-
nancy when the disease became active and the duration of disease remission prior to
pregnancy. The three cases reported to have flared during the third trimester all
resulted in healthy babies, giving some support to the idea that outcome may be
more favorable if there is no disease activity early in the pregnancy. Corticosteroids
were used in all 12 successful pregnancies. Also notable is that two patients were
independently reported with high CK levels but no weakness followed by preg-
nancy losses in the third trimester [1, 22]. This finding suggests that elevated CK
may be clinically significant even in the absence of weakness. Both patients had
massive deposits of fibrin in the placenta.
Outcomes of Women with Multiple Pregnancies
The question of whether prior pregnancy outcome can be predictive of the outcome
of a subsequent pregnancy in an individual patient is partially addressed in the cur-
rent literature. Fifteen women with inflammatory myopathy and multiple pregnan-
cies have been described [2, 3, 12, 19, 21–23, 25, 27] including three women with
three documented pregnancies each. One of these women had spontaneous abor-
tions in her first two pregnancies followed by a healthy baby [19]. One had a healthy
baby followed by an elective TOP, which was subsequently followed by another
healthy baby [21]. The third woman had onset of symptoms shortly after delivery of
a healthy baby and had two subsequent normal births after diagnosis of disease [23].
Of the remaining 12 women (who each had two pregnancies), nine had established
disease before both of their reported pregnancies. Four of these nine had a pregnancy
loss during their first pregnancy and three of them went on to have a healthy baby
during their second pregnancy, although two of these were premature births. Of the
five women who had healthy babies during their first described pregnancy, two had
elective TOP, one had a twin pregnancy where one of the twins died during the neo-
natal period and two women had healthy babies. While one must be cautious in draw-
ing conclusions from such a limited amount of information, at this point there does
not appear to be support for the idea that the outcome of one pregnancy is predictive
of subsequent pregnancies in women with inflammatory myopathies.
Neonatal Outcome
In general, neonatal outcome is good and is complicated primarily by the sequelae

associated with preterm delivery or small size for gestational age. The characteristic
rash of dermatomyositis has not been described in any newborn of a mother with
polymyositis or dermatomyositis to date. However, in one publication [15] the

authors reported elevation of the CK level in two newborns, ages 2 and 4 months.
This suggests the possibility of a passive transfer of autoimmunity from mother to
child; however, the babies were not weak and it was unclear if the source of the CK
was neonatal or maternal. This was the only article in which this potentially impor-
tant issue was examined.
New Disease Onset After Pregnancy
There are ten reports of new onset inflammatory myopathy presenting shortly after
pregnancy [3, 12, 23, 25, 33–36], ranging from 4 days to 3 months postpartum. Five
of the cases developed DM, five developed PM; one patient was anti-RNP positive
and had overlap features of systemic lupus erythematosus (SLE). At least two of the
cases followed the patient’s first pregnancy, although this information was reported
in only one-third of cases. Five cases followed the delivery of a healthy child. Two
followed a spontaneous abortion (one of a 3-week-old embryo) and two followed
fetal losses at 32 and 38 weeks. In the case of the 38-week pregnancy loss, massive
amounts of perivillous fibrin were observed in the placenta: this patient was Jo-1
positive [36]. Three of the ten cases of new onset disease after pregnancy reviewed
here were reported by Steiner et al. [23]: these authors examined their group of 22
female polymyositis patients and found that eight patients (36 %) developed PM
during their childbearing years. Three of these eight patients (38 %) developed the
disease within 3 months of delivery; the authors argue that this high percentage of
patients who develop disease temporally close to pregnancy suggests that the asso-
ciation is not coincidental.
Treatment Options
The only therapies that have been described for active inflammatory myopathy dur-
ing pregnancy are corticosteroids and IVIG. While corticosteroids are associated
with numerous pregnancy complications, their use in patients with active inflamma-
tory myopathy does not appear to be associated with pregnancy loss. Of 27 success-
ful pregnancies in patients with either new onset of disease during pregnancy or a
flare of existing disease, 20 (74 %) were treated with high doses of steroids. In
contrast, in the 14 patients with disease activity who had pregnancy loss, only seven
(50 %) were treated with steroids. When one looks at patients with preexisting dis-
ease who did not flare during pregnancy, one of nine (11 %) patients treated with
low doses of steroids had a pregnancy loss, while 3 of 17 (18 %) patients not treated
with steroids had a pregnancy loss.
There are three reports of IVIG (1g/kg/day over 2 days/per month) use during
pregnancy in patients with active inflammatory myopathy [18, 31, 32]. All three
patients had disease activity either going into pregnancy or in the first trimester and
194 S.J. Di Martino
the IVIG was started in either the first or second trimester; two of the three were also
treated with moderate-dose corticosteroids [18, 31]. In one report, the dose of 1
gram/kilogram/day (g/kg/day) for two consecutive days per month was used starting
in the second trimester and the patient received a total of four doses [18]: a healthy
baby was delivered by planned Cesarean section at 37 weeks. In a second report
[31], the patient was treated with 1 g/kg/day for two consecutive days starting at 17
weeks and continued monthly: the baby was born healthy by Cesarean section at 34
weeks after premature rupture of membranes. In the third report [32], the patient
was treated with 1 g/kg/day for two consecutive days monthly for 3 months starting
in the first trimester and remission was achieved by 19 weeks. However, the patient
flared again at 28 weeks and IVIG was resumed until a spontaneous vaginal delivery
at term of a healthy baby. This patient received six monthly cycles of IVIG in total.
Fibrin Deposition and Massive Perivillous Fibrin Deposition

in the Placenta
There are several reports of pregnancies in women with inflammatory myopathies

associated with massive perivillous fibrin deposition (MPVFD) in the placenta [1,
14, 22, 36]. MPVFD is a rare and serious condition of unknown etiology, although
autoimmune mechanisms have been suspected. Incidence is estimated between
0.028 and 0.5 % with risk factors including infection, autoimmune disease, and
thrombophilia. Autoimmune conditions that have been associated with MPVFD
include SLE, antiphospholipid antibody syndrome, systemic sclerosis, and inflam-
matory myopathy. The condition is characterized by diffuse fibrin deposition within
the intervillous space and is associated with prematurity, intrauterine growth restric-
tion (IUGR), and intrauterine fetal demise (IUFD) [22].
Four of the five pregnancies (in four patients) in which diffuse fibrin deposition
was seen in the placenta ended with intrauterine death; none of the patients were
taking medication at the time. One patient [22] had an IUFD and then a subsequent
pregnancy that resulted in a live birth after emergent Cesarean section at 32 weeks
due to abnormal findings on cardiotocography (fetal heart rate monitoring). This
patient was maintained on low doses of steroids during that pregnancy. During her
first unsuccessful pregnancy, she had isolated elevated CK without weakness and
therefore was not treated. Similarly, the second patient [1] also had elevated CK
without clinical weakness and was untreated during the pregnancy: outcome was an
intrauterine death at 34 weeks. The third patient [36] reported with MPVFD was
diagnosed with polymyositis within 3 months of a pregnancy loss at 38 weeks. Two
of these three patients were known to be Jo-1 positive, while one was PL-7 positive
[14, 22, 36]. These cases raise the possibility there may be a role for anticoagulation
in patients with inflammatory myopathy, certainly in those patients who have expe-
rienced prior pregnancy loss associated with MPVFD, and highlight the importance
of obtaining placental pathology in inflammatory myopathy patients who have had
pregnancy loss. The fact that three of the four patients with MPVFD were anti-
synthetase antibody positive (it is not clear whether the fourth patient was tested)
raises the possibility of an association with anti-synthetase syndrome (although this

is obviously a very small sample). Finally, two of four patients with MPVFD had
isolated elevated CK without other symptoms and were untreated [1, 22], raising the
question of whether elevated CK should be treated even in an asymptomatic preg-
nancy patient. The patient who had a second MPVFD pregnancy with a live birth at
32 weeks (albeit by emergent Cesarean section) was treated with prednisone during
the pregnancy.
Maternal Outcome
Just over 60 % of the reported cases of inflammatory myositis in pregnancy have

occurred in patients with preexisting myositis. Of these 48 cases, 21 (44 %) were
complicated by flare during the pregnancy, with treatments detailed as above.
Despite this significant rate of flare in cases reported in the literature, there is only a
single reported case of maternal mortality, in 1986, which occurred postpartum after
a successful delivery and was attributed to hypertension combined with a severe
exacerbation of disease [7].
Conclusions
Pregnancy in myositis patients is rare and, as a result, incompletely understood.

Confounding issues include reporting bias, accuracy of diagnosis, and the varied
nature of specific details included in each report. These factors combine to make
interpretation of the limited literature quite challenging. Systematic review of myo-
sitis pregnancy case reports and case series suggests that disease activity during
pregnancy is associated with adverse pregnancy outcome, and that treatment during
pregnancy may be associated with greater likelihood of live birth. In all, there are 41
reported pregnancies associated with disease activity, whether a flare of existing
disease or new onset of disease. Fourteen of these ended in either intrauterine death
or neonatal loss, including three elective terminations (34 %). In contrast, in the 27
reported pregnancies without disease activity, there were only five losses (18 %).
Moreover, of the 27 pregnancies complicated by disease activity but resulting in a
successful live birth, 22 were treated (81 %). Of the 14 cases with disease activity
and fetal or neonatal death, only seven were treated (50 %). While few in number,
overall review of these cases suggests that disease activity is associated with poor
outcome (especially if early in the pregnancy) and that treatment of disease may be
beneficial despite the potential negative side effects of corticosteroid use during
pregnancy. The three cases in which IVIG was used successfully [18, 31, 32] make
this agent an attractive alternative to corticosteroids. Azathioprine is another poten-
tial alternative to corticosteroid, but thus far there have not been any publications
examining its use in pregnant patients with inflammatory myopathy.
The question of whether or not to treat a myositis patient during pregnancy may
be more difficult in patients with mild disease activity such as rash, arthritis, mild
196 S.J. Di Martino
weakness, or elevated CK without weakness. In general, most patients will shy

away from medical therapy out of concern for the fetus if symptoms are not dis-
abling. However, when one looks at pregnancies with successful outcomes where
the patient did not have a flare of disease, 36 % (8/22) were treated with low-dose
steroid, whereas only 20 % (1/5) pregnancies complicated by fetal or neonatal
losses were treated with corticosteroids.
It seems likely that even subclinical disease activity may have a negative effect
on pregnancy outcome. In two of the published cases, the patients had elevated
muscle enzymes without other symptoms [1, 22], were not treated, and had preg-
nancy loss. Both cases were associated with massive deposition of fibrin in the
placenta. In all, five pregnancies in four patients [1, 14, 22, 36] were described with
MPVFD in the placentas of patients with pregnancy loss (one patient had a live birth
following a loss). Three of these four patients had the anti-synthetase syndrome.
The reported MPVFD cases underscore the importance of obtaining placental
pathology following a pregnancy loss in a patient with inflammatory myopathy.
Whether or not these patients would benefit from anticoagulation or treatment with
immunosuppression (even during instances with minimal symptoms) is unknown,
but clearly warrants further investigation.
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Part III
Additional Reproductive Issues
Chapter 11
Contraception in Rheumatic Disease Patients
Lisa R. Sammaritano
Introduction
The importance of safe and effective contraception for women with rheumatic
disease cannot be overstated. Counseling patients about the increased risks of
pregnancy during certain periods of their illness—during active disease, or while on
teratogenic medications, for example—relies on the assumption that patients can
safely and knowledgably prevent pregnancy through the use of contraception.
For the rheumatologist, a basic knowledge of currently available contraceptive
methods is essential; for the obstetrician, it is similarly critical to be able to identify
which methods are safe (or unsafe) for particular rheumatic disease patients.
Effective contraceptive methods have been underutilized by rheumatic disease
patients for many years; this may be due at least in part to the fact that until recently
all systemic lupus erythematosus (SLE) patients were advised to avoid estrogen-
containing contraceptives due to risk of flare and/or thrombosis. Despite advances
in methods of birth control as well as knowledge about safety in rheumatic disease,
however, many patients still do not utilize effective birth control.
Over 20 years ago, Julkunen and colleagues documented a decreased use of con-
traception by SLE patients compared to corresponding healthy women (59 % vs.
77 %); in addition, sexually active SLE patients more often used less effective barrier
and natural methods [1]. Recent reports continue to identify lower-than-expected
rates of contraception use in rheumatic disease patients. A 2008 survey of contracep-
tive use among 309 women with SLE of reproductive age (18–50 years old) evaluated
likelihood of unintended pregnancy [2]. Of the 212 patients who responded, 97 had
some risk of unplanned pregnancy during the previous 3 months; of these, 53 (55 %)
reported unprotected sex on at least one occasion, and 22 (23 %) reported unprotected
L.R. Sammaritano, M.D. (*)

e-mail: sammaritanol@hss.edu
202 L.R. Sammaritano
sex “most of the time.” In 2011, Yazdany et al. found a similar lack of consistent
contraceptive use in their survey of 206 women with SLE aged less than 45 years.
Eighty-six patients were at risk for unplanned pregnancy: 22 % of these reported
inconsistent contraceptive use, and 55 % depended solely on (less effective) barrier
methods. Most importantly, women on teratogenic medications were no more likely
than women not on these medications to have used effective contraception [3].
The current pattern of inconsistent contraceptive use is not limited to the USA: a
recent Swiss survey of rheumatic disease patients found that 27 % of the women on
the potentially teratogenic drugs methotrexate or leflunomide were not using any
form of contraception, although most of these patients indicated that they were
aware of the medications’ potential teratogenicity [4]. As a point of comparison, a
recent survey of reproductive-aged women in the general population revealed that
only 11 % of those at risk for unintended pregnancy do not regularly use any form
of contraception [5], demonstrating a decreased attention to contraception in women
with rheumatologic disorders.
At least part of the problem may be that rheumatologists do not always screen
patients for sexual activity and contraceptive use, whether due to time constraints or
for other reasons. A prospective study of pediatric rheumatology clinic visits looked
at screening for sexual activity and alcohol use in 178 adolescent patients [6].
Investigators then implemented an office-based intervention to improve rheuma-
tologists’ identification of risk factors: as a result, screening for sexual activity
increased from 12.4 to 36.2 %. Time was reported by physicians to be the major
barrier to screening, although other factors cited included logistical problems, dis-
comfort with the subject area, and ambivalence about the role of the rheumatologist
in behavior screening. In a survey of adult female SLE patients at the University of
California San Francisco, 59 % of 86 women at risk for unintended pregnancy stated
they had not received contraceptive counseling in the past year, and women on tera-
togenic medicines were no more likely to have received contraceptive counseling
than those not on these medications [3].
Efforts are underway within the rheumatology community to remedy this incon-
sistent attention to contraceptive issues. Counseling patients regarding the impor-
tance of contraception while on teratogenic medications is becoming increasingly
formalized (internally or externally imposed) to assure all patients are educated
regarding risk. For example, distribution of a methotrexate information booklet in a
rheumatology outpatient clinic increased the awareness of the need for contracep-
tion from 60 to 100 % in one placebo-controlled trial [7]. In a recently published
quality indicator set for SLE, of 20 quality indicators presented as priorities in lupus
care, three focus on reproductive health: one of these cites the need for patient edu-
cation regarding potential teratogenicity of medications and the necessity of contra-
ception when starting a new lupus medication [8].
In addition to the proposed quality guidelines above, the Food and Drug
Administration (FDA) has mandated patient education regarding need for contra-
ception for certain medications [9]. In September 2012, the FDA mandated an edu-
cational program for medical professionals and patients to prevent unplanned
11 Contraception in Rheumatic Disease Patients 203
pregnancies in patients using mycophenolate-containing medicines commonly used

to treat SLE and other connective tissue diseases. The system, called the
Mycophenolate REMS (Risk Evaluation and Mitigation Strategy), includes a medi-
cation guide, training for health care professionals, and the establishment of a preg-
nancy registry for women who become pregnant while on the medication and who
agree to participate [10]. Formalized education will hopefully lead to both better
rates of counseling by physicians and contraception use by patients.
Contraception: The Basics
Not all contraceptives are created equal: effectiveness varies widely, and so counsel-
ing for patients must include not only the necessity of contraceptive use but also
guidance on the most effective and safe methods. Effectiveness of contraceptive
methods is described in two ways: the “perfect use” (or theoretical) effectiveness is
the effectiveness when used exactly as prescribed, and the “typical use” (or actual)
effectiveness reflects “real world” use that includes forgotten pills or misplaced
diaphragms. Perfect use and typical use effectiveness are closest for those methods
not directly related to the act of intercourse, such as oral contraceptives, and are
nearly identical for long-acting reversible contraceptives that require no effort on
the part of the patient, such as an intrauterine device (IUD) or progesterone implant
[11]. Rates for perfect and typical use for commonly used contraceptive methods
are summarized in Table 11.1.
Table 11.1 Perfect use and typical use effectiveness for contraceptive methods
Effectivenessa
Method Perfect use (%) Typical use (%)
None 85 85
Barrier methods
Condom 2 15
Diaphragm 6 16
IUDs
Copper IUD 0.6 0.8
Levonorgestrel IUD 0.2 0.2
Progesterone-only
Progesterone pill 0.5 8
Progesterone implant 0.05 0.05
DMPA injection 0.3 3
Combined hormonal (pill, patch, vaginal ring) 0.3 8
Adapted from U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 [12]
IUD intrauterine device, DMPA depot medroxyprogesterone acetate
a
Percentage of women experiencing pregnancy during first year of use
Long-acting reversible contraception is widely considered the most effective

form of contraception. A recent prospective cohort study of 9,256 women using
contraception for a 3-year period found that long-acting reversible contraception
(IUD or implant) was more effective than other commonly prescribed contracep-
tives (including oral contraceptive pills, patch, and vaginal ring). The contraceptive
failure rate was 4.55 per 100 participant-years for the oral, patch and vaginal ring
contraceptives compared to 0.27 per 100 participant-years for the long-acting meth-
ods. The failure rate for the depot medroxyprogesterone acetate (DMPA) injection
was also quite low, and similar to that for the IUD and implant [13]. Despite the
demonstrated greater efficacy for long-acting methods, the most common contra-
ceptive methods overall used by women of childbearing age (15–44 years) in the
USA are the oral contraceptive pill (27 %) and female sterilization (28 %). Rate of
IUD use has increased from 1995 (when it was 0.8 %) to the present, but only to
5.6 %, despite its greater effectiveness and convenience [5].
Contraception may be reversible or nonreversible. This discussion of methods
will focus on reversible contraception. Nonreversible contraception for women
should only be performed after counseling and is achieved through tubal ligation or
obstruction. It may be performed as a surgical ligation, with mechanical blockage
by clips or plugs, or through coagulation-induced blockage [14].
Reversible contraception includes barrier methods, intrauterine devices, and hor-
monal contraceptives. “Natural” or fertility awareness methods are least effective
and are not generally recommended as acceptable forms of contraception for rheu-
matic disease patients, especially for those on teratogenic medications.
Barrier Methods
Barrier methods include the condom (male and female), diaphragm, cervical cap,
and contraceptive sponge. Importantly, barrier methods of contraception have a sig-
nificantly lower typical use effectiveness than do hormonal methods or intrauterine
devices. Despite the lower effectiveness, condoms offer certain advantages. The
male condom is easily available and protects against sexually transmitted diseases
including human immunodeficiency virus (HIV). A female condom is also avail-
able: approved by the FDA in 1993, it is composed of two flexible polyurethane
rings (inner and outer) surrounding a polyurethane sheath and is designed to protect
against both pregnancy and sexually transmitted diseases. The diaphragm is avail-
able only by prescription, since it must be fitted by a health care professional. It is a
soft rubber cap on a wound metal spring that is inserted vaginally, and must be used
with spermicide. The cervical cap is similar to the diaphragm, but may remain in
place for up to 48 h, as opposed to 6–9 h for the diaphragm. The over-the-counter
contraceptive sponge may remain in place for up to 24 h. Spermicide, most com-
monly nonoxynol-9, may be used alone or in combination with other methods [14].
Efficacy of barrier contraception is increased if two methods are used, e.g. condom
and spermicide: as a result, this should be a standard recommendation for patients
who wish to use barrier protection [15].
Intrauterine Devices
The IUD is an effective form of birth control even for most adolescents and nullipa-
rous women, with few contraindications to use [12]. The IUD is the most commonly
used form of reversible contraception worldwide [16], although prevalence of use in
the USA is relatively low. The IUD is available worldwide in a medicated or non-
medicated (inert) form; however, only medicated devices are available in the USA.
Medicated IUDs contain either copper or levonorgestrel (20 mcg/24 h), a second
generation progesterone. The mechanisms of action include an inflammatory endo-
metrial foreign-body response as well as local changes due to release of medication.
The less expensive copper-containing IUDs may remain in place for 10 years, but
are associated with heavier menses and dysmenorrhea. The levonorgestrel-
containing IUD (LNG IUD) remains in place for 5 years, but has several advantages
over both the copper IUD and alternative progesterone-only contraceptives [14].
Unlike the copper IUD, the LNG IUD generally reduces dysmenorrhea and men-
strual bleeding: complete amenorrhea occurs in up to 50 % of patients by 24 months
[17]. In contrast to other progesterone-containing contraceptives that are adminis-
tered orally, subdermally, or intramuscularly, the progestin effect of the LNG IUD
is primarily local (although a small proportion of patients do report systemic side
effects). Fertility quickly returns to normal with removal of the device.
Complications associated with IUD use include risk of expulsion of the device
(5 % over 5 years) and risk of pelvic inflammatory disease (PID) [18]. With current
IUDs, the risk of PID is mildly increased only in the 20 days following insertion and
then returns to near baseline; the overall rate of infection from World Health
Organization data is 1.6 infections per 1,000 woman-years [19]. This rate is quite
low in comparison with older, less well-designed IUDs; as a result, IUDs are now
recommended for use in nulliparous women.
Risk of infection is of particular concern in rheumatic disease patients especially
in those patients treated with immunosuppressive therapy. Nonetheless, these are
most often the patients with the greatest need for effective contraception. Although
there are limited data on risk of infection with IUD use in patients treated with
immunosuppressive medications, several reports show no increased risk of infection
in immunocompromised HIV-infected women [20]. Most experts agree that the
minimal risk of infection with IUD use is far outweighed by the significant risks
associated with unintended pregnancy in women with active inflammatory disease
on immunosuppressive medications [21].
In general, the efficacy of IUDs seems unaffected by medication use, but a single
case report has described failure of the copper IUD in two patients on immunosup-
pressive regimens for renal transplant, perhaps related to an alteration in the local
immune response generated by the copper [22] Absolute contraindications to any
IUD use include current pregnancy or acute pelvic infection, unexplained uterine
bleeding, and severe uterine distortion. Specific IUD type contraindications include
current breast, uterine, or endometrial cancer (LNG IUD); or Wilson’s disease or
copper allergy (copper IUD) [23]. IUD use is discouraged in women at high risk for
sexually transmitted diseases, i.e. those with multiple sexual partners.
For patients with underlying chronic disease and ongoing health issues, it is
helpful to know that women with IUDs in place may safely undergo magnetic reso-
nance imaging when necessary.
Hormonal Contraception
Hormonal contraception is generally divided into two major categories: combined

estrogen–progesterone preparations, and progestin-only preparations. Hormonal
contraceptives may be administered through a variety of methods. Limited to “the
pill” in previous years, various types of hormonal contraception may now be given
orally or through a transdermal patch, vaginal ring, injection, subdermal implant,
or IUD.
Combined Hormonal Contraceptives
The first birth control pill contained 150 mcg of the synthetic estrogen mestranol,
three to five times the estrogen content of most current oral contraceptives. Current
combined oral contraceptives contain a synthetic estrogen (ethinyl estradiol or mes-
tranol, 20–50 mcg) and a progestin, one of multiple 17-α ethinyl analogs of
19-nortestosterone. The 19-nortestosterones include norethindrone, norethindrone
acetate, levonorgestrel, and others, and are commonly termed “second generation
progestins.” “Third generation progestins” include norgestimate, desogestrel, and
gestodene; these were developed to decrease androgenic side effects (such as acne,
hirsutism, nausea, and lipid changes) and increase progestational effects.
Drospirenone is considered a “fourth generation progestin”: it is an analog of spi-
ronolactone and exhibits progestational, anti-androgenic, and anti-mineralocorticoid
activity [14]. Importantly, progestins’ potential side effects differ according to their
generation, which is especially pertinent for evaluation of suitability for rheumatic
disease patients.
Combination hormonal contraceptives may be “monophasic” or “multiphasic”:
monophasic contraceptives offer the same dose of each hormone over 21 days fol-
lowed by a drug-free 7-day period. Newer formulations tend to be multiphasic
(biphasic or triphasic): these formulations vary the amounts of estrogen and proges-
tin over the course of the menstrual cycle in an effort to reduce total drug exposure
while maintaining efficacy. Extended-cycle hormonal contraception preparations
can safely limit menses to several times per year without loss of efficacy or increased
risk of side effects.
Newer formulations of combined hormonal contraceptives with novel adminis-
tration methods meant to enhance convenience and compliance include the trans-
dermal patch and the intravaginal ring. The transdermal patch is applied weekly
for 3 weeks, followed by 1 week with no patch: it delivers 20 mcg ethinyl estradiol
and 150 mcg norelgestromin (an active metabolite of norgestimate) per 24 h.
Efficacy is similar to the pill, however overall estrogen exposure is increased, with
a suggested increased risk of venous thromboembolism [24–26]. The intravaginal
ring releases 15 mcg ethinyl estradiol and 120 mcg etonogestrel (an active metabo-
lite of desogestrel) per 24 h: it is kept in place for 3 weeks and removed for 1 week
every month before a new ring is inserted.
Combined hormonal contraceptives have multiple effects on the reproduction
system that account for the high rate of effectiveness with perfect use: ovulation is
blocked due to inhibition of the mid-cycle surge of gonadotropins, sperm penetra-
tion is inhibited because of changes in cervical mucous, uterine and tubal motility is
altered, and blastocyst survival is impaired by inhibition of endometrial gland func-
tion [14].
Occasionally non-contraceptive benefits of combined hormonal contraceptives
are the primary indication for use: these include regulation of menstrual dysfunction
and dysmenorrhea, prevention of functional ovarian cysts, and treatment of endo-
metriosis. In addition, combination oral contraceptive has been shown to decrease
risk of PID and certain cancers (ovarian, uterine, and colorectal) and to exert a posi-
tive effect on bone mass [27].
Mild side effects of combined hormonal contraceptives include nausea, edema,
malar facial pigmentation (chloasma), breast tenderness, and abnormal mid-cycle
uterine bleeding: these may be significant enough in certain patients to cause dis-
continuation or a change to an alternative preparation. Impaired glucose tolerance
and increased risk of hypertension are possible. Likelihood of specific side effects
depends on amount of estrogen and amount and type of progestin. For example,
mid-cycle ovulatory spotting is more likely with the lower-dose estrogen prepara-
tions. The more androgenic progestins (i.e. the second generation progestins) are
more likely to have an adverse effect on the lipid profile than are later (third or
fourth) generation progestins [14]. A positive effect on mood and acne has been
suggested for combined contraceptives containing the fourth generation progestin
drospirenone, due to its anti-mineralocorticoid and anti-androgenic effects [28].
While risk of serious complications is low with combined hormonal contracep-
tives, they do occur. Such complications can be limited with careful assessment to
exclude patients at greatest risk. Usual contraindications to use are listed in
Table 11.2. Serious complications are usually vascular in nature, including venous
thromboembolism, stroke, and myocardial infarction. Risk of cerebral vein throm-
bosis appears to be particularly increased with combined hormonal contraceptive
use [29]. There is also an increased risk of cervical cancer [30] and a slightly
increased risk of breast cancer in current (but not past) users [31].
Effects of combined hormonal contraceptives on the hemostatic system are com-
plex and involve multiple mechanisms, although the overall net effect is clearly
prothrombotic. Plasma levels of most coagulation factors (except factor V) increase
while antithrombin III levels decrease. APC resistance is demonstrated that is only
partly explained by an observed decrease in protein S. Multiple changes in the fibri-
nolytic system lead to an overall down-regulation of fibrinolysis. As a result of these
multiple and additive effects on hemostasis, the overall risk of venous thromboem-
bolism in women on current combined hormonal contraceptives is increased by a
Table 11.2 Absolute and Absolute contraindications

relative contraindications to Pregnancy
the use of estrogen-
Postpartum <21 days
containing contraceptives
Age >35 and >15 cigarettes/day
Multiple risk factors for cardiovascular disease
Uncontrolled hypertension, hypertension with vascular disease
Acute DVT/PE
History of DVT/PE with high risk for recurrence including
Thrombophilia
History of estrogen-induced DVT/PE
Recurrent DVT/PE
DVT/PE associated with active cancer
Surgery with prolonged immobilization
Known thrombogenic mutations
Current and history of ischemic cardiac disease
Stroke
Complicated valvular disease
Peripartum cardiomyopathy (acute mild or severe)
Systemic lupus erythematosus with positive or unknown aPL
Migraine with aura or age ≥35
Current/recent breast cancer
Diabetes with complications, >20 years duration, other
vascular disease
Acute viral hepatitis, severe cirrhosis, other severe liver
disease
Hepatocellular adenoma or hepatoma
Complicated organ transplant (rejection or vasculopathy)
Undiagnosed genital bleeding
Relative contraindications
Postpartum >21 days with other risk factors for VTE,
or breastfeeding
Age >35 and <15 cigarettes/day
Bariatric surgery (malabsorptive procedure)
Hypertension
History DVT/PE with no risk factors
Known hyperlipidemia
Peripartum cardiomyopathy (chronic mild)
Migraine without aura (<35)
History of breast cancer, NED >5 years
Inflammatory bowel disease
Symptomatic current gallbladder disease, OC related cholestasis
Certain antiretroviral therapies
Certain anticonvulsant therapies
Rifampin therapy
Adapted from US Medical Eligibility Criteria for Contraceptive
Use, 2010 [12]
factor of 3–5 from the baseline annual risk in healthy women of 1 in 10,000 [32].
While the likelihood of venous thromboembolism overall is still low given the low
baseline risk in healthy young females, the estimated 100 million women world-
wide who use combined hormonal contraception make the absolute number of
events significant. Non-oral preparations have at least similar risks to the oral prepa-
rations, and the transdermal patch has been suggested to have a greater risk of
thrombosis due to about 60 % greater estrogen exposure [33].
Although focus is commonly on level of estrogen as the primary culprit in pro-
moting thrombosis, both estrogen and progestin components may contribute to
increased venous thrombosis risk. The relative risk of venous thromboembolism
was increased by a factor of 10 with the earliest oral contraceptives: reducing the
estrogen content has markedly reduced the thrombosis risk of oral preparations.
Since lower doses of estrogens have been used, variation in type of progestin now
accounts for some of the variability in venous thrombosis risk among different prep-
arations of hormonal contraceptives: the third generation progestins confer greater
venous thrombosis risk than do second generation progestins due to greater demon-
strated APC resistance. Lowest risk of venous thromboembolism is in combined
contraceptives containing levonorgestrel [34]. Duration of use also affects risk: risk
is highest in the first year of use and decreases in later years; increased risk disap-
pears once the drug is discontinued.
Combined hormonal contraceptive-associated risk of venous thromboembolism
is increased further in the presence of genetic or acquired thrombophilia: the pres-
ence of a family history of thrombosis should prompt a prothrombotic work-up
prior to institution of combined hormonal contraception. Risk of clotting events is
also increased in the presence of smoking (more than ten cigarettes per day), age over
35 years, and obesity. Obesity—defined as a body mass index (BMI) > 25 kg/m2—
increases the risk of venous thromboembolism by a factor of 2 in the general popu-
lation and by a factor of 10 in users of combined hormonal contraception [35, 36].
Although combined hormonal contraceptives may be continued in patients under-
going low risk surgery, if possible they should be discontinued 4–6 weeks before
planned moderate or high risk surgery and only restarted when the patient returns to
ambulatory status.
There is an observed twofold stroke risk among all combination oral contracep-
tive users that is dependent on the presence of additional risk factors such as hyper-
tension, migraine, smoking, and age greater than 35 years [37]. Healthy normotensive
non-smoking women aged 35 years or younger do not have an increased risk of
ischemic stroke with current low dose combination oral contraceptives [38]. Risk of
hemorrhagic stroke is also increased in women over age 35 [39]. Lower estrogen
content of oral contraceptives (20 mcg versus 50 mcg) is associated with a lower
risk of ischemic stroke. In contrast to venous thromboembolism risk, likelihood of
stroke associated with use of third generation progestins is no higher than that asso-
ciated with second generation progestins, and may in fact be slightly lower [40].
Myocardial infarction risk is twice as high among all users of oral combined con-
traceptives, and risk is greatest among patients with the classical risk factors of
older age, cigarette use, hypertension, diabetes mellitus, hyperlipidemia, and obesity.
As with ischemic stroke, risk for myocardial infarction may be lower in patients
using contraceptives containing third generation rather than second generation pro-
gestins [41]. Likelihood of peripheral arterial disease is also increased in users of
combination hormonal contraceptives [42].
Progesterone-Only Contraceptives
Progesterone-only contraceptives present an alternative and highly effective option

for patients who cannot or will not take estrogen-containing preparations. They may
also be a good option for patients on hepatic enzyme-inducing drugs, such as anti-
convulsants, depending on the preparation. Although recommendations differ, most
authorities agree that progesterone-only contraceptives are safe and effective for
patients who are at increased risk for venous or arterial thromboembolism. In gen-
eral, the progestins used are most often second generation, which have a lower rela-
tive risk for venous thrombosis.
Oral progestin-only contraceptives contain norethindrone or norgestrel: they are
less popular than combination contraceptive pills because they have greater rates of
side effects, particularly irregular vaginal bleeding, and are slightly less effective in
perfect and typical use rates (Table 11.1). Progestin-only pills do not reliably inhibit
ovulation, as do combination estrogen-progestin pills, although other mechanisms
of action are present including changes in cervical mucous, altered tubal motility,
and inhibition of endometrial gland function. It is important to take the progestin-
only pill (also called the “mini-pill”) at the same time each day to ensure a stability
in serum level that maximizes effectiveness [43]. Unlike combination pills, the
progesterone-only pill is considered safe to use while breastfeeding.
Other progesterone contraceptives reliably confer more stable serum levels
through different methods of delivery. The progesterone-only contraceptive DMPA
is administered as an intramuscular or subcutaneous injection every 3 months: it is
convenient and efficacy is greater than with the oral progestin preparations due to
the additional mechanism of ovulation suppression. Another advantage is that effi-
cacy of DMPA is not reduced by high BMI or use of concurrent medications, and it
can be initiated without a pelvic or breast exam or routine labs.
Although the first generation of subdermal implantable contraceptive devices
were withdrawn from the market, a currently available single rod subdermal implant
placed in the inner upper arm releases etonogestrel over a 3-year period. It may
initially inhibit ovulation for a time in the period following insertion, but does not
consistently inhibit ovulation in the latter part of the 3 years, although other mecha-
nisms remain intact [14]. A two-rod subdermal device that releases levonorgestrel
has also been FDA-approved but is not marketed in the USA.
Non-contraceptive benefits of progesterone-only contraceptives are occasionally
the primary reason for use and include decreased menstrual bleeding, cessation of
menses, and amelioration of endometriosis symptoms. Minor side effects are more
common than with combined contraceptives, however: progestin-only preparations
are more likely to cause irregular, “break-through” bleeding (the most common
cause of discontinuation) and weight gain [44]. Unpredictable bleeding with
progesterone-only contraceptives is greatest within the first 3 months of use and
diminishes significantly with time [45]. While later-generation progestins may
increase blood pressure, DMPA does not impair glucose tolerance or cause hyper-
tension. In general, progestin-only contraceptives have little effect on lipid levels.
Importantly for rheumatic disease patients, DMPA, but not the progesterone-only
pill or LNG IUD, may cause reversible bone loss due to inhibition of ovulation: the
reduction in bone density in healthy women is 5.7–7.5 % after 2 years of use [46].
History of fragility fracture, known osteoporosis, or strong risk factors for osteopo-
rosis (such as corticosteroid use or rheumatoid arthritis) are generally considered
contraindications to use of DMPA. An additional disadvantage of DMPA is that
there may be a delayed return to fertility: it is not recommended for patients who
plan pregnancy within the next year.
Risk for thromboembolism with progesterone-only contraception, while clearly
lower than for combination hormonal contraceptives, is uncertain. Package inserts
often list a history of venous thromboembolism as a contraindication to use of
progesterone-containing products, but the WHO and CDC believe these methods to
be generally safe for use in such patients with benefit outweighing risk [47]: this
discrepancy has been a source of some confusion among physicians and patients
[48, 49]. Woman with multiple risk factors for arterial cardiovascular disease,
women with a history of stroke or ischemic heart disease, and women with current
venous thromboembolism are still classified by the WHO and CDC as “category 3”
(where “the risk of use may exceed the benefits”) [47]. These patients also require
effective contraception, however, and decisions are must be made on a case-by-case
basis, weighing the relative risk of unintended pregnancy against the risk of the
contraceptive method.
Emergency Contraception
Emergency contraception, to prevent pregnancy after unprotected intercourse, is

widely available. Options include physician placement of a copper IUD within 5 days,
prescription-only oral selective progesterone receptor modulators (ulipristal or
mifepristone) within 120 h, and non-prescription oral levonorgestrel within 72 h
(currently available over the counter for patients age 17 or older). There is an ongo-
ing movement to remove the age restriction for over-the-counter sales to younger
women [50] and recent legal decisions suggest the medication may soon be avail-
able to individuals aged 15 or older without a prescription.
The copper IUD is widely considered to be the most effective form of emergency
contraception, but placement requires a doctor’s visit and exclusion of pregnancy
first (as does the ulipristal or mifepristone pill). The copper IUD has the advantage
of providing continued long-term protection after insertion. Oral levonorgestrel,
available as a single 1.5 mg pill or as two 0.75 mg tablets, is slightly less effective,
but it is the most readily available and safest method: it does not interrupt an estab-
lished pregnancy and can be obtained without a prescription. The most common
side effects are nausea and vomiting. Both of the oral preparations (levonorgestrel
and selective progesterone receptor modulators that require a prescription) are
strongly affected by BMI and, as a result, risk of pregnancy is four times higher in
obese women using these methods. Thus, the copper IUD may be the preferred
choice for emergency contraception in obese women. Cardiovascular disease and
thrombophilia are not contraindications to the use of any form of emergency contra-
ception. Drugs that induce hepatic enzymes may reduce the efficacy of the oral
medications [51].
Specific Issues for Rheumatic Diseases
Certain issues are of obvious concern when evaluating risk of contraceptive methods
in patients with rheumatic diseases. For example, a long-held perception that estro-
gen’s immunostimulatory effects promote flare in systemic lupus has limited use of
combined hormonal contraceptives in these patients. Studies published within the
last 10 years, however, have established that risk of flare from estrogen-containing
oral contraceptives is low in stable lupus patients without significant renal disease.
Presence of antiphospholipid antibodies (with the associated thrombosis risk) should
limit choice of hormonal contraception, however, to non-estrogen (progesterone-
only) medications or devices. Additionally, hormonal contraceptives have the poten-
tial to interact with many medications used for rheumatic disease patients: medication
interactions for these chronically ill patients must be carefully evaluated.
Systemic Lupus Erythematosus
Multiple observations contribute to the reluctance of many rheumatologists to con-

sider estrogen-containing contraceptives for their patients with SLE, including dis-
ease demographics with a female-to-male ratio of 9:1 during the reproductive years
(when estrogen levels are at their highest), exacerbation of lupus in mouse models
with administration of exogenous estrogen [52], estrogen metabolism alterations in
patients with SLE [53] and clinical reports [54]. Estrogen has demonstrated an in
vitro immunostimulatory effect that includes depression of cell-mediated immunity,
natural killer cell function, and immune surveillance [55]. In addition, physicians
may have personal experience with patients flaring or developing SLE in the setting
of new oral contraceptive use.
Large-scale epidemiology studies offer conflicting data on whether oral contra-
ceptive use in the general population increases risk of development of new SLE.
A slight increase in risk of developing SLE with past use of oral contraceptives was
demonstrated in the prospective Nurses’ Health Study (RR 1.9; 95 % CI 1.1–3.3) [56]
and others [57] but alternate population-based case–control studies do not confirm an
increased risk [58, 59]. Early reports suggested risk of flare of lupus in patients with
established disease exposed to combined oral contraceptives [54, 60, 61].
Two randomized controlled clinical trials published in 2005 suggest no signifi-
cant increase in risk of flare from combination hormonal contraceptives in well-
defined lupus populations with stable disease activity. The Safety of Estrogen in
Lupus Erythematosus National Assessment (SELENA) trial randomized 183 lupus
patients with inactive or stable-active disease to either oral contraceptive (triphasic
ethinyl estradiol 35 mcg/norethindrone 0.5–1 mg) or placebo for twelve 28-day
cycles. Patients with any history of thrombosis or the presence of antiphospholipid
antibodies (moderate to high anticardiolipin antibody or positive lupus anticoagu-
lant) were excluded, as were patients with significant disease activity. The severe
flare rates at one year did not differ between the treated and the placebo groups
(0.084 vs. 0.087 for treatment group vs. placebo group, respectively). Mild-moderate
flares were also equivalent in both groups, and there was no difference in overall
combined flare rates between the two groups [60].
Rather than utilizing a placebo control, the study by Sanchez-Guerrero and col-
leagues compared use of combined oral contraceptive (ethinyl estradiol 30 mcg/
levonorgestrel 150 mcg/day) in patients with SLE with two other commonly used
methods of birth control, a progestin-only contraceptive (levonorgestrel 0.3 mg/
day) and a copper IUD. Disease activity was similar among the three groups, includ-
ing rates of severe flare, global disease activity, and overall flare. The progesterone-
only group had a higher rate of discontinuation, and the severe infection rate was
slightly higher in the copper IUD group (although there were no instances of pelvic
infection in the IUD group) [61].
A systematic review published in 2009 evaluated 14 articles concerning contra-
ceptive use in patients with SLE, including the two randomized trials cited above.
The authors concluded that many women with SLE are good candidates for most
contraceptive methods including hormonal contraception, but discouraged use of
combined hormonal contraception in women with antiphospholipid antibodies [62].
In summary, combined hormonal contraceptives are an effective and generally
safe form of birth control for many patients with SLE. Even in the general popula-
tion, however, they are not for everyone: 16 % of unselected women ages 20–51 in
a USA national sample [63] were ineligible for combined hormonal contraceptives
based on traditional contraindications (Table 11.2). It is to be expected that a higher
proportion of lupus patients will be ineligible based on the presence of antiphospho-
lipid antibodies, active or severe disease, and the presence of traditional contraindi-
cations. However, combined hormonal contraceptives do not appear to significantly
increase risk of flare in the subset of lupus patients with inactive or stable-active
SLE (who do not have antiphospholipid antibodies) and offer an attractive option
for these patients.
In contrast, progesterone has not been suggested to increase risk of lupus flare or
risk of thrombosis in these patients. Progestin contraceptives have also been evalu-
ated: the oral pregnane progestins chlormadinone acetate and cyproterone acetate
(anti-androgenic, anti-estrogenic weak progestins available in Europe but not in the
USA) have been recently studied as a potential contraceptive alternative in patients

with SLE. The authors reported a decrease in disease activity with a low incidence
of thrombosis (one venous and two arterial thromboses) in 187 patients treated for
a mean period of 46 months [64].
Clearly, use of any form of contraception in lupus patients involves careful
thought. Important considerations in choice of contraceptive method include details
particular to the individual patient as well as the specifics of the contraceptive under
consideration. To minimize risk of increased disease activity, it would seem prudent
to avoid combined hormonal contraceptive methods with higher estrogen exposures
than were used in the published studies, particularly the transdermal patch with its
overall higher estrogen exposure. In addition, the type of progesterone may be of
concern: in addition to the differences in thrombotic risk associated with the differ-
ent generations, the fourth generation progestin drospirenone (a spironolactone ana-
log) may cause hyperkalemia in susceptible individuals. Women taking medications
that increase serum potassium or alter renal function (such as angiotensin convert-
ing enzyme inhibitors) or women with renal insufficiency require careful monitor-
ing of serum potassium if taking drospirenone-containing oral contraceptives.
For SLE or other rheumatic disease patients unable to take estrogen-containing
preparations, the progesterone-only contraceptives offer an alternative to barrier
methods. The LNG IUD is an option that appears to be safe for most patients.
Although risk of infection (PID) is not well studied in patients on immunosuppres-
sive medications, extrapolation from safety data in immunocompromised HIV-
infected patients suggests low risk of infection. DMPA is not a good long-term
option for patients with osteoporosis or long-term corticosteroid use due to risk of
decrease in bone density. There are no good data on the etonorgestrel subdermal
implant in SLE patients, although thrombosis risk might, in theory, be slightly
higher than with levonorgestrel-containing preparations due to the inclusion of a
third generation progestin.
Antiphospholipid antibodies (aPL) are well recognized as significant risk factors for
thrombosis and pregnancy morbidity in patients with primary antiphospholipid syn-
drome as well as those with underlying SLE and other rheumatic diseases. About
30 % of SLE patients have positive aPL although rates of antiphospholipid syn-
drome (APS)—presence of the antibody as well as typical clinical complications—
are lower. Ability to predict risk of thrombosis or pregnancy complications for an
asymptomatic aPL-positive patient is limited, although risk appears to be highest
for those patients with lupus anticoagulant and/or high titer IgG anticardiolipin
[65]. Current data suggest that presence of additional prothrombotic risk factors,
whether genetic variants, medical comorbidities, or exogenous factors, additionally
increase risk [66]. Genetic factors include factor V Leiden, prothrombin gene
(G20210A) mutation, hyperhomocysteinemia due to MTHFR homozygous
mutations, and deficiencies of proteins C, S and antithrombin III. Medical factors

include malignancy, pregnancy, nephrotic syndrome, and traditional cardiovascular
disease risk factors such as hypercholesterolemia and hypertension. Exogenous fac-
tors include cigarette smoking, estrogen use, surgery, and prolonged bedrest.
Combinations of prothrombotic risk factors are surprisingly frequent. aPL are
rare in the general population, but certain of the prothrombotic genotypes are quite
common. Heterozygous factor V Leiden affects 3–8 % of the population and
accounts for 20 % of first time venous thromboembolism; the prothrombin gene
mutation (G20210A) affects 2–4 % of the Caucasian population and, by increasing
plasma prothrombin levels, leads to a two to fourfold increased risk of thrombosis
[67]. Use of a combined hormonal contraceptive exerts an additive effect on the risk
of thrombosis in patients with hereditable thrombophilias, many of whom are not
aware of their increased thrombotic risk [68]. In general, experts do not recommend
screening for inherited thrombophilias in patients without a personal or family his-
tory of thrombosis before starting combined hormonal contraceptives, due to the
low yield and high cost [69]; patients with a family history of thrombosis or other
relevant risk factors are usually screened.
As might be expected, the addition of aPL to other prothrombotic conditions
increases the overall risk of thrombosis. For example, aPL-positive patients with
thrombosis are far more likely to be positive for heritable risk factors such as factor
V Leiden and prothrombin gene mutation than are asymptomatic aPL-positive
patients [70]. Factor V Leiden and the prothrombin gene mutation have been shown
to contribute to risk of venous thromboembolism in patients with systemic lupus,
and risk was potentiated when combined with presence of antiphospholipid
antibodies [71].
No prospective controlled studies have been designed to specifically evaluate the
thrombotic risk of combined hormonal contraceptive use in patients with aPL for
obvious reasons. Multiple case reports and series, however, describe aPL-positive
patients who have developed vascular thrombosis presumably triggered by oral con-
traceptives [72–76]. Since aPL increase risk of arterial as well as venous thrombo-
sis, use of combined hormonal contraceptives will almost certainly increase risk of
both types of vascular events in these patients. Additional factors which increase
risk of arterial vascular complications—such as complicated migraine, atheroscle-
rosis, or hyperlipidemia—may be present or increased in patients with aPL and may
further increase risk of stroke or myocardial infarction. These case reports, as well
as the more general demonstration of potentiated thrombotic risk with multiple pro-
thrombotic risk factors, have generated significant concern regarding use of com-
bined hormonal contraceptives in women with aPL, especially those with high titer
aCL antibody or the lupus anticoagulant. In the SELENA (Safety of Estrogen in
Lupus Erythematosus—National Assessment) study, designed to assess risk of flare
in stable SLE patients treated with combined oral contraceptives, the study design
specifically excluded patients with moderate to high titer IgG, IgM, or IgA aCL’s or
any positive lupus anticoagulant, including patients with positive antibody but no
history of thrombosis. Although some patients in both treatment and placebo groups
presumably had low titer aCL (no numbers are reported), there was no increase in
thrombotic complications in the oral contraceptive group versus the placebo group:
two treated patients and three placebo patients developed clots [60]. In another
group of SLE patients, treatment with either combined or progestin-only oral con-
traceptives resulted in the same rate of thrombosis, two patients out of 54 in each
group (all four were reported to be aPL positive) [61].
Non-thrombotic aPL manifestations are not uncommon, and it is not known
whether they might be affected by combined oral contraceptives. Risk of chorea,
however, which is associated with both aPL and SLE, may be increased further by
addition of combined oral contraceptives [77, 78]. It has been suggested that com-
bined oral contraceptives may induce development of aPLs in healthy women, spe-
cifically anti-β2 Glycoprotein I IgG [79], but this is not generally accepted and has
yet to be confirmed.
Use of progesterone-containing contraceptive methods, while still debatable, is
generally accepted as a lower risk but effective method of birth control in patients
unable to use estrogen-containing methods. In addition, they may offer a unique
advantage in addition to contraceptive efficacy in patients on warfarin: they can
reduce heavy menstrual blood flow associated with anticoagulation. Several reports
describe life-threatening luteal ovarian cyst hemorrhagic rupture in APS patients on
warfarin requiring surgical hemostasis and blood transfusion; post-surgical treat-
ment with certain progesterone contraceptives was shown to be protective [80, 81].
Rheumatoid Arthritis and Other Inflammatory Arthritides
In distinct contrast to the concerns expressed for SLE patients regarding risk of
combined hormonal contraceptives, it has been suggested that rheumatoid arthritis
(RA) patients may potentially benefit from treatment with combined hormonal con-
traceptives. This is based on anecdotal reports, as well a demonstrated improvement
of symptoms during pregnancy [82] and an increased risk of flare postpartum [83].
Most clinical research on contraceptive use in RA, however, has focused on the
related but different question of whether combined oral contraceptives reduce the risk
of developing new RA: this issue remains unresolved. A number of reports suggest
the rate of RA development to be reduced in current oral contraceptive users [84–87].
Hazes et al. demonstrated a relative risk of new RA in current users of oral contracep-
tives to be 0.58, and 0.39 in ever-users, independent of dose, duration of use, or pres-
ence of HLA DR4 [87]. Other studies have suggested a duration-dependent protective
effect [88] as well as a protective effect against development of severe or seropositive
RA [89], while others show no effect [90–92]. Analysis from the Nurses’ Health
Study did not show a protective effect of past use of oral contraceptives, although
authors could not rule out a modest protective effect of current use [93].
Several epidemiologic studies do suggest a reduction in development of severe
disease in current RA patients who are using oral contraceptives. A meta-analysis by
Spector et al. suggested that oral contraceptive use does not have a protective effect
on the development of RA, but may prevent the progression to severe disease [88].
A case–control study evaluated 176 women with RA and 145 control subjects; RA
patients were further categorized as having severe or mild disease. Use of oral con-
traceptives seemed to have a protective effect on the development of severe RA:
44 % of patients with mild RA used oral contraceptives as compared with just
21.7 % of those with severe RA (p < 0.001) [89]. In addition, after adjusting for age,
parity, and breastfeeding, the relative risk of developing severe disease for RA
patients using oral contraceptives for greater than 5 years was 0.1 (95 % CI 0.01–
0.6). Another study following an inception cohort of 132 female RA patients for an
average of 12 years suggested a trend for patients using oral contraceptives to have
both less radiographic joint damage and a better functional level than those patients
not using them [92]. A recent limited systematic review of contraceptive methods in
rheumatoid arthritis did not identify any effect of hormonal contraceptives on RA
progression [94].
Post-menopausal use of estrogen therapy has also been evaluated in RA patients
and showed no significant effect on disease activity but was associated with an
increase in bone density [95, 96].
Despite the suggestion of benefit in protecting against severe disease progres-
sion, therapeutic use of combined hormonal contraceptives in established RA has
not been studied in a placebo-controlled manner. Part of the reason may rest on the
fact that hormone studies in RA patients do not suggest unusually low endogenous
estrogen levels: rather, they show normal estrogen levels with low androgen levels:
low levels of gonadal and adrenal androgens (testosterone and dehydroepiandros-
terone) have been demonstrated in serum and synovial fluid of RA patients of both
sexes [97, 98], yielding a reduced ratio of androgen/estrogen that suggests a poten-
tial reduction in immunosuppressive effect.
Based on these data, several hormonal attempts at RA therapy have focused on
androgenic supplementation, with mixed results [99–101]. Early efforts with testos-
terone therapy showed improvement in disease activity but patients developed com-
plications of masculinization and menstrual disturbances [99]. Treatment with the
anabolic androgenic steroid nandrolone (19-nortestosterone) was not helpful in
reducing disease activity [100]. A more recent double-blind placebo-controlled
study of testosterone in post-menopausal RA patients suggested a response in pain
score, ESR and disability; 21 % patients showed improvement that was not statisti-
cally significant [101].
In summary, although there are suggestions that combined hormonal contracep-
tives may protect against development of severe disease in RA patients, they have
not been definitively shown to have a non-contraceptive benefit on RA disease
activity. There is certainly no evidence, however, to suggest that their use would
exacerbate disease and so hormonal contraceptive methods represent a safe and
effective option for patients with RA.
While purely theoretical, given the low androgen levels demonstrated in some
RA patients, a case could be made for use of oral contraceptives containing the rela-
tively more androgenic (second generation) progestins, to maximize androgenic
immunosuppression, if one is hoping for a non-contraceptive disease modifying
benefit.
In terms of the particular method chosen for RA patients, combination oral hor-
monal contraceptives or the transdermal patch may be effective and especially con-
venient for patients with RA. Insertion of a diaphragm or of the vaginal ring may be
difficult for patients with severe arthritis affecting the hands or hips. The LNG IUD,
placed by a physician for 5 years, offers convenient and long-lasting protection
although safety with intensive immunosuppressive treatment regimens has not been
evaluated. Finally, the subdermal etonorgestrel implant may provide convenience
without concern for pelvic infection, although ovulation may be inhibited in the
early months of use leading to a theoretical (and as yet undocumented) negative
effect on bone density. DMPA, with its attendant risk of decreasing bone density,
would not seem a good long-term choice for the RA patient.
Other Rheumatic Diseases
Contraceptive methods in patients with other rheumatic diseases have not been well
studied. Estrogen alone has been evaluated as a potential vasodilator therapy in
several cases of severe Raynaud’s phenomenon associated with systemic sclerosis.
Estrogen administered intravenously improved endothelial function in ten female
patients with systemic sclerosis and Raynaud’s phenomenon with a significant
increase in endothelium-dependent dilatation [102], and similarly reversed cold-
induced myocardial ischemia on nuclear imaging in a patient with Raynaud’s and
systemic sclerosis [103]. Use of oral estrogen in the form of combined hormonal
contraceptives has not been demonstrated to affect patient-reported frequency,
severity, or duration of Raynaud’s attacks, however, although many patients do
report improvement in Raynaud’s symptoms during pregnancy [104]. In contrast,
exogenous hormones administered in the form of hormone replacement therapy
potentially prevents the development of isolated pulmonary hypertension in post-
menopausal women with systemic sclerosis [105], presumably by replicating the
protective effect of estrogen on the endothelium.
There are no significant data on effects of estrogen in patients with vasculitis, but
it seems reasonable to avoid estrogen-containing contraceptives in patients with
atherosclerosis or vasculitis who have increased risk for ischemia or stroke. While
most vasculitides affect males and older individuals preferentially, Takayasu’s arte-
ritis affects women during the reproductive years and use of estrogen-containing
contraceptives may be a concern in these patients.
There are interesting and preliminary animal data that demonstrate that estrogen
may positively influence the degree of disruption in skeletal muscle after ischemia-
reperfusion-induced damage, suggesting a theoretical potential for estrogen to posi-
tively influence rate of skeletal muscle recovery [106]; how this might translate to
clinical myositis in humans is not clear. Conversely, anti-estrogen medications
(tamoxifen and anastrozole) have been reported to improve dermatomyositis rash in
two patients; however, no data suggest that exogenous estrogen in any form worsens
dermatomyositis rash [107].
Medication Interactions
Potential interactions of hormonal contraceptives with other medications are well

recognized, and may lead to decreased efficacy of either the contraceptive or the
alternative medication. Since many rheumatic disease patients are on multiple med-
ications, it is important to check for pharmacologic interactions before advising
hormonal contraception (Table 11.3). Medications commonly used in rheumatic
disease patients that have potential interactions with estrogen-containing contracep-
tives include anticonvulsants, corticosteroids, warfarin, cyclosporine, and myco-
phenolate [108, 109]. Most antibiotics, with the exception of rifampin, do not
significantly affect efficacy [110]. Herbal medications may also increase clearance
of oral contraceptives and decrease efficacy, for example St. John’s wort [111].
Summary
There are several general points regarding various modes of contraception that are
relevant to most patients with rheumatic disease (Table 11.4). While general guide-
lines are useful, contraceptive choice ultimately depends on the individual patient,
her medical condition, and her stage in reproductive life; it may also be influenced
by social and religious factors.
Table 11.3 Medication interactions with combined hormonal contraceptives

Effect with concomitant combined hormonal
Medication contraceptive (CHC)
Antibiotics
Penicillins, cephalosporins, macrolides, ↓ CHC efficacy due to ↑ intestinal transport and ↓
metronidazole, sulfa, tetracyclines enterohepatic reabsorption (small effect)
Rifampin; Griseofulvin; Certain antivirals ↓ CHC efficacy
Anticonvulsants
Barbiturates; Carbamazepine, ↓ CHC efficacy
Oxacarbazine; Topiramate
Phenytoin ↑ phenytoin concentration and ↓ CHC efficacy
Lamotrigine ↓ lamotrigine concentration
Modafinil ↓ CHC efficacy
Corticosteroids ↑ steroid concentration
Cyclosporin ↑ cyclosporine concentration
Mycophenolate Possible ↓ CHC efficacy
Warfarin ↑ or ↓ warfarin effect due to alterations in
metabolism
Thyroid hormone ↓ levels of free thyroxine due to ↑ levels of
thyroxine binding globulin
Potassium-sparing diuretics Hyperkalemia risk with drospirenone-containing CHC
Adapted from Fotherby [108] and Amy and Tripathi [11]
Table 11.4 Benefits and disadvantages of various contraceptives for rheumatic disease patients
Contraceptive Relative Risk of Gynecologic side
method: efficacy Ease of use Risk of flare Risk of thrombosis infection Risk of osteoporosis effects
Barrier
Condom + OTC; some protection None (NT) – – – –
against STI’s
Diaphragm + Rx by MD; possible None (NT) – – – –
difficulty with
insertion hand or hip
arthritis
IUD
Copper ++++ Placed by MD; lasts None – Low risk first – Increased cramps
10 years 20 days; NT and bleeding
in IC pts
LNG ++++ Placed by MD; Lasts None (NT) – Low risk first – Decreased cramps
5 years 20 days; NT and bleeding; fewer
in IC pts hormonal SE than
systemic prog
methods
Progesterone-only
Pill ++ Rx by MD; must take None Min-none – – Spotting and
same time every day; decreased menstrual
only method rec for bleeding
use during lactation
Implant ++++ Insertion by MD; None (NT) NT likely min Unknown (inhibits Initial spotting then
lasts 3 years ovulation for some time decreased menstrual
after initial placement) bleeding
DMPA ++++ Injection by MD; None (NT) Min-none – Decreases bone density: Initial spotting then
Every 3 month avoid with known low decreased menstrual
bone density, steroid use bleeding; delayed
or RA return to fertility
Morning-after pill ++ OTC (most ages) None (NT) Min-none – – –
Combined
Pill +++ Rx by MD; take daily No increased risk Increased: avoid in aPL(+) – May increase bone Regular cycle
in stable aPL(-) or other thrombotic risk density
inactive patients factors
Patch +++ Rx by MD; replace NT but estrogen Increased: avoid in aPL(+) – May increase bone Regular cycle
weekly levels higher than or other thrombotic risk density
pill factors may be higher than
other CHC’s
Vaginal ring +++ Rx by MD; replace NT estrogen levels Increased: avoid in aPL(+) – May increase bone Regular cycle
weekly; possible similar to pill or other thrombotic risk density
difficulty with factors
insertion hand or hip
arthritis
Relative efficacy: + Poor effectiveness, ++ Moderate effectiveness, +++ Good effectiveness, ++++ Excellent effectiveness
OTC available over-the-counter, STI sexually transmitted infection, NT not tested, IC pts Immunocompromised patients, RA rheumatoid arthritis, Prog progesterone, SE side
effects, Min minimal, Combined and CHC combined estrogen–progesterone contraceptives, aPL antiphospholipid antibody
Combined hormonal contraceptives may be used in most rheumatic disease

patients but should not be used in those with active SLE or increased risk for throm-
bosis including those with history of thrombosis, positive aPL, or active vasculitis.
Progesterone-containing methods are good alternatives for most patients who cannot
take estrogen, and may be useful for decreasing heavy menstrual blood loss in
patients on warfarin. Long-acting methods of birth control, such as the IUD, are
effective and convenient for most patients. While use of IUDs has previously been
discouraged in women who have not completed childbearing, IUDs are now recom-
mended for use in most women including nulliparous women who are not at increased
risk for sexually transmitted diseases (i.e., those without multiple partners). While
unclear how to best assess risk for IUD-associated infection in rheumatic disease
patients on immunosuppressive therapy, peri-insertion antibiotic treatment has been
suggested to reduce the slight risk of post-insertion infection in the first 20 days [21].
Finally, when prolonged immobilization is necessary in patients with rheumatologic
illness, whether due to flare of disease, surgery, or other hospitalization; estrogen-
containing contraceptives should be discontinued if possible, and prophylactic hepa-
rin therapy added to reduce risk of venous thromboembolism.
Whatever the patient’s clinical and social situation, ongoing discussion between
the patient, her rheumatologist, and her gynecologist is the best way to ensure use
of the most appropriate safe, effective, and acceptable contraceptive method.
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Chapter 12
Assisted Reproductive Techniques
in Rheumatic Disease Patients
Carl A. Laskin, Kenneth I. Cadesky, Christine A. Clark,

and Karen A. Spitzer
Introduction
Definitions
Infertility: The American Society of Reproductive Medicine has recently revised

their definition of infertility. This accepted definition is as follows: “Infertility is a
disease, defined by the failure to achieve a successful pregnancy after 12 months or
more of appropriate, timed unprotected intercourse or therapeutic donor insemina-
tion. Earlier evaluation and treatment may be justified based on medical history and
physical findings and is warranted after 6 months for women over age 35 years” [1].
The 1-year timeframe is explained by the probability that 85–90 % of healthy young
couples will conceive within 12 months, which means that infertility affects
10–15 % of the population.
Fecundity: This is the probability that a single menstrual cycle will result in a
live birth whereas fecundability is the probability that a single cycle will result in a
pregnancy. The probability of a pregnancy in a single cycle is 20–25 % of otherwise
normal couples.
C.A. Laskin, M.D., F.R.C.P.C. (*)

Departments of Medicine (Rheumatology) and Obstetrics & Gynecology, (Reproductive
Endocrinology and Infertility), LifeQuest Centre for Reproductive Medicine,
University of Toronto, 655 Bay Street, Suite 1800, Toronto, ON, Canada, M5G 2K4
e-mail: calaskin@gmail.com
K.I. Cadesky, M.D., F.R.C.S.C.
Department of Obstetrics and Gynecology (Reproductive Endocrinology and Infertility),
Mount Sinai Hospital; LifeQuest Centre for Reproductive Medicine, Toronto, ON, Canada
C.A. Clark, Ph.D. • K.A. Spitzer, M.Sc.
LifeQuest Centre for Reproductive Medicine, Toronto, ON, Canada
230 C.A. Laskin et al.
The probability of a pregnancy is dependent upon a number of factors, the most

important of which is the woman’s age. In those individuals afflicted with a rheu-
matic disease, the disease itself or the medications used to treat the underlying con-
dition may adversely affect fertility and fecundity. Bearing these factors in mind,
one would suspect that men and women with rheumatic disorders may not have the
same fertility as an age-matched general population. Furthermore, one would expect
that fecundability and fecundity are likewise impaired in women with rheumatic
diseases. These two issues need to be further investigated.
“Fertility 101”
The majority of people with systemic, inflammatory rheumatic diseases are women
of childbearing age. It is therefore incumbent upon the attending specialist to dis-
cuss family planning with these women at least on a regular basis. It is essential that
the woman enter into a pregnancy electively, planned with her attending specialist.
A similar approach applies to the couple having difficulty conceiving. Every fertil-
ity evaluation should be viewed as a pre-pregnancy evaluation: if the woman’s dis-
ease is too active to assure a safe pregnancy, then assisted reproductive technology
(ART) should be avoided. Most internists/rheumatologists have little knowledge of
reproductive medicine and fertility management. If the rheumatologist’s evaluation
suggests that the woman is in a quiescent stage of disease that would maximize the
chances of a safe pregnancy, then a referral to a reproductive endocrinology and
infertility (REI) specialist will be necessary. The referring rheumatologist should
provide important details regarding the patient including the underlying disease
entity and the medications currently prescribed. Prior to any management decisions
by the REI, a dialogue should be established with the rheumatologist. This will be
the best way to ensure that the woman can become pregnant safely using ART.
The Female Menstrual Cycle
Understanding the physiology of the menstrual cycle gives insight into how fertility
issues are investigated in women. Figure 12.1 illustrates the events in a normal men-
strual cycle. The ovulatory woman will often experience a repeated pattern of pre-
menstrual symptoms followed by recognizable symptoms during menses. The
cycles in such women are regular and predictable whereas those in women who may
not be ovulating are irregular and unpredictable. The events of the cycle that are the
target of investigation are the basal hormone levels: Day 3 follicle stimulating hor-
mone (FSH), luteinizing hormone (LH), and estrogen. The rise in progesterone lev-
els in the latter phase of the cycle is indicative of ovulation. The best method to
study the events of a woman’s menstrual cycle would be to monitor the hormone
levels and correlate with follicle development using ultrasound. Cycle monitoring
provides a dynamic view of the woman’s physiology and may provide clues to
understanding the reasons underlying the failure to conceive.
12 Assisted Reproductive Techniques in Rheumatic Disease Patients 231
Menstrual Cycle
Ovarian Cycle
Follicular Phase Ovulation Luteal Phase
Progesterone
Hormones
Ovarian
Estrogen
Hormones
Pituitary
LH
FSH
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Endometrium
Fig. 12.1 The female menstrual cycle. Each level of the diagram illustrates the response of
the various targets to the pituitary hormones, FSH and LH. Production of each of the ovarian
hormones, estrogen and progesterone, is dependent upon the growth of the maturing follicle.
The development of the endometrium in turn is dependent upon the appropriate production of the
ovarian hormones
Fertility Evaluation and Investigation
Aging and Fertility
It becomes very clear when assessing female fertility that there is no substitute for
age. The ability to both conceive and maintain a pregnancy is strongly influenced by
a woman’s age. Whether career choice or life circumstances, those women who delay
childbearing may face infertility by the time they are ready to become pregnant.
When a woman reaches 37 years of age, her chances of becoming pregnant decreases
significantly with each passing year; indeed, as many as 99 % of women at age 45 are
infertile. Although the average age of menopause is 51.8 years, reproductive meno-
pause occurs 6–7 years earlier. Beyond age 37, the remaining oocyte quality declines
exponentially as the better quality oocytes have already been released. A decrease in
oocyte quality refers to an increased prevalence of aneuploid oocytes owing to dys-
function of the meiotic spindle. This will lead to higher frequency of chromosomal
abnormalities, which in turn leads to miscarriage or infertility.
Assessment of the Infertile Couple
The fertility assessment can be conceptualized as “macrofertility” involving the

assessment of ovulation, fallopian tubes, uterus, and sperm analysis. When all such
studies are found to be normal, the diagnosis of “unexplained infertility” is made.
To explore this further involves a “microfertility” assessment. There are literally
thousands of steps involved in the interaction of sperm and oocyte. We are currently
able to identify about 42 known abnormalities at this level of investigation.
The Office Visit
A targeted, detailed history and physical exam is the starting point for assessment of
the woman. The gynecologic and obstetric history should include the menstrual his-
tory (onset of menarche; regularity of cycles; dysmenorrhea and dyspareunia); his-
tory of pelvic surgery; type and use of contraceptives; and a history of any pregnancy
complications and outcomes. Other aspects to the history such as exercise program;
weight loss or gain; smoking and alcohol intake; work, travel and dietary prefer-
ences may also have significant adverse effects on ability to conceive. The physical
exam should include weight and body mass index; thyroid abnormalities; breast
abnormalities including secretions; hirsutism and other signs of androgenicity, and
a pelvic exam
The male assessment will similarly require a complete history and physical
exam. Discovery of an abnormality from the semen analysis requires ruling out
systemic illness or medication that adversely affects sperm. Specific points in the
history include smoking, alcohol intake, use of recreational drugs, and occupation.
Prior reproductive issues in other relationships should be discussed. In addition, a
history of erectile dysfunction or difficulty ejaculating may prove to be an underly-
ing cause of the infertility, although this is frequently more difficult to elicit from the
patient. A history of varicocele repair, vasectomy, hernia repair, undescended testis,
testicular injury or mumps orchitis as well as certain medications such as testoster-
one, finasteride, or minoxidil may explain abnormalities in the semen analysis.
The last step in the office evaluation is to discuss details of sexual intercourse
with the couple. Too often or too infrequent sexual intercourse may explain failed
conception. Is the intercourse timed? Are there problems with intercourse? Are they
using lubricants, many of which are spermostatic? These are sensitive topics and
must be approached with that in mind.
Fig. 12.2 Fertility assessment flow chart. This is a simplified view of the fertility assessment in
both the male (a) and female (b). FSH follicle stimulating hormone, E2 estradiol, LH luteinizing
hormone, AMH anti-Müllerian hormone, TSH thyroid stimulating hormone
“Macrofertility” Investigations
The investigations in the female are more involved at all levels (Fig. 12.2a, b).
Ovulation is assessed through the history as well as hormone levels, including estra-
diol (E2), LH, FSH, and progesterone, measured at Day 3, midcycle, and after sus-
pected ovulation. The fallopian tubes are assessed using a hysterosalpingogram
(HSG) or a sonohystogram (SHG). The former is a much better test for tubal patency
while the latter is a good screening test. In addition to the tubal assessment, these
two investigations will also delineate the uterine cavity assessing for the presence of
polyps or impinging fibroids. With the utilization of 3D imaging, the SHG gives a
more detailed view of the uterine cavity compared to the HSG.
The Hormone Evaluation of the Woman
The hormone evaluation includes those hormones that are directly involved in the
menstrual cycle. The hormones E2, LH, FSH, and progesterone measured at Day 3
of the woman’s cycle indicate that the woman is indeed at the beginning of her cycle
and represent the basal hormone evaluation. The FSH should be at 10 IU/L or lower
with a low E2, LH, and progesterone. At midcycle, the LH should rise or surge
thereby triggering ovulation. After ovulation, all hormones fall except the proges-
terone, which should rise (Fig. 12.1). Other hormones that play a role in ovulation
indirectly are thyroid stimulating hormone (TSH) and prolactin. TSH should be
below 2.5 mU/L. If the prolactin is elevated, it should be measured fasting and
include a macroprolactin level, which is a biologically inactive molecule that may
account for what appears to be hyperprolactinemia.
Ovarian Reserve
Over the past 20 years, increasing emphasis has been placed on determining the
remaining follicular pool (or ovarian reserve): a diminishing ovarian reserve is
expected as a woman ages. However, younger women might also be found to have
diminished ovarian reserve underlying a fertility disorder. A basal FSH level mea-
sured at Day 3 appears to correlate with ovarian reserve: serum FSH is considered
elevated when above 10 IU/L and suggests a diminished ovarian reserve; it may also
indicate low oocyte quality.
An antral follicle count (AFC) is the number of follicles in the ovaries as deter-
mined by ultrasound between days 2–4 of the menstrual cycle. The normal range is
not standardized but a count of 12 (the sum total in both ovaries) is usually consid-
ered as the lower limit of normal. The AFC appears to be another reliable measure
of ovarian reserve and correlates with the probability of pregnancy as well as suc-
cess in an in vitro fertilization (IVF) cycle.
A more recent test that is the subject of a rapidly growing literature is the anti-
Müllerian hormone (AMH) evaluation: AMH is a peptide growth factor produced in
females by granulosa cells from pre-antral and antral follicles [2]. High levels of
AMH indicate good ovarian reserve. Routine fertility assessment now includes
measurement of circulating AMH, based on reports that it is a more reliable indica-
tor of ovarian age than other markers including Day 3 FSH and inhibin [3]. AMH is
easier to measure, as levels remain relatively stable throughout the menstrual cycle
in contrast to FSH and is less invasive than ultrasound-guided AFC. AMH decreases
with declining AFC and increasing age [4].
In summary, an accurate assessment of ovarian reserve should be part of every
female fertility evaluation and includes Day 3 FSH, Day 2–4 AFC, and an AMH
level, which can be measured at any point in the cycle.
Investigation of the Male
In men, the semen analysis provides the majority of data regarding fertility evalua-
tions (Fig. 12.2a). Routine semen analysis measures volume of the ejaculate, sperm
count, motility, and percentage of normal sperm cells. A more detailed sperm analy-
sis utilizes a computer analyzed sperm assessment (CASA) which includes an index
of fragmentation of genetic material in the sperm cells called the DNA fragmenta-
tion index (DFI). A DFI above 30 % is associated with a fourfold reduction of fertil-
ity in natural cycles; some studies suggest a doubling of first trimester miscarriages
as well, but this is more controversial [5]. Men may have all sperm parameters
normal except for the DFI, highlighting the critical importance of the DFI in the
male fertility evaluation. Hormone studies may be helpful in understanding some
abnormal results of the sperm analysis
Initial Management
The initial management of a couple with infertility involves identifying and correct-
ing these “macrofertility” abnormalities. Lifestyle issues such as smoking, alcohol
intake, stress, diet, exercise, and travel are important management decisions that are
under the couple’s control. They should be addressed and may need appropriate
counseling. The couple must understand the “correct” window of opportunity and
need to know the optimal time in the female partner’s cycle that has the highest
probability for conception: that is, they must have intercourse around ovulation. In
a woman with a 28-day cycle, having intercourse every 2 days between Days 10 and
20 will generally cover the “fertile” period. When these simple measures are unsuc-
cessful, ovulation induction or superovulation under the care of the REI may be
necessary. When there are issues of sperm quality, referral to an andrologist should
be made. Improving sperm quality is not always easy or successful but with appro-
priate guidance by an andrologist, reasonable treatment programs should be
attempted. If the above measures are unsuccessful after a reasonable time, ART
treatment options are necessary.
Microfertility Management
Most causes of infertility are due to disruptions in microfertility. All ART treatment
modalities are based upon superovulation: the administration of fertility drugs
(exogenous FSH) stimulates the ovaries to mature a number of follicles as opposed
to the single follicle matured in a natural cycle. As the follicles grow and mature
they produce estrogen resulting in an increase in the endogenous estrogen level.
This may be important to consider when we address such treatment in rheumatic

diseases. The least invasive ART protocol is controlled ovarian hyperstimulation
followed by intrauterine insemination, which involves the careful administration of
exogenous FSH to produce two to three mature follicles. Sperm must then be safely
prepared for injection into the uterine cavity. Although this treatment is not associ-
ated with a high success rate, outcome is better than the couple simply trying on
their own with timed intercourse. A limited number of cycles should be attempted
(three to six cycles); if a pregnancy is not achieved, the more invasive IVF technol-
ogy can be undertaken.
IVF involves a more aggressive stimulation with exogenous FSH leading to the
maturation of a larger number of follicles (and higher levels of estrogen). Once the
follicles have matured, the oocytes are surgically extracted, fertilized in vitro, and
then incubated over 3 or 5 days. Concerns regarding low sperm count or motility
can be addressed utilizing intracytoplasmic sperm injection (ICSI) where a single
sperm cell is injected directly into the oocyte. Depending upon the management
plan, a specific number of embryos (3-day incubation) or blastocysts (5-day incuba-
tion) are transferred directly into the uterine cavity. The woman is usually given
progesterone until a pregnancy test is performed. If pregnancy has been achieved,
then the progesterone is continued until sometime in the latter part of the first tri-
mester (usually 10–12 weeks gestation).
Fertility Management in the Rheumatic Diseases
When the underlying rheumatic disease is active, there may be negative feedback on
the hypothalamic–pituitary–ovarian axis in the woman or on spermatogenesis in the
male [6, 7] contributing to fertility. In addition, certain drugs used in the treatment
of the underlying condition may adversely affect fertility in either gender [8, 9]. The
remainder of this chapter will cover specific rheumatic diseases giving special con-
sideration to the impact of the disease and medication on the individual’s fertility, as
well as the potential effect of fertility management on the disease course. Fertility
issues specific to some of the more common rheumatic disorders such as rheuma-
toid arthritis (RA), systemic lupus erythematosus (SLE), anti-phospholipid syn-
drome (APS), ankylosing spondylitis (AS), and scleroderma (SSc) will be discussed
below. In addition, some special considerations regarding various medications used
in the treatment of specific rheumatic diseases will be discussed.
Rheumatoid Arthritis
Most chronic rheumatic diseases such as RA are not known to directly affect fertil-
ity [10]. However, disease activity may impact on ovulatory function through an
interruption of the hypothalamic–pituitary–ovarian axis. In addition, medications
used in the treatment of RA may adversely affect fertility both in women and in
men. Hargreaves reported in 1958 that a group of women with known RA had fewer
children than a group without the disease [11]; this observation has been substanti-
ated by others and most recently by Clowse et al. [12]. Variables such as lifestyle,
disease activity, or a change in perspective by women and their partners may all
contribute to the ultimate size of the family. Recent studies tend to support the origi-
nal observation from a controlled study by Kay and Bach that fertility is lower in
women both before and after the onset of disease [13]; furthermore, menopause
occurred earlier in those who ultimately developed RA compared to controls. The
major shortcoming of all of these studies suggesting decreased fertility in women
with RA is that they are all based on self-report questionnaires and address life
events as opposed to a more physiological approach to ovarian function in RA. Until
such studies are done, we are left with the limited conclusion that for women with
RA, family size tends to be smaller.
Investigation and Management of Infertility
The investigation and management of infertility in RA differs little from that in the
general population. However, as in all scenarios with an underlying medical problem
in a woman contemplating pregnancy, it is imperative that disease be under optimal
control and that all medications are compatible with pregnancy (Chap. 14). The fer-
tility evaluation should be undertaken as outlined above and in (Fig. 12.2a, b). While
adjustments to medications need to be made in terms of potential teratogenicity, most
medications do not interfere with fertility. There are exceptions. Most nonsteroidal
anti-inflammatory drugs (NSAIDs) can be taken prior to conception. It is important
to know that NSAIDs can interfere at the ovulation step by inhibiting follicular rup-
ture [14] and affect implantation; therefore, it is advisable to discontinue these medi-
cations during a conception cycle. Once an intrauterine pregnancy is documented,
NSAIDs can be used until 32 weeks gestation. Ibuprofen and naproxen may be pref-
erable as there is considerable experience with these medications. The other drug to
consider is sulfasalazine, which leads to reversible oligospermia and/or asthenosper-
mia demonstrated on semen analysis in approximately 30 % of males on the drug [9].
The low sperm count is reversed in 3 months after discontinuation.
In summary, fertility investigation and management in men and women with RA
is directed to controlling disease activity and then ensuring that medications are safe
for use before and during pregnancy. With few exceptions, the majority of drugs
used in the treatment of RA have little or no impact on fertility.
Systemic Lupus Erythematosus and APS
SLE has its greatest prevalence among women of reproductive age. Unlike RA, SLE
seems to be a more hormonally sensitive disorder which leads to significant impli-
cations for the treatment of infertility. Medications tend not to be the limiting
step in the treatment of a woman with SLE undergoing fertility therapy.
Disease manifestations and certain potential risk factors such as the presence of an
anti-phospholipid antibody may directly influence the treatment program. In con-
trast to the generally accepted position that fertility is unaffected, some recent stud-
ies suggest that there may be a direct impact of the disease on fertility [15, 16]. As
is the case in any medical disorder in a woman contemplating a pregnancy, if there
is concern regarding the woman becoming pregnant, then assisting the woman to
become pregnant would be contraindicated.
There is a wide body of literature regarding a higher prevalence of various auto-
antibodies in women with unexplained infertility [17–21]. However, if any of these
autoantibodies are associated with infertility, it is unclear which ones may be pre-
dictive and there is little if any evidence supporting the routine screening of women
or men for the presence of such autoantibodies when investigating infertility.
A number of REI specialists routinely assay various autoantibodies in otherwise
healthy women being investigated for infertility [17–21] based primarily upon stud-
ies in recurrent pregnancy loss, which, in turn, is based on the observation that
women with SLE have a higher prevalence of recurrent miscarriage and fetal wast-
age [22–24]. This extrapolation from the recurrent miscarriage and SLE literature is
both questionable and fraught with the risk of erroneous treatment decisions.
Medical Evaluation
The initial evaluation of a couple with infertility where the woman has SLE should
be considered a pre-pregnancy evaluation. Once the woman has been medically
cleared for pregnancy, the couple can then be referred to an REI specialist for inves-
tigation and management of infertility.
Fertility Evaluation
Fertility assessment for patients with SLE does not differ from a routine fertility
assessment. Recent papers suggest that there may be diminished ovarian reserve in
SLE patients as determined by the measurement of AMH [25, 26]. Lawrenz et al.
reported that AMH levels in 33 SLE patients were lower than in healthy controls
and concluded that SLE itself may have a negative influence on ovarian reserve,
although there were no differences in number of children or miscarriages between
the two groups [25]. Mok et al. reported that AMH was significantly lower in
women exposed to cyclophosphamide (CYC), suggesting ovarian damage (no effect
was seen in women exposed to other immunosuppressive agents). Increasing age
and each cumulative 5 g CYC exposure were independently associated with
decreased AMH [27]. However, it has also been reported that low levels of AMH
are not necessarily predictive of either reduced fecundability or of reduced live birth
rate in healthy young women [4]. This latter finding suggests a need for caution
before assuming the strength of correlation between AMH and long-term fertility,
whether in a general or autoimmune population [2, 28]. Until a comprehensive
study of fertility evaluation is undertaken in women with SLE, it is premature to

assume that such women have diminished ovarian reserve.
Timing of the fertility evaluation appears to be important. Whether in the male or
female lupus patient, active disease may negatively impact fertility whereas inactive
or well-controlled disease will lead to a more accurate assessment of fertility in the
individual. In a woman with active lupus or chronic renal failure, fertility may be
impaired by anovulation through interruption of the hypothalamic–pituitary–ovarian
axis; high doses of corticosteroids may interfere with ovulation through a similar
mechanism. Whether the disease itself negatively impacts fertility is unclear, and
there is considerable variation in opinion [7, 15, 17, 19–21].
Anti-Phospholipid Antibodies and Infertility
Anti-phospholipid antibodies (aPL) have been reported to be associated with recur-

rent pregnancy loss and adverse pregnancy outcomes [29–33]. However, several
recent studies do not find a strong association, if any, between aPL and early preg-
nancy loss [34, 35]. Recent studies support the association of late pregnancy loss
primarily with the lupus anticoagulant (LAC), with little association with anti-
cardiolipin antibodies and no association with antibodies to β2-glycoprotein I [36,
37]. There continues to be ongoing controversy regarding an association of aPL
with infertility and failed implantation [38–44]. When women with aPL undergoing
IVF are treated with heparin +/− ASA +/− corticosteroids, most show no benefit in
terms of pregnancy outcome [41–43]. Hornstein et al. in 2000 performed a meta-
analysis of seven studies on aPL and IVF outcome [45] including 2,053 women, 703
of whom had at least one positive aPL result: these authors found no association
between aPL and either clinical pregnancy or live birth. A further point, based on a
pathogenetic mechanism, calls into question the relevance of aPL to female infertil-
ity and failed implantation [39]. Finally, the American Society for Reproductive
Medicine has issued a statement from the Practice Committee in which they state
that there is no indication for the assessment of aPL in otherwise healthy couples
undergoing IVF and that therapy to treat such antibodies is not justified based upon
the existing data [46].
In summary, despite a few studies implicating aPL in female infertility and
implantation failure in IVF, there is a dearth of evidence supporting such an associa-
tion. Based upon the evidence at this time, there is no reason to routinely screen
healthy women undergoing fertility evaluation or treatment for aPL.
Ovulation Induction and IVF
It has been hypothesized that SLE is a disease that can be exacerbated by changes in
sex hormone concentrations, particularly elevated estrogen levels. If so, then fertility
treatment incorporating ovulation induction or superovulation may present a risk of
induction of SLE or a flare of disease in those with known SLE through the
generation of endogenous hyperestrogenemia and enhancement of humoral immu-

nity [47]. Although induction of SLE appears to be a rare possibility, flare of estab-
lished SLE may occur with evidence supporting the occurrence of disease exacerbation
in women undergoing fertility therapy [48–50]. However, in the well-selected patient,
ovulation induction with or without IVF can be carried out safely.
Identifying the patient in whom ovulation induction is safe involves a careful and
complete medical assessment of the woman with respect to her underlying SLE.
Clinically the patient should show no evidence of active disease for the 6 months
preceding an attempt at pregnancy. Despite the absence of Level I or II evidence, most
physicians support the expert recommendations regarding this 6-month time frame.
Blood pressure must be normalized, so any anti-hypertensive medication in use must
be safe for pregnancy. With this information, a “clinical profile” of the patient can be
formulated so that all involved in the patient’s care know which clinical manifesta-
tions that appear during ART or later during pregnancy are those of active lupus.
The “laboratory profile” will consist of the patient’s baseline, routine laboratory
tests as well as the lupus serology. The patient’s rheumatologist will know if the
patient’s clinical disease activity is concordant or discordant with serology. If dis-
cordant, then clearly the clinical assessment is critical. Testing for aPL is necessary
as those SLE patients positive for this antibody may be at greater risk of a thrombo-
embolic event in the presence of hyperestrogenemia. In those with documented
APS with a high risk of thrombosis, it may be inadvisable to undergo ovulation
induction especially if it is part of an IVF cycle. This issue will be discussed further
below. The clinical and laboratory profiles are helpful to “define” the woman’s dis-
ease. In this way all involved will be aware of which manifestations and laboratory
parameters to monitor. In addition, a management plan can be formulated in advance
should the woman flare during the fertility therapy or during pregnancy.
To complete the assessment prior to undertaking ovulation induction or IVF,
medications must be reviewed and the woman stabilized on pregnancy-safe drugs.
The ideal patient with SLE deemed to be a good candidate for ovulation induction
therapy (with or without IVF) has minor organ disease and is on minimal medica-
tion. Women with stable clinical lupus who may have renal disease are also accept-
able provided the disease and renal status are stable, with minimal risk during a
pregnancy. In contrast, women with complicated lupus on numerous medications as
well as higher doses of prednisone, hypertension, renal insufficiency, and/or cytope-
nias are not suitable candidates for ovulation induction with or without IVF.
Ovarian Hyperstimulation Syndrome
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovula-

tion induction therapy. It is an exaggerated response typically associated with the use
of exogenous gonadotropin stimulation. The ovaries are markedly enlarged with
numerous maturing follicles. A capillary leak syndrome develops mediated by vascu-
lar endothelial growth factor (VEGF), which ultimately results in a third space fluid
shift into the peritoneal and/or pleural cavities [51]. OHSS can be mild or of sufficient
severity to warrant admission to an ICU. Severe OHSS occurs in approximately 1 %

of those undergoing ovulation induction whereas mild to moderate OHSS occurs in
4–10 %. The mortality rate of OHSS is 1/45,000–1/500,000 [7]. OHSS presents a risk
of renal compromise and thromboembolism which may be additive in the woman
with SLE, especially if she also has aPL. It is therefore prudent to be certain the REI
specialist managing the patient is aware of her status and designs a stimulation proto-
col that minimizes the risk of OHSS.
APS and Fertility Management Including IVF
In those women (with or without underlying SLE) with documented APS, there are
definite risks to ovarian induction therapy and IVF due to the hyperestrogenemia. In
IVF cycle protocols, combined oral contraceptives are often used at the start of the
cycle: this may place the woman at significant risk of a thromboembolic event. In
those with previous arterial events, it may be prudent to avoid ovulation induction
therapy completely. Alternatively, a minimal stimulation protocol or natural cycle
could be used in IVF [52, 53]. Although some centers report a reasonable pregnancy
rate with such protocols, many clinics find that they are often accompanied by a much
lower pregnancy rate [54]. In those patients where hyperestrogenemia is absolutely
contraindicated, eliminating the use of gonadotropins, aromatase inhibitors such as
letrozole can be used in cycles using intrauterine insemination. Although letrozole
could be used alone in an IVF cycle, this will usually result in a single follicle and
single oocyte. This is equivalent to a natural cycle IVF but with more control [55].
In aPL-positive women with a history of venous events, stimulation may be car-
ried out using anticoagulation with heparin or low-molecular-weight heparin, which
is then held prior to oocyte recovery, following which it is restarted soon thereafter.
In such patients it is critical to avoid OHSS, which in and of itself, presents an added
risk to hypercoagulability and thrombosis. With proper attention to management of
women with APS including a coordinated approach by the rheumatologist/hema-
tologist and the REI specialist, ovulation induction with or without IVF can be
undertaken safely [50, 56, 57].
Ankylosing Spondylitis
Ankylosing spondylitis (AS) is one of the rheumatic disorders that has a predilection
for males, with a male to female ratio of 2:1–3:1. The disease has its onset during the
reproductive years usually between 20 and 30 years of age. A study surveying a
large number of women with AS in the USA, Canada, and Europe found no adverse
effects on pregnancy, fertility, or neonatal outcome [58]. In particular, of 649 women
with previous pregnancies there were 2.4 pregnancies per woman, of which 1.4
pregnancies occurred during active disease suggesting that fertility was not adversely
affected by AS. In contrast to this observation in women, a recent study has found a
significantly higher frequency of varicocele in male AS patients than controls (40 vs.
8 %) [59]. Comparing those AS patients with a varicocele to AS patients without, the
median of normal sperm forms was 13.5 % compared to 22 % indicating the poten-
tial for increased failed conception in those with the varicocele. No other studies
have suggested any affect of AS on fertility in men or women [58, 60].
Apart from the lack of effect of the disease on fertility, some medications com-
monly used to treat AS are associated with subfertility. Sulfasalazine is known to
cause reversible azospermia or oligospermia as well as reduced sperm motility and
an increase in abnormal forms [61, 62]. In one early study, Birnie et al. found 86 %
of men on sulfasalazine for inflammatory bowel disease had an abnormal semen
analysis with 72 % having oligospermia [50]. In those men on sulfasalazine having
an abnormal semen analysis which was discovered during a fertility assessment,
2–3 months off the drug usually corrected the abnormality. Tumor necrosis factor
alpha (TNFα) antagonists have become a mainstay in the treatment of AS. At least
two studies have shown no adverse effect of infliximab, etanercept, or adalimumab
on male fertility [63–65].
Based upon the above literature, fertility assessment in women with AS usually
proceeds routinely. There are no specific adverse effects of the disease on female
fertility. However, a recent study by Nukumizu et al. suggests that all men with AS
should be assessed for a varicocele [59]. In addition, a routine semen analysis in
men on sulfasalazine should identify drug-related abnormalities. In such individu-
als, the drug should be discontinued for 2–3 months and the semen analysis repeated
to determine if the abnormalities are now corrected. Since this may have been the
cause of the infertility, no additional treatment needs to be instituted for several
months. Should fertility treatment be necessary, there appears to be no contraindica-
tion to any intervention provided all medications used to treat the AS are
pregnancy-safe.
The fertility evaluation in AS must be a pre-pregnancy evaluation: if pregnancy
is not advised, then treatment of a fertility problem must be viewed as
contraindicated.
Scleroderma
Scleroderma (SSc) is a rare disease with an incidence of two to ten cases per million
usually presenting in the fifth to sixth decades. The ratio of female to male is 3:1 with
an even greater female predominance in the reproductive years of 15:1 [66, 67].
Renal crisis remains the most serious complication of this disease; therefore, the
major concern when considering pregnancy or fertility management is the extent of
organ involvement. To minimize the risk of renal crisis or other major complications
such as severe cardiopulmonary manifestations, pregnancy should be avoided in
those women with rapidly progressive diffuse disease [68]. To reemphasize, the fer-
tility evaluation in scleroderma must be a pre-pregnancy evaluation. If pregnancy is
not advised, then treatment of a fertility problem must be viewed as contraindicated.
Psychosocial Variables
Fertility issues in women with SSc can involve some variables quite distinct from
those of other rheumatic diseases. In a survey by Steen et al. of 214 SSc female
patients, a significantly higher proportion had never been pregnant compared to a
group with RA or normal controls [69]. This study discovered that unique to patients
with SSc, a disproportionate number of women with had never married, were sexu-
ally inactive, or chose not to have children. Other contributing factors that nega-
tively impact inter-personal relationships are an increased incidence of vaginal
dryness and dyspareunia affecting up to 37 % of such patients in addition to joint
contractures, which may prevent sexual intercourse [70].
Infertility and “Pre-scleroderma”
An unusual theory applicable only to SSc is that a history of reproductive failure,

i.e. infertility or recurrent miscarriage, may predate the onset of SSc [68, 71]. The
most recent study by Silman and Black using a postal questionnaire showed twice
the rate of miscarriage and three times the rate of infertility (the women with SSc
had no pregnancy by age 35) compared to a control population [71]. These authors
and others hypothesize that the female predominance of the disease and the peak
onset just after the reproductive years is due in part to this adverse reproductive his-
tory [71, 72]. The postulated mechanism associating reproductive failure with SSc
is that of microchimerism in which there is a transplacental transfer of fetal cells
during prior pregnancies or miscarriages that then initiates a chronic graft-versus-
host reaction [72–77]. The theory is intriguing and suggests that in the appropriate
host, there is a serious consequence to infertility or recurrent miscarriage that
extends beyond the reproductive years.
Fertility Evaluation and Treatment
No woman with SSc should undertake fertility therapy without a pre-pregnancy

medical assessment by a rheumatologist or internist who is very familiar with the
condition: this evaluation becomes the start of the fertility evaluation. Once it is
determined that it is safe for the woman to become pregnant, a routine fertility
assessment can be undertaken in the woman and her partner. It is important that
the REI specialist be cognizant of the unique psychosocial variables that may play
a role as female factors in the couple’s infertility as these issues may be the reason
underlying the infertility. After consultation between the rheumatologist/internist
and the REI specialist, the patient may undergo ovulation induction and even IVF
provided no relative or absolute medical contraindications are present. Success
rates should be similar to the general population based upon the observations of
Steen and Medsger [69]. These investigators found that the overall rate of a suc-
cessful pregnancy following at least 1 year of failed conception was 37 %
compared to 40 % in an RA group which was no different than 43 % seen in nor-

mal controls. The miscarriage rate, however, is increased in SSc especially in
those with diffuse disease (24 %) compared to women with limited skin involve-
ment (12 %) [77].
In conclusion, women with SSc contemplating a pregnancy require a detailed
pre-pregnancy evaluation. This should include an evaluation for the presence of
underlying vasculopathy and the extent of such involvement. If a fertility problem
is present, only after the woman is cleared by medical evaluation should investiga-
tion proceed. Fertility therapy can be implemented as necessary with reasonable
expectations on the part of the patients and the physicians. Should the woman
become pregnant, in the absence of significant vascular disease, most pregnancies
are accompanied by few adverse maternal or neonatal complications.
Alternative Options for the Patient with Complicated

Connective Tissue Disease
There will be patients who are advised not to undergo a pregnancy owing to the
severity of their underlying medical condition. This is a significant hardship for both
the individual and the couple. The rheumatologist has an important role in offering
support and referring the patient and/or couple to counseling and support groups
when appropriate. Family planning includes a range of options in addition to preg-
nancy including adoption, gamete donation, and surrogacy utilizing a gestational
carrier. In the latter scenario, the IVF cycle proceeds with the resulting embryos
being transferred to the woman who has agreed to be the gestational carrier. Utilizing
a gestational carrier eliminates the risk of OHSS and pregnancy in a woman with an
underlying medical condition. Finally, choosing to be child-free is a family plan-
ning option that should also be discussed with patients.
Fertility Preservation
In those cases where it may be possible for a woman to carry a pregnancy at a later
date but her current disease status contraindicates doing so at the present time, cryo-
preservation of oocytes, sperm, or embryos until the disease is inactive may be an
option. If the patient has a partner of the opposite sex, the preferred option is to
cryopreserve embryos, which have an excellent survival rate upon thawing, exceed-
ing that of cryopreserved oocytes [78]. Where there is a woman without a partner,
cryopreservation of oocytes is a viable option provided the woman is well enough
to undergo ovulation induction and retrieval of oocytes. Cryopreservation of sperm
is an established technology with an excellent survival rate on thaw provided the
sperm is of good quality originally.
Prevention of Infertility
CYC therapy can be life-saving for a woman experiencing a major flare of a connec-
tive tissue disease such as SLE. However, knowledge of the long-term side effects
of infertility and premature ovarian failure will often complicate this management
decision. Studies have shown that the woman’s age at the time of treatment and the
cumulative dose of CYC administered to either a man or a woman are major risk
factors that contribute to CYC-induced gonadal failure [79]. Combined oral contra-
ceptives may be protective for women while testosterone may offer similar benefit
to men who are to be treated with CYC. However, there is a paucity of evidence to
support such a preventative measure. The prior administration of the long-acting
GnRH analogue, leuprolide, may prevent ovarian failure in the female [8]. In males,
cryopreservation of sperm is optimal to preserve fertility in those who will require
CYC treatment.
Conclusion
It is still maintained that individuals with rheumatic disease have normal fertility.
Recent studies have questioned that conclusion but detailed, methodical studies are
necessary to confirm or refute the assumption. Women with rheumatic disease who
have a fertility problem must be assessed to determine if it is safe for them to undergo
a pregnancy. When the disease activity itself renders it inadvisable to enter into a
pregnancy, then fertility treatment should be withheld. Appropriate management of
a fertility problem in such individuals requires close cooperation and collaboration
between the attending rheumatologist and the REI specialist. Once pregnant, the
woman should be referred to an obstetrician with experience in dealing with such
patients. With close monitoring and appropriate intervention, most women with
rheumatic disease should be able to undergo fertility therapy which will ideally
result in a successful pregnancy with no adverse maternal or neonatal effects.
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Chapter 13
Neonatal Lupus
Barbara Mendez, Amit Saxena, Jill P. Buyon, and Peter M. Izmirly
Abbreviations
Anti-TG Anti-thyroglobulin
Anti-TPO Anti-thyroperoxidase
CHB Congenital heart block
EFE Endocardial fibroelastosis
HCQ Hydroxychloroquine
La48 48 kDa SSB/La
LTCC L-type cardiac calcium channels
MHC Major histocompatibility complex
NL Neonatal lupus
Ro52 52 kDa SSA/Ro
Ro60 60 kDa SSA/Ro
RRNL Research registry for neonatal lupus
SLE Systemic lupus erythematosus
SS Sjögren’s syndrome
UAS Undifferentiated autoimmune syndrome
B. Mendez, M.D.
Albert Einstein College of Medicine, Department of Rheumatology, Montefiore Medical
Specialists, 495 Central Park Avenue, Scarsdale, NY 10583, USA
A. Saxena, M.D.
NYU Langone Medical Center, Center for Musculoskeletal Care, 333 East 38th Street,
4th Floor, New York, NY 10016, USA
J.P. Buyon, M.D.
Department of Rheumatology, New York University School of Medicine,
301 East 17th Street, Suite 1410, New York, NY 10003, USA
P.M. Izmirly, M.D. (*)
Department of Rheumatology, New York University School of Medicine,
301 East 17th Street, Room 1611B, New York, NY 10003, USA
e-mail: Peter.izmirly@nyumc.org
252 B. Mendez et al.
Introduction
Fetuses exposed to maternal anti-SSA/Ro and anti-SSB/La antibodies can

develop a syndrome known as neonatal lupus (NL), which is comprised of car-
diac, cutaneous, hepatic, and hematologic abnormalities [1–8]. The term “neona-
tal lupus” originated with the observation that the cutaneous lesions of the
neonate resemble those associated with systemic lupus erythematosus (SLE) [3,
4]. The clearance of maternal autoantibodies in the 6–8 months of postnatal life
is accompanied by the resolution of the cutaneous, hematologic, and hepatic
abnormalities. In contrast, cardiac manifestations of NL, most typically congeni-
tal heart block (CHB), are often irreversible and associated with significant mor-
bidity and mortality [9]. The term cardiac-NL is used to denote the varied
spectrum of cardiac disease, inclusive of heart block (complete or incomplete),
cardiomyopathy, and endocardial fibroelastosis (EFE). While CHB may result in
long-term sequelae, the pathophysiologic processes leading to disease occur dur-
ing the pre- and postnatal period in which maternal anti-SSA/SSB autoantibodies
are present in the fetal or neonatal circulation. This concordance between anti-
body presence and disease manifestations implicates NL as a disease of passively
acquired humoral autoimmunity.
Epidemiology
Cardiac-NL occurs exclusively in infants born to mothers with anti-SSA/Ro and/or

anti-SSB/La antibodies, while the cutaneous manifestations can be seen when the
mother has these antibodies or antibodies to RNP [10, 11]. The population preva-
lence of CHB is approximately 1:15,000 live births [12, 13]. In children born with
CHB in the absence of documented structural abnormalities, antibodies to anti-SSA/
Ro are found in over 85 % [11]. Among anti-SSA/Ro positive mothers, prospective
studies show that approximately 2 % of pregnancies will result in infants affected by
cardiac disease [14–17] and the recurrence rate is approximately 8- to 9-fold this
risk [12, 18–22]. The risk of developing cutaneous manifestations of NL is 7–16 %
in offspring of anti-Ro and anti-La positive mothers [15, 17]. The recurrence rate of
cutaneous NL is estimated to be between 23 and 29 %, and having an initial child
with cutaneous NL appears to increase the risk of a subsequent child developing
cardiac-NL [23]. Mothers of children with either cutaneous NL or CHB may be
asymptomatic themselves, or they may have an autoimmune disease such as
Sjögren’s syndrome (SS), SLE, or an undifferentiated autoimmune syndrome
(UAS). In many cases, the presence of anti-SSA/Ro and/or anti-SSB/La antibodies
is only detected after the diagnosis of NL is made in an affected child [24]. Studies
show that presence of maternal rheumatic disease does not appear to influence the
recurrence of the NL [12, 25]. However, about half of asymptomatic mothers of NL
offspring will go on to later develop an autoimmune disease, the most common
being SS [26].
13 Neonatal Lupus 253
Cutaneous NL
The rash of NL is transient and can be present at birth, but is more often observed at
a mean of 6 weeks after birth [27]. An association with UV exposure suggests that
a skin response to UV light may liberate antigenic elements that then permit the
onset of the local autoimmune rash [27]. Once begun, the mean duration of the rash
is 17 weeks [27]. The rash is characterized by erythematous annular lesions or arcu-
ate macules with slight central atrophy and raised active margins, which are located
primarily on the scalp and periorbital area. A review of the corporeal distribution of
rash among 57 infants with cutaneous NL enrolled in the research registry for neo-
natal lupus (RRNL) revealed that 100 % had facial involvement. Other areas of
involvement included the scalp, trunk, extremities, neck, intertriginous areas and
rarely the palms or soles, in descending order [27]. NL lesions resemble those of
subacute cutaneous lupus erythematosus seen in adults, with basal cell damage in
the epidermis and a superficial monocyte cell infiltrate in the upper dermis [28].
Immunofluorescence staining of skin biopsies reveals IgG deposition within the
epidermis [28]. The rash is usually self-limiting and almost always resolves by
6–8 months of age, when the maternal antibodies are cleared from the affected child
[28]. Although residual skin abnormalities are rare, some that have been docu-
mented include atrophy, scarring, pitting, hypopigmentation or hyperpigmentation,
and telangiectasias [27, 28]. In rare instances, cutaneous NL has been seen in the
presence of an autoantibody other than anti-SSA and/or anti-SSB. In that instance,
the mother produced an autoantibody to RNP [10].
Management and Treatment of Cutaneous NL
Once identified, infants with NL should be protected from excessive exposure to

sun and/or other sources of UV radiation. In fact, just the presence of anti-SSA/Ro
and/or anti-SSB/La antibodies in the mother should prompt counseling with regard
to sun exposure, for both herself and the neonate, even if no rash is observed. Topical
steroids, preferably those that are non-fluorinated, have been used on infants who
have developed cutaneous NL. However, the efficacy of such steroids has been
questioned. Neiman and colleagues looked at steroid treated or untreated cutaneous
NL and reported no significant differences in outcome; however, the study was lim-
ited by a small number of cases [27]. Systemic therapies are not recommended
given the transience and almost universal benignity of NL skin lesions.
Hepatic Abnormalities
It is likely that the prevalence of hepatic involvement as a manifestation of NL has

been underestimated, since neonatal evaluation does not routinely include a liver
enzyme profile [29]. One prospective study did show that 26 % of children born to
mothers with anti-SSA/Ro had elevated liver enzymes [15]. Laxer described NL
associated with significant hepatic involvement in four infants, three living and one
who died postnatally [1]. The clinical picture in these neonates was cholestatic.
Pathologic changes included giant cell transformation, ductal obstruction, and
extramedullary hematopoiesis [1]. Lee described an additional three infants with
hepatic dysfunction, all with abnormal hepatic panels and histologic evidence of
cholestasis [30]. One of these three infants had concurrent CHB and congestive
heart failure. Post-mortem immunofluorescence studies of the liver tissue revealed
widespread IgG deposition. The second infant had hepatosplenomegaly and throm-
bocytopenia at birth, followed by a cutaneous eruption at 3 weeks of age. His liver
biopsy revealed hepatocellular cholestasis, lobular disarray, and mild pseudoacinar
formation. The third neonate developed a typical NL rash at 2 weeks and transami-
nitis with jaundice by 8 weeks. Liver biopsy revealed canalicular and hepatocellular
cholestasis [30]. Lee further investigated the incidence of hepatobiliary manifesta-
tions among 219 NL patients in the RRNL and noted that recognized hepatobiliary
disease occurred in 19 of 219 infants (9 %), usually in conjunction with either
cardiac or cutaneous involvement [29]. Three clinical variants were observed:
1—severe liver failure present during gestation or in the neonatal period (least
common); 2—conjugated hyperbilirubinemia with mild or no elevations of amino-
transferases occurring in the first few weeks of life; and 3—mild elevations of
aminotransferases occurring at approximately 2–3 months of life. The prognosis for
the children in the last two categories was excellent [29].
Hematologic Abnormalities
Hematologic manifestations of NL include thrombocytopenia, neutropenia, anemia,

and rarely, aplastic anemia [15]. Thrombocytopenia usually comes to recognition as
a result of petechial or purpuric eruptions. Thrombocytopenia was present in 10 %
of the neonates referred to Lee and her colleagues [28]. Gastrointestinal bleeding
was rare, occurring in only one child [28]. While NL thrombocytopenia is presumed
to be autoimmune in nature, its exact pathogenesis remains unclear, and it is uncer-
tain if it is mediated via anti-platelet antibodies or anti-SSA/Ro-SSB/La antibodies
targeting the surface of fetal platelets.
Neutropenia has also been documented in NL [31]. In vitro, exposure of intact
neutrophils to anti-SSA/Ro positive maternal and/or infant serum from affected
families results in immunoglobulin deposition on neutrophils, suggesting a possi-
ble immune-mediated basis for NL neutropenia [31]. Indeed, the neutrophil/immu-
noglobulin interactions were neutralized by pre-incubating the sera with 60 kDa
Ro antigen that bound the autoantibody, suggesting that anti-60 kDa SSA/Ro
directly drives the pathogenesis of neutropenia [31]. NL neutropenia has been
shown to resolve as maternal antibodies are cleared from the neonate without
known sequelae to the child [31]. In one prospective study, 25 of 107 infants born
to mothers with anti-SSA/Ro or anti-SSB/La antibodies had neutropenia but no
cases of neonatal sepsis occurred [15]. Wolach described a 5-month-old child with
typical cutaneous NL and complete marrow aplasia that resolved at 8 months,
which coincided with the clearance of anti-SSA/Ro antibodies [32]. This child
died at 16 months from sepsis.
Neuropsychological Impairment
Since the blood–brain barrier is not fully formed in utero, it seems reasonable to
speculate that neurologic dysfunction might also be a part of the spectrum of anti-
SSA/Ro associated injury. Boros and colleagues reported results from a Canadian
cohort of 87 infants exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibod-
ies [33] . Five of 47 infants with a manifestation of NL and two of the children
without any manifestation of NL had hydrocephalus resulting in a prevalence of
8 % in the entire cohort. This is considerably higher than in the general population.
The authors suggested that hydrocephalus is a manifestation of NL that tends to
resolve spontaneously, with only one child requiring surgical intervention.
Maternal immunological dysfunction has been associated with reports of devel-
opmental language delay, learning difficulties, and left-handedness [34]. A self-
report survey of 468 children and their parents suggested that parents with reported
immunologic disorders described a higher prevalence of learning and behavior
problems in their male children than did parents without immunologic disease [35].
In one study an association was found between dyslexia and CHB lesions in the
children of women with SLE [36]. In a second study of 45 mothers of dyslexic chil-
dren, anti-SSA/Ro sera levels were found to be 20 times greater than those of con-
trols [37]. More recently Ross evaluated 58 children of mothers with SLE during
pregnancy and found that 26 % of the children had some form of learning disability
[38]. Boys were more affected than girls. The presence of anti-SSa/Ro and/or anti-
SSB/La antibodies and disease activity during pregnancy were significantly related
to the higher prevalence of learning disability in the offspring.
Askanase and colleagues evaluated the prevalence of neuropsychological dis-
orders in children known to be exposed to anti-SSA/Ro and/or anti-SSB/La anti-
bodies in utero [39]. This retrospective study used detailed questionnaires,
telephone interviews, and reviews of medical records of children with NL, their
unaffected siblings, and healthy controls who were friends of similar age. It was
noted that behavioral problems, either isolated or associated with attention disor-
der, were present in all groups with no statistical difference. The prevalence of
depression, anxiety, developmental delays, learning disability, hearing and speech
problems, and use of stimulants were also not significantly different between
groups. The authors suggested that parental reporting of neuropsychiatric abnor-
malities was high in antibody-exposed children; however, it did not meet statisti-
cal significance when compared to the controls. Further evaluation with
neurocognitive testing is needed to characterize the potential brain injury by auto-
antibodies seen in NL [39].
Cardiac Manifestations
The most serious manifestation of NL is cardiac disease, including heart block

(complete or incomplete), associated cardiomyopathy, EFE and valvular abnormali-
ties [9]. The risk of having a child with cardiac-NL is approximately 2 % for an
anti-SSA/Ro positive woman who has either never been pregnant or has previously
had only healthy offspring [14–17]. If an anti-SSA/Ro positive mother has a previ-
ous child affected with cardiac-NL, the risk increases nearly tenfold to roughly
18 % in her next pregnancy [12, 19, 20, 40, 41]. If an anti-SSA/Ro antibody-positive
mother has had a previous child with cutaneous NL, the chance of having a subse-
quent child with cardiac-NL is 13 % [23].
The incidence of CHB appears to be more common in offspring of women with
high titers of anti-SSA/Ro and anti-SSB/La compared with mothers with low titers
[42]. However, there is considerable overlap in antibody titers between affected and
unaffected cases and most women have high titers that remain stable over time. In
one study, the risk of CHB was slightly higher if a mother had antibodies to both
anti-SSA/Ro and anti-SSB/La [43]. In any event, it is clear that antibodies to anti-
SSA/Ro remain the primary drivers of the condition.
Second degree heart block detected in utero, and first or second degree heart
block identified in infants at birth, can progress to complete heart block [18, 22, 44].
It is unclear whether first degree heart block detected in utero also progresses to
more advanced heart block. In a prospective study of 95 RRNL cases, all reported
patients with in utero prolonged PR interval that were treated or not had spontane-
ous resolution of the prolong PR interval [17]. A recent study questioned the signifi-
cance of first degree block, as serial echocardiograms in 165 anti-SSA/Ro
antibody-exposed fetuses with AV prolongation did not reliably predict progression
to second or third degree heart block [45]. These distinctions are important, because
there is evidence for the efficacy of treatment in cases of low-grade heart block,
whereas third degree heart block is currently irreversible [46].
Other documented arrhythmias and conduction abnormalities seen in NL include
sinus node dysfunction, long QT interval, ventricular and atrial ectopy, ventricular
and junctional tachycardia, and atrial flutter, but generally these arrhythmias have
not been clinically significant [47, 48]. Autoantibody-mediated heart block in NL is
typically associated with a structurally normal heart; however, structural abnormali-
ties such as flail mitral valve secondary to chordal disruption from EFE have been
reported [49]. In an evaluation of 18 autopsies of cardiac-NL cases from the RRNL,
fibrosis of the AV node and distal conduction system was the most characteristic
histopathological finding [50]. However, fibrosis of the SA node and bundle of His,
EFE, and valvular damage were also part of the spectrum of anti-SSA/Ro injury.
Valvular pathology was identified at the tricuspid, mitral, aortic, and pulmonary
valves. One of these fetuses had aortic insufficiency and stenosis together with
severe pulmonary valve stenosis and mild hypoplasia of the mitral and tricuspid
valve leaflets. Pre-mortem echocardiograms did not consistently predict the patho-
logical findings on autopsy [50].
Another cardiac abnormality that may be associated with NL is congestive heart

failure due to cardiomyopathy, which is often associated with EFE. EFE has been
reported both in isolation and in association with conduction defects [9, 51–54]. In
addition, a few cases of late onset cardiomyopathy have been reported in infants
with CHB despite receiving early pacemaker implantation [52].
Morbidity and Mortality of Cardiac-NL
Two recent large studies addressed the morbidity and mortality of cardiac-NL [9,
55]. The first, from the U.S.-based RRNL, addressed mortality rates and associated
risk factors [9]. In this study, in which all cases of cardiac-NL were due to exposure
to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, the case fatality rate was
17.5 % [9]. In utero deaths accounted for one third of the fatalities, with most occur-
ring before 30 weeks. Fetal echocardiographic risk factors associated with increased
mortality included EFE, hydrops, earlier diagnosis of cardiac-NL, and lower ven-
tricular rate. The additional presence of EFE and dilated cardiomyopathy was asso-
ciated with increased case fatality rates of 51.9 and 53.3, respectively, compared to
those with only isolated advanced heart block [9]. The majority of postpartum
deaths occurred before 1 year of life. Of the children born alive, the cumulative
probability of survival at 10 years was 86 %. By age 10 the cumulative probability
of requiring a pacemaker was approximately 70 %. Although rare, some children do
require cardiac transplant. There also was a trend toward increased mortalities in
children of mothers who had established diagnosis of SLE and/or SS at the time of
pregnancy, which became significant in the multivariable analysis. In addition there
was a significantly higher case fatality rate in minorities compared to Caucasians,
possibly because they had a higher risk for developing hydrops and EFE [9].
In a second multicenter study of advanced heart block from Europe and Brazil,
of which the majority were exposed to anti-SSA/Ro and/or anti-SSB/La antibodies,
91 % resulted in live births and 93 % of those were alive after the neonatal period
[55]. They found similar risk factors associated with mortality as reported in the
U.S. RRNL, including a gestational age <20 weeks at diagnosis, ventricular rate
<50 bpm, fetal hydrops, and impaired left ventricular function at diagnosis. In that
study at 1 year of life, 69 % of children were paced [55].
Proposed Mechanisms for Cardiac-NL
The precise mechanisms through which maternal anti-SSA/Ro-SSB/La antibodies

contribute to the pathogenesis of autoantibody-mediated cardiac tissue injury
remains unclear. Discordance of CHB in monozygotic twins of mothers with anti-
SSA/Ro and/or anti-SSB/La antibodies implies that a combination of fetal genetics,
the passive transfer of anti-SSA/Ro and anti-SSB/La antibodies, and the environ-
ment are needed for the CHB phenotype. Two non-mutually exclusive hypotheses
have been proposed to explain the mechanism by which maternal autoantibodies to
normally sequestered intracellular antigens initiate injury, one based on apoptosis
and the other on direct calcium channel effects [56, 57].
Apoptosis, Antibodies, and Tissue Inflammation and Injury
In vitro studies have demonstrated that apoptosis results in translocation of the SSA/
Ro and SSB/La antigens to the surface of the fetal cardiomyocytes [58–60]. It has
been shown that healthy fetal cardiocytes in cell culture are capable of phagocytos-
ing neighboring apoptotic cardiocytes, which implies that during embryogenesis of
the human heart this is a physiologic property of healthy cardiocytes [61]. However,
during this critical period of remodeling, SSA/Ro and SSB/La antigens may become
accessible to the cognate maternal autoantibodies with the subsequent formation of
immune complexes.
In vitro data generated both from cultured human fetal cardiocytes and from in
vivo work in a murine model confirms the binding of anti-SSA/Ro and anti-SSB/La
antibodies to the surface of apoptotic cells [59, 60]. The autoantibody binding to
apoptotic cardiocytes results in inhibition of phagocytosis and clearance by neigh-
boring healthy cardiocytes. It has been proposed that this leads to pathologic clear-
ance of the apoptotic cardiocytes opsonized with anti-SSA/Ro and anti-SSB/La by
infiltrating macrophages [61]. In contrast to the physiologic clearance by neighbor-
ing cardiocytes, phagocytosis by macrophages results in macrophage activation and
secretion of pro-inflammatory cytokines and fibrotic cytokines, resulting in
inflammation-induced tissue damage and fibrotic scarring [58].
Consistent with this model, a study which examined four available autopsy spec-
imens from patients enrolled in the RRNL revealed exaggerated apoptosis, IgG
deposition, and macrophage/fibroblast cross talk [62]. Apoptosis was extensive in
fetuses dying early, and most pronounced in regions containing conduction tissue.
Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but
not in control hearts, and was co-localized with apoptotic cells. Giant cells and
macrophages were present in septal and thickened fibrous sub-endocardial regions.
Septal tissue revealed extensive areas of fibrosis and microcalcification, in which
predominant smooth muscle actin infiltrates (myofibroblast scarring phenotype)
were observed [62].
Direct Calcium Channel Effects
In addition to inducing tissue damage, anti-SSA/Ro and /or anti-SSB/La antibodies

cross-react with L-type cardiac calcium channels (LTCC), resulting in channel
inhibition [63–65]. L-type channel function is crucial for the generation of action
potentials in AV and SA nodes—both areas of NL vulnerability. A recent study

showed that mouse pups passively immunized with anti-SSA/Ro and anti SSB/La
antibodies developed sinus bradycardia and heart block, but that pups could be
protected from these arrhythmias by transgenic over-expression of LTCC, suggest-
ing that the antibodies adversely impact LTCC function. LTCC knockout pups
born to immunized mothers had sinus bradycardia, advanced heart block and
decreased fetal parity, confirming that these channels are necessary for normal
cardiac function [65].
Target Antigens of the SSA/Ro-SSB/La System
The candidate antigens and their cognate antibodies have been extensively charac-
terized at the molecular level. Initial cloning of 60 kDa SSA/Ro (Ro60) identified a
zinc finger and an RNA-binding protein consensus motif [66–69]. It has been sug-
gested that Ro60 may function as part of a novel quality control for ribosome bio-
genesis [70]. Xue et al. [71] reported that autoimmunity develops in a murine
Ro60-knockout model and UVB irradiation results in significantly increased num-
bers of apoptotic keratinocytes compared to wild-type mice. This model suggested
that Ro60 plays a role in preventing autoimmunity, possibly by removing defective
ribonucleoproteins from cells, allowing them to escape immune surveillance, thus
Ro60 could be involved in cell survival. However, an alternative explanation is that
the increased numbers of keratinocytes present after photoprovocation represent a
defect in clearance of these cells, either because anti-Ro60 antibodies inhibit phago-
cytic uptake or the Ro60 ligand for uptake is absent.
Anti-SSB/La antibodies recognize a 48 kDa polypeptide (La48) that does not
share antigenic determinants with either 52 kDa Ro (Ro52) or Ro60 [72, 73]. Anti-
SSB/La antibodies facilitate maturation of RNA polymerase III transcripts, directly
bind a spectrum of RNAs, and associate at least transiently with Ro60 [74, 75].
In addition to the well-characterized Ro60 and La48 autoantigens, another target
of the autoimmune response in mothers whose children have CHB is Ro52 [76, 77].
Like several other TRIM proteins, Ro52 has E3 ligase activity and functions in the
process of ubiquitination [78].
There was recent excitement regarding the autoantibody response against the
p200 epitope, which spans Ro 52 amino acids 200–239, as a candidate biomarker
conferring an increased risk for the development of cardiac-NL in an offspring [79,
80]. While several groups have confirmed the high prevalence of the p200 response
in women giving birth to a child with cardiac-NL, there have been inconsistencies
regarding its utility in high-risk assessment relative to the pregnancy exposure [81].
It has not been determined whether antibodies to the p200 region of Ro52 confer
any added risk over that observed to full length Ro52.
Joanne Reed and colleagues addressed some of these limitations by assessing
umbilical blood from both affected and unaffected siblings, or simultaneously
evaluating maternal and neonatal sera for anti-Ro60, anti-Ro52, anti-p200, and
anti-La antibodies [82]. They noted that the presence of both anti-Ro52 and p200
antibodies was more common in mothers pregnant with a child with cardiac-NL
or who had a previous child with cardiac-NL compared to mothers who never had
a child with cardiac-NL. However, both anti-Ro52 and p200 autoantibodies were
of low specificity for cardiac-NL [82]. Based on the 2 % prevalence of cardiac-
NL in anti-Ro60 positive mothers [14–17], the presence of anti-Ro52 and anti-
p200 minimally increases the risk of cardiac-NL to 2.2 and 2.6 %, respectively
[82]. Overall the presence of p200 antibodies was common in each group, sug-
gesting that p200 is a dominant epitope in the anti-Ro52 response regardless of
fetal outcome [82].
In a murine study, passive transfer of anti-SSA/Ro and anti-SSB/La antibodies
from mothers of children with heart block resulted in bradycardia and PR interval
prolongation in 70 and 90 % of pups, respectively [83]. In contrast, active immuni-
zation with p200 peptide results in 20 % of rat pups with first degree block and none
with complete heart block [84]. These data suggest that anti-p200 antibodies are not
sufficient to account for all cases of cardiac-NL.
Environmental Contribution
A recent study in a Swedish population-based cohort of 190 pregnancies identified

maternal age and seasonal timing of pregnancy as being novel risk factors for CHB
in mothers with anti-SSA/Ro and/or anti-SSB/La antibodies [85]. Older maternal
age (29.5 vs. 26.6) was significantly associated with cardiac-NL. This study also
demonstrated that cardiac-NL was present in 58.5 % of births in which weeks 18–24
occurred during January–March, compared with 39 % of all births during the
remainder of the year. The study authors posited that a decrease in sun exposure and
vitamin D levels during the winter months in Sweden may explain this phenome-
non. The average vitamin D level in each month, calculated based on samples from
healthy Swedish woman, was inversely correlated with the number of heart block
pregnancies in autoantibody positive women [85]. The authors acknowledged that
other winter-related events such as viral infections might also contribute to the
above observation [85].
Genetic Contributions
The initial genetic approach to NL exploited the finding that a variant in the TNFα
promoter (rs1800629) associated with high cytokine production [86, 87] and was
considered a potential candidate for risk of disease. In a study of 40 children with
cardiac-NL, 17 with cutaneous NL, 31 unaffected siblings, and their 74 mothers,
the frequency of the risk allele at rs1800629 was greatest in the mothers and
affected siblings, although the frequency was significantly increased in all family
members compared to population controls [88]. Furthermore, a polymorphism at
codon 10 of the TGF-β gene that is associated with increased fibrosis was signifi-
cantly higher in CHB children compared to unaffected offspring and controls [88].
Cimaz et al. studied the TNFα and TGF-β polymorphisms in two families, one with
a cardiac-NL affected child among a set of twins, and another with an affected
child among a set of triplets. No differences regarding TNFα polymorphisms were
observed [89].
A focus on variation at the major histocompatibility complex (MHC) was a logi-
cal choice for genetic studies, since the extended HLA-A1;B8;DR3 haplotype block
contains risk alleles for inflammation and certain autoimmune diseases, and is
strongly associated with anti-SSA/Ro-SSB/La antibodies [90–93]. Allelic variants
within the MHC may influence not only the development of the requisite patho-
genic antibodies in the mother, but separately confer susceptibility to fetal injury in
response to these antibodies. For example, Strandberg et al. demonstrated in a
rodent model that maternal MHC regulated the generation of anti-Ro52 antibodies
and that fetal MHC determined susceptibility to the development of a prolonged PR
interval [94].
The role of fetal genetics in development of human disease was investigated in
a genome-wide association study of 116 Caucasian cardiac-NL children and 3,351
controls, using a 370,000 SNP platform [95]. The 17 most significant associations
were found in the HLA region at 6p21.3. The strongest association, found at
rs3099844, is near the class-III MHC region and 94 kb from the TNFα gene, which
contains the rs1800629 polymorphism previously associated with cardiac-NL [88].
Outside of the HLA, no individual locus previously implicated in autoimmune
diseases achieved genome-wide significance. However, a cluster of associated
SNPs at 21q22 were in proximity to the REG-ETS2/WDR4 transcription factor
that serves as a “brake” to both apoptosis and inflammation, represses the expres-
sion of interleukin-8, and plays a role in augmenting the expression of TGF-β
receptor type-2 [95] .
A missense variant at rs7775397 within the C6orf10 gene, which codes for an
uncharacterized protein and lies in the Class III–Class II boundary was also associ-
ated with cardiac-NL in the GWAS [95]. This SNP and the TNFα promoter
rs1800629 were evaluated in a multigenerational family study to determine the role
of maternal grandparents in the development of the autoimmune phenotype of NL
mothers [96]. Genotyping was performed in families consisting of 41 NL mothers,
38 grandmothers, and 29 grandfathers. There was an increased frequency of the two
candidate genetic variants in the NL-mothers compared to HAPMAP controls. The
clustering of each genetic variant in NL-mothers was related to a preferential skew-
ing of inheritance from grandparents, as shown by a transmission disequilibrium
test (TDT). These results imply that mothers accumulate genetic determinants spe-
cific to NL, which are not present in grandparents. The preferential transmission of
risk alleles represents a selection pattern which demonstrates the “perfect storm” of
events leading to cardiac-NL [96].
Clinical Management of Neonatal Lupus: Screening,

Diagnosis, Monitoring, and Treatment
Screening
Presently, anti-SSA/Ro and anti-SSB/La antibody screening is not part of routine

prenatal care. However, all women with SLE, SS, or UAS should be screened
for these antibodies prior to pregnancy or early in pregnancy, as should women
with a prior child having a neonatal rash or heart block, even if not previously
recognized as NL. If antibodies are identified in an asymptomatic woman, she
should be referred to a rheumatologist for evaluation. In a review of the RRNL,
50 % of mothers had progression of autoimmune symptoms. The probability of an
asymptomatic mother developing SLE or SS by 10 years is roughly 19 and 28 %,
respectively [26]. The NL manifestation of the child was not predictive of maternal
disease progression [26].
In a prospective study of 87 women with anti-SSA/Ro and/or anti-SSB/La anti-
bodies, Spence and colleagues found a 10 % prevalence of thyroid abnormalities
(nine either had hypothyroidism or had a history of hypothyroidism) [97]. The chil-
dren of these nine women with hypothyroidism had a significantly higher incidence
of CHB when compared to mothers without hypothyroidism (55 vs. 13 %) [97].
Within the RRNL, 11 of 69 mothers (16 %) with NL children had clinical thyroid
disease [98]. Thirty-three percent of these mothers had anti-thyroglobulin (anti-TG)
antibodies and 22 % had anti-thyroperoxidase (anti-TPO) antibodies [98]. Thus,
evaluation of thyroid disease may be warranted in mothers of NL-affected children
or possibly even individuals with anti-SSA/Ro and anti-SSB/La antibodies [98].
Diagnosis
The diagnosis of cardiac-NL is made when a fetus or newborn of a mother with

anti-SSA/Ro and/or anti-SSB/La antibodies develops heart block and/or evidence
of cardiomyopathy, EFE, or hydrops fetalis. The most vulnerable period for the
onset of cardiac-NL occurs between 18 and 24 weeks of gestation, correlating with
an increase in transplacental passage of IgG autoantibodies from the maternal to the
fetal circulation [99, 100].
Monitoring for CHB
There are no formal guidelines for the type and the frequency of testing to detect fetal
heart block, but performing weekly pulsed Doppler fetal echocardiography from 18
to 26 weeks of gestation and every other week until 32 weeks should be strongly
considered. Normal sinus rhythm can progress to complete heart block in 1 week
during this vulnerable period [17, 40]. New onset heart block is less likely during the
26th through the 30th week, and it rarely develops after 30 weeks of pregnancy [18].
Incident heart block is much less likely to occur after the neonatal period [18].
Children with conduction abnormalities in utero should have an EKG and echo-
cardiogram at birth. A prolonged PR interval in utero or at birth warrants the child
being followed by a cardiologist for at least the first year of life. Fetal echocardio-
gram is essential for diagnosis and following the course of disease. Although not
absolute, one can generally reassure the mother that if there is no evidence of cardiac
injury by 1 week of postnatal life, the chances of developing a cardiac problem are
quite slim [18]. Any conduction defect should also trigger immediate testing of the
mother for anti-SSA/Ro antibodies regardless of whether the mother has symptoms.
Antibody Testing
Commercial testing is usually done by ELISA but laboratories may differ in the
source of antigen. Certain laboratories identify only anti-Ro60, while others test anti-
Ro60 and anti-Ro52. Isolated anti-Ro52 is extremely uncommon [101] and thus a
positive anti-Ro60 finding is sufficient to place a pregnancy at risk. A negative anti-
Ro60 finding is likely sufficient to rule out NL, although certain investigators suggest
specific testing of anti-Ro52, which may or may not be available commercially. The
finding of an isolated anti-SSB/La antibody is extremely unusual [9]. The recently
adapted BioPlex 2200 assay for ANA screening will report antibodies for SSA/Ro60,
SSA/Ro52 and SSB/La antigens.
Maternal antibodies to other antigens may cause neonatal disease in some cases.
Anti-U1 RNP antibodies in the absence of anti-SSA/Ro or anti-SSB/La antibodies
were found in a few instances of NL [102]. These cases had the classic rash of NL,
but not CHB. There was one report of cardiac injury associated with anti-RNP in the
absence of anti-SSA/Ro-SSB/La, which presented as transient first degree block
that spontaneously reversed [103].
Prophylaxis and Treatment
Fluorinated steroids such as dexamethasone cross the placenta and may play a role
in mitigating inflammation in affected NL individuals. Beta-agonists, such as terbu-
taline, can increase fetal heart rates in those affected by CHB. Jaeggi and colleagues
[104] investigated the treatment impact of dexamethasone and beta-agonists on
heart rates less than 55 bpm in patients with fetal complete atrioventricular block.
The study concluded that both treatments improved 1 year survival and reduced
morbidity. However, Eliasson and colleagues [55] noted no significant effect on
mortality of fetuses based on treatment with fluorinated corticosteroids. In a large
U.S.-based study [9], fluorinated steroids were associated with an increased
mortality in fetuses dying in utero, which was attributed to their use in cases with
more severe disease. At present there is no consensus on treatment guidelines.
The use of prophylactic treatment of pregnancies at risk for cardiac-NL with
maternal steroids has been previously evaluated but this study combined fluorinated
steroids with non-fluorinated steroids, the latter of which are not active in the fetus
[105]. Accordingly, the interpretation of their benefit in reducing the risk of cardiac-
NL is limited [106]. Two other studies restricted to fluorinated steroids showed that
their prophylactic use did not associate with a reduction in recurrent cases of car-
diac-NL [25, 107].
Steroids can cause many adverse effects in both the mother and the fetus. In the
mother they may result in hypertension (and preeclampsia), gestational diabetes,
bone death and bone loss, and increased risk of infection. The fetus can be affected
by intra-uterine growth restriction, oligohydramnios (probably independent of
CHB), increased risk of pre-term labor, increased post natal activity of the hypo-
thalamus pituitary axis, and possible increased neurodevelopmental disabilities
[105]. The side effects to the mother and fetus outweigh the potential unproven
benefit of using steroids as prophylaxis against cardiac-NL.
Two prospective studies evaluated intravenous gamma globulin (IVIG) to pre-
vent CHB in mothers who were anti-SSA/Ro positive and had a previous child with
CHB [40, 41]. These patients were given IVIG at 400 mg/kg every 3 weeks from 12
to 24 weeks of gestation. The trials were terminated early, and it was concluded that
IVIG at the above dose was ineffective at reducing the recurrence rate of cardiac-NL
[40, 41]. It is unknown whether higher doses, such as 1 g/kg, would be efficacious.
A recent study evaluated outcomes of maternal autoantibody-mediated fetal car-
diomyopathy/EFE following IVIG and corticosteroid therapy [108]. Twenty patients
were treated with IVIG at approximately 1 g/kg administered between one and three
times. Their results indicated that 16/20 (80 %) patients were alive at a median
follow-up of 2.9 years and none required cardiac transplantation. This suggested a
possible benefit of IVIG in patients with fetal cardiomyopathy/EFE related to NL.
A potentially promising approach to prevention of cardiac-NL is the use of
hydroxychloroquine (HCQ). A case–control study explored the hypothesis that
HCQ might reduce the risk of disease [109]. This initial study was limited to chil-
dren born to mothers with SLE and anti-SSA/Ro antibodies, and comprised 50
cardiac-NL cases and 151 non-cardiac-NL controls. Seven (14 %) cardiac-NL chil-
dren were exposed to HCQ compared with 56 (37 %) controls (p = 0.002; OR 0.28).
A multivariable analysis yielded an OR associated with HCQ use of 0.46 (p = 0.10).
Although HCQ was no longer a statistically significant predictor of cardiac-NL, the
estimate of the OR remained in the direction of a protective effect, consistent with
the results from the overall unadjusted analysis [109]. A subsequent study was per-
formed to evaluate whether HCQ reduces the increased risk of recurrence of car-
diac-NL, independent of maternal health status [25]. Using an international cohort,
257 pregnancies subsequent to the birth of a child with cardiac-NL were evaluated
(40 exposed and 217 unexposed to HCQ). The recurrence rate of cardiac-NL in
fetuses exposed to HCQ was 7.5 % (3/40) compared to 21.2 % (46/217) in the unex-
posed group (p = 0.05). There were no deaths in the HCQ exposed group compared
to a case fatality rate of 22 % in the unexposed group. In both multivariable and

propensity score analyses, the latter an alternative approach to adjust for possible
confounding by indication, HCQ use remained significantly associated with a
decreased risk of cardiac-NL. These data suggest that HCQ may protect the fetus
from disease in those exposed to the pathogenic antibody as evidenced by a previ-
ous sibling with CHB [25].
Recommendations
In affected children with first degree heart block in utero, a watchful approach should
include a repeat echocardiogram within 24 h. If there is a persistent prolonged PR,
dexamethasone at 4 mg/day is a consideration to be discussed with the team of
obstetricians, pediatric cardiologists, and rheumatologists. The echocardiogram
should be repeated within a week, and if the PR interval returns to normal, the deci-
sion to discontinue dexamethasone and follow with weekly echocardiograms may
be reasonable. If there is persistence of first degree block after several weeks, a
watchful approach without dexamethasone would be reasonable. The reluctance in
making a firm recommendation is that the abnormal PR interval may in fact revert
spontaneously. Second degree block may progress to complete heart block, and
treatment with dexamethasone is likewise reasonable. Treatment with dexametha-
sone is also suggested for cases with cardiomyopathy, EFE, and hydrops fetalis. If
there is no change after 2 weeks of therapy, there may be no justification for continu-
ation. IVIG in addition to steroids can be considered in cases where disease extends
beyond the AV node.
Breastfeeding
A study examined breast milk in mothers with SSA/Ro and/or SSB/La antibodies
[110]. Based on ELISA and immunoblot, the antibody profiles of the breast milk
paralleled those observed in the serum. Two hundred and sixty-six children of moth-
ers with SSA/Ro and/or SSB/La antibodies in the RRNL were studied, of which 136
were breastfed. NL was present in 149 of the children (55 rash only, 72 CHB only,
22 rash and CHB). Fisher’s exact test revealed no significant differences between
the breastfed and non-breastfed NL-affected children compared to the unaffected
children. There was a trend for the children who were breastfed to have cutaneous
manifestations at a later age than those who had rashes and were formula fed; the
difference in mean age at presentation of the rash was not statistically significant.
The duration of the rash was not influenced by breastfeeding. In a second study of
32 children of mothers with anti-SSA/Ro, Ro and La specific IgM and IgA levels
were low or nondetectable in children raised with and without breastfeeding.
Cutaneous NL lesions developed independent of breastfeeding. The available data
do not suggest that breastfeeding has pathologic consequences [111]. The maternal
antibodies transferred to the fetus during gestation are present for several months
postpartum, and the additional antibodies from breast milk are inconsequential.
Mothers should be advised that autoantibodies are present in the breast milk but
reassured that, at least within the limits of published literature, breastfeeding is not
associated with postnatal NL [110, 111].
Long-term Follow-Up of Children with Varied Manifestations of NL
Little is known about the health outcomes of children with NL and their unaffected
siblings. Martin and colleagues [112] obtained information on the health of children
>8 years of age, 49 who had a manifestation of NL and 45 of their unaffected sib-
lings. ANA positivity was found in 2 of 33 children with NL and 2 of 22 unaffected
siblings. Six children with NL were noted to develop an autoimmune process
(2 with juvenile rheumatoid arthritis, 1 psoriasis and iritis, 1 diabetes and psoriasis,
1 congenital hypothyroidism and nephrotic syndrome) despite the absence of anti-
SSA/Ro or anti SSB/La antibodies in these individuals. All, however, had mothers
who likewise had an autoimmune disease (four mothers had Sjögren’s syndrome
(SS), one SLE/SS, one with undifferentiated autoimmune disease). Likewise,
Esscher and Scott reported a 15-year-old girl who developed SLE [113]. Jackson,
Fox, and Waterworth also reported three other patients with NL who developed SLE
(2 at age 13 and 1 at age 19) [114–116]. Lanham reported 2 other children with
CHB, one which developed SS at age 23 and in the other had arthritis with a positive
ANA and dsDNA at age 19 [117] .
In contrast, Brucato followed 13 children with CHB for a mean of 18 years and
none developed clinical symptoms or serologic abnormalities suggesting immune
disease [118]. Despite this encouraging report, the data suggest that NL-affected
children of mothers who have an autoimmune disease may require continued fol-
low-up prior to adolescence. During adolescence and young adulthood, individuals
with NL and their unaffected siblings do not appear to have an increased risk of
developing systemic rheumatic disease [118].
Acknowledgments The authors are grateful to Amanda Zink for assistance in preparing the
manuscript.
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Chapter 14
The Medical Management
of the Rheumatology Patient During
Pregnancy
Bonnie L. Bermas
Risk Assessment of Medications
Congenital anomalies occur in 3 % of normal pregnancies [1]. Therefore, risk

assessment of any particular agent during pregnancy needs to take into account this
background rate of teratogenicity. For many years, clinicians relied on the FDA risk
categories (A, B, C, D, and X) to assess drugs for safety for use in pregnancy. As
Briggs, author of the major textbook in this field, points out, these risk assessments
are limited because they are “confusing and simplistic” and incorrectly gave the
impression that risk increases from category to category [2]. The FDA is currently
considering new labeling for pregnancy risk. The approach this chapter will take is
to present the available data on medication safety in pregnancy and lactation and to
synthesize the information regarding drug safety.
Each pregnant woman has her own view about assuming risk during her preg-
nancy. For example, some women will avoid any substance that could have potential
risk during pregnancy (caffeine, over-the-counter medications, food-additives)
while other women will be willing to assume some risk and modify their ingestion
of these substances. Similarly, treating physicians have varying tolerance to risk.
While one clinician may be willing to prescribe TNF-α blockers during pregnancy,
others will be uncomfortable recommending these medications. Therefore, when
approaching management decisions of rheumatic diseases during pregnancy, it is
helpful for the treating clinician to be aware of both the patient’s and their own risk
tolerance, in addition to the available medical data. To this end, up-front discussions
prior to conception or early in pregnancy regarding what medications may be used
safely and comfortably in the case of a disease flare are ideal.
B.L. Bermas, M.D. (*)

75 Francis Street, Boston 02115, MA, USA
e-mail: bbermas@partners.org
274 B.L. Bermas
Table 14.1 Basic principles Know the treating clinician and patient’s risk tolerance
of disease management Discuss potential medications prior to pregnancy
during pregnancy
Disease should be in remission prior to conception
Use lowest doses of medications possible
Treat clinical manifestations, not lab test results
The ramifications of treatment choices during pregnancy differ with the various
rheumatic diseases. In women with inflammatory arthritis, while disease flares can
be painful and decrease functional status they rarely cause permanent joint damage.
In contrast, disease exacerbations of systemic rheumatic diseases such as systemic
lupus erythematosus or vasculitis can have detrimental effects on a woman’s health.
For example, a renal flare in an SLE patient during pregnancy not only can compro-
mise the pregnancy but also can impact a woman’s long-term renal function. Thus,
decisions regarding disease management during pregnancy in these two scenarios
may be decidedly different.
Many of these concerns can be avoided by making certain that disease is in remis-
sion when a pregnancy is planned, thereby minimizing medication use during preg-
nancy. This is particularly important in systemic disorders such as systemic lupus
erythematosus and vasculitis. It is crucial for those patients with preexisting renal
disease to be in remission for 6 months prior to conception to ensure a safe and suc-
cessful pregnancy [3]. Treating laboratory test results without corresponding clinical
manifestations is unnecessary. Likewise, empiric use of glucocorticoids or other med-
ication without evidence of disease activity is unwarranted. Keeping the abovemen-
tioned treatment tenets in mind contributes to better pregnancy outcomes (Table 14.1).
Medications
This section will discuss individual medications’ safety profiles. For a summary of
this information, please refer to Table 14.2.
Aspirin, Nonsteroidal Anti-Inflammatory Drugs,

COX-2 Inhibitors
Pain management for rheumatologic disorders includes aspirin, NSAIDs, and

COX-2 inhibitors. Animal data on the safety of these medications for use during
pregnancy rely on supra-pharmacologic dosing. Therefore, studies that focus on
congenital anomalies found in utero exposed rodents may not accurately represent
risk of in utero exposure in humans [4].
In humans, a large meta-analysis failed to show increased risk of fetal malformations
after aspirin use during pregnancy [5]. Furthermore, aspirin has been used for the man-
agement of antiphospholipid syndrome and pre-eclampsia with no untoward effect [6].
Table 14.2 Potential side effects and toxicities of rheumatic disease medications during pregnancy and lactation
Drug Maternal Fetal Breastfeeding
Minimal risk
Hydroxychloroquine None None Compatible
Sulfasalazine None None Compatible
IVIG Risk of hepatitis C Risk of hepatitis C, SGA, No data probably
autoantibodies compatible
Heparin Bleeding None Compatible
LMW Heparin Bleeding None Compatible
Some risk
Aspirin and NSAIDs Reduced fertility Possible increase in miscarriage Compatible
Premature closure of the ductus
arteriosus after 28 weeks
Glucocorticoids PROM, glucose SGA, adrenal hypoplasia, Compatible-
intolerance, 3.4-fold risk of cleft palate doses > 20 mg/day
hypertension Flourinated glucocorticoids discard breast milk
osteoporosis promote lung maturity for first 4 h
following dose
Azathioprine None SGA, prematurity, IUGR Contraindicated
6-Mercaptopurine None SGA, prematurity, IUGR Contraindicated
Cyclosporine A Renal insufficiency SGA, prematurity, IUGR Contraindicated
Tacrolimus None SGA, prematurity, IUGR, Little transmitted in
transient hyperkalemia breast milk
in neonates
Etanercept None VACTERL syndrome reported Currently
but unproven contraindicated but
Adalimumab None little absorbed by
Infliximab None infants GI tract
Certalizimab None Minimal placental transfer
Colchicine None Limited studies without issues
High risk
Methotrexate Embryotoxic skeletal and facial Contraindicated
malformations
Leflunomide Multiple congenital anomalies Contraindicated
Mycophenolate Shortened digits and hypoplastic Contraindicated
mofetil nails, auditory canal atresia,
cleft lip and palate
Cyclophosphamide Micrognathia, hypertelorism Contraindicated
ocular coloboma, SGA, limb
abnormalities, coronary
artery agenesis, tumors in
offspring
Warfarin Embryopathy, eye defects, Compatible
deafness, congenital heart
disease, hypoplasia of
extremities, developmental
retardation
Unknown risk
Rituximab Contraindicated
Abatacept Contraindicated
Anakinra Contraindicated
Tocilizumab Contraindicated
Belimumab Contraindicated
SGA small for gestational age, PROM premature rupture of the membranes, IUGR intrauterine growth
restriction
276 B.L. Bermas
NSAIDs may be used during the first two trimesters with no increased risk of
fetal malformations [7]. After the 30th week of gestation, NSAIDs can contribute to
the premature closure of the ductus arteriosus and increase the risk of pulmonary
hypertension [8]; therefore, NSAIDs need to be discontinued prior to the 30th week
of gestation to circumvent these issues.
Recently, there has been concern that use of NSAIDs early in pregnancy can
increase the risk of spontaneous abortions prior to 20 weeks of gestation. One nested
case–control study of 4,705 spontaneous miscarriages demonstrated an odds ratio
of 2.43 for spontaneous miscarriages in those exposed to NSAIDs versus those who
were not exposed [9]. In contrast, in another study of 2,780 pregnancies there was
no increased NSAID exposure in the 367 women who experienced a spontaneous
miscarriage [10]. Given the conflicting data, NSAIDs ought to be used judiciously
during the first trimester of pregnancy and discontinued by week 28.
There is limited information on the safety of COX-2 inhibitors during pregnancy.
Accordingly, use of these medications during pregnancy should be limited or
avoided. In animal studies, COX-2 inhibitors can impede both ovulation and implan-
tation [11, 12]. Thus, both NSAIDs (because of their COX-2 inhibitory effect) and
COX-2 inhibitors ought to be discontinued during a conception cycle in order to
circumvent ovulation and implantation issues.
The American Academy of Pediatrics considers aspirin and most NSAIDs com-
patible with nursing [13].
Glucocorticoids
Glucocorticoids are frequently used to control the symptoms of many rheumato-

logic disorders. The non-flourinated preparations, prednisone and methylpredniso-
lone, that are generally used in rheumatology are not metabolized well by the
placenta and therefore reach the fetus in low concentrations [14]. In contrast, the
flourinated forms such as betamethasone and dexamethasone reach the fetus at
higher concentrations and are thus used later in pregnancy to hasten fetal lung matu-
rity when an early delivery is anticipated [15]. Animal studies of in utero exposure
to glucocorticoids during pregnancy have demonstrated increased aggressive behav-
ior in offspring [16]. There are also reports of congenital anomalies, in particular,
cleft palate formation [17]. The data in humans are more equivocal. One large case
series of over 800 asthmatic patients who were maintained on prednisone (average
dose 8 mg) during pregnancy showed no increased rate of congenital anomalies
[18]. In contrast, a meta-analysis of studies of prednisone exposure (of any dosage)
during pregnancy demonstrated a 3.4 fold increased rate of cleft palate formation in
offspring exposed to prednisone in utero [19]. In a more recent review of 1,449
pregnancies in which mothers used either inhaled or oral corticosteroids 1 month
prior to conception through the first trimester, only one cleft palate occurred, a rate
lower than the control group [20]. Based on the available data, one can conclude
that there may be a small increased risk of cleft palate formation in fetuses exposed
to glucocorticoid therapy during the first trimester. After 12–14 weeks of gestation,
14 The Medical Management of the Rheumatology Patient During Pregnancy 277
the palate has formed and this risk ends. Glucocorticoid use during the second and
third trimesters brings risks to the mother as well, such as increased incidence of
pregnancy-induced hypertension, gestational diabetes, osteoporosis, and adrenal
suppression. Despite these issues, glucocorticoids offer a viable option for disease
management during pregnancy. For those patients who have been on steroids
throughout pregnancy, stress dose steroids are indicated for labor and delivery or
cesarean section.
Very little prednisone is transferred to breast milk. For those women taking under
the equivalent of 20 mg of prednisone daily nursing can proceed as usual. In those
women taking greater than 20 mg of prednisone, women should wait 4 h after their
dose of prednisone to nurse [21].
Antimalarials
Antimalarials are used in the management of systemic lupus erythematosus and

mild inflammatory arthritis. In the USA, hydroxychloroquine is the preferred form.
Animal studies have demonstrated retinal toxicity in rodents exposed to antimalari-
als in utero [22]. Initially, hydroxychloroquine and chloroquine were considered
contraindicated during pregnancy based on one case series published in 1964 detail-
ing multiple pregnancies in the same woman who took hydroxychloroquine during
pregnancy [23]. All of the offspring exposed to hydroxychloroquine developed ocu-
lar or hearing issues. However, larger case series of offspring exposed to hydroxy-
chloroquine during pregnancy have failed to demonstrate a higher than background
rate of congenital anomalies [24]. Most recently, a comprehensive review evaluated
the exposure of 588 offspring born to mothers treated with either chloroquine or
hydroxychloroquine. There were no cases of fetal ocular toxicity in any of these
offspring [25]. This suggests that the risk of in utero exposure to antimalarials is
negligible. Furthermore, a survey of North American rheumatologists revealed that
most rheumatologists will maintain their patients on antimalarials throughout preg-
nancy [26]. Importantly, there is strong evidence that maintaining women with SLE
on their antimalarials during pregnancy improves both patient and pregnancy out-
comes [27]. Furthermore, recent evidence suggests that this medication may have a
role in secondary prevention of congenital complete heart block (CCHB) in anti-Ro,
anti-La positive women who have previously given birth to a child with CCHB [28].
Hydroxychloroquine may be continued during breastfeeding.
Sulfasalazine
Sulfasalazine is used for the management of inflammatory arthritis and inflamma-

tory bowel disease. Sulfasalazine and its metabolite sulfapyridine do cross the pla-
centa [29]. While birth defects have been reported in case reports of offspring whose
278 B.L. Bermas
mothers took sulfasalazine during pregnancy [30], large studies have failed to
confirm this finding. Importantly, since sulfasalazine can impede the absorption of
folic acid in the gastrointestinal tract, pregnant women should take additional folic
acid while on this medication [31]. Sulfasalazine is permitted in women who are
breastfeeding although rarely infants may develop diarrhea.
Immunosuppressive Agents
Immunosuppressive agents are often critical in the management of SLE, vasculitis,

and in some cases inflammatory arthritis. In rheumatology, azathioprine and
6-mercaptopurine, mycophenolate mofetil, cyclosporine, and tacrolimus are the
most commonly used medications in this class. Most of the information on the
safety of these medications during pregnancy can be gleaned from the organ trans-
plant literature. International registries have data on thousands of offspring born to
mothers with organ transplants who are usually maintained on immunosuppressive
medications for the duration of pregnancy.
Azathioprine and its metabolite 6-mercaptopurine are used to manage inflamma-
tory bowel disease and transplant rejection. In rheumatology, azathioprine is prefer-
entially used and is administered to those with lupus nephritis, skin disorders, and
vasculitis. Animal studies have demonstrated teratogenicity with azathioprine [32].
However, the human placenta lacks the enzyme that metabolizes azathioprine to its
active metabolite 6-mercaptopurine; therefore, very little of the active form of this
medication enters fetal circulation [33]. The gastroenterology and transplant litera-
ture provides reassuring data that in utero exposure to azathioprine does not increase
the risk of congenital anomalies [34, 35]. The data on the safety of 6-mercaptopurine
stems from the gastroenterology literature and while less robust than the data on
azathioprine, this literature likewise suggests low risk to fetuses exposed in utero
[36]. Although the food and drug administration categorizes these as category D for
safety in use during pregnancy, the existing evidence suggests that these medica-
tions, in particular azathioprine, may be used when immunosuppression is required
during pregnancy such as a flare or new onset lupus nephritis. This viewpoint is
endorsed by the American Gastroenterological Association Institute [37].
Breastfeeding is not generally recommended for those women taking these medica-
tions, although in some circumstances, the benefit of continuing these medications
during lactation may outweigh the potential risks. Cyclosporine A has been used for
management of some of the renal manifestations of systemic lupus erythematosus
and less frequently in inflammatory arthritis. While animal studies demonstrate sug-
gest that this agent is teratogenic, studies in humans are more encouraging [38, 39].
As with azathioprine, very little cyclosporine A is transported across the placenta
[40]. Data gleaned from transplantation registries have not shown an increased risk
of congenital anomalies in cyclosporine exposed offspring [41]. However, maternal
increases in creatinine in pregnant women taking cyclosporine and fetal growth
restriction have been reported [41]. While not completely benign, cyclosporine can
be used during pregnancy when immunosuppression is required.
The American Academy of Pediatrics does not consider cyclosporine compatible

with nursing [13]. Nonetheless, other studies suggest that very little cyclosporine is
detected in the blood of nursing infants whose mothers are taking cyclosporine [42].
Mycophenolate mofetil has revolutionized the way we treat lupus nephritis.
While formerly, therapy was limited to high dose steroids and cyclophosphamide,
studies in the past decade have proven the efficacy of this medication in both the
induction and maintenance phases of lupus nephritis therapy [43]. Initially, limited
data suggested that these medications could potentially be used during pregnancy;
however, recent case series have suggested a fairly high rate of congenital anomalies
[44]. What is particularly concerning is that a particular pattern of malformations
including cleft lip and palate, micrognathia, microtia, and external auditory canals
were observed [45]. The FDA now considers this medication as category D for
safety in pregnancy and has mandated a patient educational program for women of
child-bearing age who begin this drug. Mycophenolate mofetil is contraindicated in
women who are breastfeeding.
Tacrolimus is an immunosuppressive agent that has predominately been used to
prevent solid organ transplant rejection. More recently, however, this medication
has been used for the therapy of lupus nephritis [46]. Several transplant series have
suggested that tacrolimus is tolerated during pregnancy with few side effects and no
increased rate of congenital anomalies [47, 48]. Thus, like other agents also used for
the immunosuppression of organ transplant recipients, tacrolimus appears to be
compatible with pregnancy. Little of this agent gets transferred to breast milk
suggesting that it may be compatible with nursing [49].
Methotrexate
Since the early 1980s when methotrexate was shown to be effective in the treatment
of rheumatoid arthritis, this medication has become the mainstay of therapy for
rheumatoid arthritis and other inflammatory arthritides [50]. It can be used in other
rheumatologic disorders as well. Methotrexate is profoundly abortogenic and tera-
togenic, and because of these effects methotrexate is now standard therapy for the
medical termination of ectopic pregnancies [51]. In pregnant rodents, this agent
causes skeletal abnormalities in the offspring and increased fetal resorption rate [52,
53]. In humans, severe cranial-facial anomalies, absent limbs, and mental retarda-
tion have been reported [54]. The peak risk period for exposure is between 6 and 8
weeks of gestation at doses of methotrexate greater than 10 mg a week [55]. Lloyd
and colleagues suggest that there is no safe window, with a 10/42 chance of abnor-
mality in a fetus exposed to methotrexate during the first trimester: they suggest
discontinuing the medication for 6 months prior to conception [56]. Donnenfeld and
associates suggest that the medication should be discontinued 12 weeks before con-
ception because of the high spontaneous abortion rate [57]. Given that it may not be
feasible to discontinue this medication far in advance of pregnancy, current recom-
mendations are to discontinue methotrexate in men 3 months prior to conception
280 B.L. Bermas
and three menstrual cycles in women. Given the extreme teratogenicity of this med-
ication, women taking methotrexate need to be counseled about reliable contracep-
tive methods. Methotrexate is not compatible with nursing.
Leflunomide
Leflunomide is used to manage inflammatory arthritis and skin manifestations of

SLE. Like methotrexate, this medication is profoundly teratogenic in animals [58].
There are few case reports of congenital anomalies of infants exposed to this medi-
cation in utero [59]. Recently there was a report on 45 pregnancies in which inad-
vertent exposure to leflunomide occurred either just prior to conception or during
gestation [60]. The authors reported 2 of 16 offspring exposed to leflunomide in
utero had major malformations and three more had minor anomalies. While the
authors conclude that leflunomide is not a major teratogen, the numbers presented
in the study suggest a higher than background rate of congenital anomaly. Thus,
patients who are taking leflunomide should be carefully counseled regarding appro-
priate contraception. While this medication has a half-life of 15 days, its major
metabolite, teriflunomide, stays in the circulation for up to 2 years. Thus, lefluno-
mide needs to either be discontinued 2 years prior to conception, or cholestyramine
washout (8 g three times a day for 11 days) must be completed. Leflunomide is not
considered compatible with nursing.
Cyclophosphamide
Cyclophosphamide is generally reserved for use for SLE nephritis and vasculitic
disorders. This medication is profoundly teratogenic in both animals and humans
[61, 62]. In general, this medication should be avoided during pregnancy. There
have been case reports of cyclophosphamide being used in the third trimester of
pregnancy with no untoward effects; thus in life-threatening circumstances later in
pregnancy, this medication can be considered [63, 64]. There is a significant risk of
premature ovarian failure when this medication is used in premenopausal women.
Age greater than 30, cumulative dose of greater than 10 g and duration of therapy
are all risk factors [65]. This medication is not compatible with nursing.
Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) has been used for refractory thrombocytopenia

and dermatomyositis. While data on the use of this medication during pregnancy are
limited, there have been several case reports suggesting safety of IVIG during
pregnancy [66]. Moreover, this medication has also been used to manage refractory
obstetric complications of the antiphospholipid antibody syndrome without inducing
congenital malformations [67]. There is a small risk of hepatitis C exposure with
IVIG use. This medication may be used during lactation.
Biologics
In the past two decades, biologics have changed the management and outcomes of
rheumatic disorders. In particular, the TNF-α antagonists have revolutionized the
treatment of inflammatory arthritis. The FDA has rated these medications as cate-
gory B for safety in use during pregnancy. Nonetheless, in 2008, there were two
potential cases of VACTERL (Vertebral anomalies, Anal atresia, Cardiac defects,
Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb dyspla-
sia) syndrome reported [68]. Given that the true denominator of actual exposures
was unknown and likely underestimated, subsequent editorials and opinion articles
concluded that the risk of congenital anomalies was negligible [69]. A later analysis
from the European Surveillance of Congenital Anomalies did not reveal an increased
risk of congenital anomaly after in utero TNF-α exposure [70]. Preliminary data
suggests that the PEGylated form of these agents may not cross the placenta in sig-
nificant concentration and does not lead to an increased incidence of anomalies
[71]. There are no data on safety of these agents during breastfeeding; some physi-
cians permit use while nursing.
Rituximab
Current package insert information on rituximab is that this medication should be

discontinued 1 year prior to conception. Nonetheless, several case reports have
shown that this medication may be used closer to pregnancy with relative impunity
[72, 73]. Given that IgG antibodies do not cross the placenta until the 12th week of
pregnancy [74], little if any of this medication should reach the fetus prior to the
second trimester of pregnancy. Later in pregnancy, this medication could impact the
fetus’s immune system as there are reports of the B-cell depletion lasting well until
the first year of neonatal life [75]. There are no data on safety of breastfeeding while
receiving rituximab.
Other Biologics
The safety during pregnancy and lactation of the other commonly used biologics in
rheumatology including anakinra, abatacept, tocilizumab, and belimumab is
unknown. Therefore, we recommend avoiding these medications during pregnancy
and discontinuing these medications for at least several months prior to conception.
282 B.L. Bermas
Anti-coagulants
In women with the antiphospholipid syndrome and other clotting disorders, anti-
coagulation during pregnancy may be necessary. Warfarin, a potent anti-coagulant,
is extremely teratogenic. First trimester exposure, in particular during the 6–9th
weeks of gestation can lead to a pattern of anomalies including nasal hypoplasia,
eye defects, hypoplasia of the extremities, deafness, and congenital heart disease
[76]. While some clinicians may allow patients to stay on this medication until a
positive pregnancy test, others will advocate transitioning patients to either unfrac-
tionated or fractionated heparin once conception is attempted. These latter two
classes of medication are compatible with pregnancy and nursing [77, 78].
Adjustments to delivery timing and type may need to be adjusted in women taking
these medications during pregnancy.
Colchicine
Colchicine is used in the management of gout and pseudogout and for familial
Mediterranean fever (FMF). While crystal-induced arthropathies are rare in repro-
ductive age women, FMF can and does occur in women of child-bearing age. One
case series of 238 colchicine-exposed pregnancies did not show an increased rate of
major congenital anomalies when compared with controls [79]. In another study of
179 pregnancies in which women with FMF were taking colchicine, not only was
there no congenital malformation but also there was a trend towards better outcome
for those women who were treated with colchicine [80]. Thus, in women who need
to be on colchicine for disease management of FMF, one can consider maintaining
patients on this medication during pregnancy. Data on breastfeeding while taking
colchicine are limited.
Inadvertent Drug Exposure During Pregnancy
Inadvertent exposure to potentially teratogenic medications during pregnancy poses

a difficult clinical challenge to the practicing rheumatologist. Patients and clinicians
views on family planning are firmly grounded in religious, ethical, and cultural
beliefs. Ethics literature suggests that the clinician’s role is to be non-directive, pro-
viding information and support but not decisions [81]. If a drug exposure to a known
teratogen occurs early in pregnancy, the clinician’s role is to provide pregnant
women with available information regarding other cases of exposure and potential
risk. Referral to a geneticist with expertise in this area may be helpful. Later in
pregnancy, a high sensitivity ultrasound to screen for potential anomalies can aug-
ment this information so that patients can make an informed decision about how
they would like to proceed with the pregnancy.
Conclusion
Treating the pregnant rheumatology patient can be challenging but extremely

rewarding. While not all medications can be used safely during pregnancy, most
disease flares can be adequately managed during pregnancy. If possible, pregnan-
cies should be planned so that the underlying rheumatologic disease is under good
control and medications can be appropriately adjusted for safety. Ideally, pre-
pregnancy evaluation with both the rheumatologist and in cases of complicated dis-
ease, a maternal–fetal obstetrical specialist, should be done. This pre-conception
counseling is an ideal time to discuss and formulate a plan in case of flares.
In general, NSAIDs can be used judiciously from after implantation (first missed
menstrual cycle) up until the third trimester. Glucocorticoids may be used through-
out pregnancy with the caveat that patients ought to be counseled about the small
increased risk of cleft palate formation in fetuses exposed during the first trimester.
Hydroxychloroquine ought to be continued throughout pregnancy. The immuno-
suppressive medications azathioprine, cyclosporine, and tacrolimus can be used for
more severe disease, while mycophenolate mofetil cannot. Methotrexate, lefluno-
mide, and cyclophosphamide are contraindicated for use during pregnancy.
Intravenous immunoglobulin can be used throughout pregnancy. Many rheumatolo-
gists will discontinue TNF-α blockers either prior to pregnancy or at the time of the
first missed menstrual cycle. Based on existing literature, those patients with severe
inflammatory arthritis can probably be continued on TNF-α blockers during preg-
nancy. The other biologics should be discontinued for several months prior to con-
ception (Table 14.2).
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Chapter 15
Long-Term Outcome of Children
of Rheumatic Disease Patients
Cecilia Nalli, Alessandro Iodice, Rossella Reggia, Laura Andreoli,

Andrea Lojacono, Mario Motta, Antonella Meini, Elisa Fazzi,
and Angela Tincani
Introduction
Rheumatic diseases often affect women during their childbearing years. For a long
time, pregnancy was not recommended in women affected by most of the rheumatic
diseases, because it was reported that the disease could become more aggressive
during pregnancy, putting both the mother and the fetus at high risk. However, in the
last 20 years the diagnosis and management of these diseases has greatly improved
and the approach to pregnancy along with it: now, affected women are no longer
C. Nalli, M.D. • R. Reggia, M.D. • L. Andreoli, M.D. • A. Tincani, M.D. (*)

Rheumatology and Clinical Immunology, Department of Clinical and Experimental Sciences,
Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia 25133, Italy
e-mail: cecilianalli@libero.it; rossyr85@alice.it; box.lauraandreoli@libero.it;
tincani@bresciareumatologia.it
A. Iodice, M.D. • E. Fazzi, M.D.
Unit of Child and Adolescent Neuropsychiatry, Department of Clinical
and Experimental Sciences, Spedali Civili and University of Brescia,
Piazzale Spedali Civili 1, Brescia, 25133, Italy
e-mail: alle.iodice@gmail.com; elisa.fazzi@gmail.com
A. Lojacono, M.D.
Obstetrics and Gynecology, Department of Clinical and Experimental Sciences,
Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
e-mail: alojacono2005@libero.it
M. Motta, M.D.
Neonatology and NICU, Spedali Civili and University of Brescia,
Piazzale Spedali Civili 1, Brescia, 25133, Italy
e-mail: Ivmott@tin.it
A. Meini, M.D.
Unit of Pediatric Immunology and Rheumatology, Pediatric Clinic,
Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
e-mail: antonella.meini@yahoo.it
290 C. Nalli et al.
discouraged from bearing children, as long as the disease can be sufficiently

controlled during pregnancy.
Therefore, it is more important than ever that clinicians caring for women with
rheumatic disorders introduce and discuss pregnancy and related issues with their
patients. In order to both increase maternal compliance with a treatment plan and
manage difficult cases, a multidisciplinary team (rheumatologists/internists, obste-
tricians, and neonatologists) should ideally care for patients throughout gestation.
Recent data strongly support the validity of such a multidisciplinary team to ame-
liorate pregnancy outcome in women with rheumatic diseases [1].
Some important issues must be initially addressed with a patient suffering from
a rheumatic disease who wishes to become pregnant:
• Impact of pregnancy on disease activity
• Impact of disease on gestational outcome
• Drug compatibility with pregnancy
• Presence of factors such as autoantibodies and disease severity that may interfere
with pregnancy outcome.
Moreover, women with rheumatic diseases may be concerned that medication
and/or disease activity could somehow influence the physical and mental develop-
ment of the child. With this in mind, the short- and long-term outcome of the off-
spring of the pregnancies in women with rheumatic disorders becomes one of the
most important issues in this field.
Pregnancy and Rheumatic Diseases
In order to fully understand the potential long-term impact of a mother’s rheumatic

disease on her offspring, it is important to first understand the potential interactions
between pregnancy and autoimmune disease, and the resulting immediate fetal and
neonatal issues. These topics are discussed in detail in earlier chapters, a brief sum-
mary follows.
Pregnancy affects the course of various rheumatic diseases differently. As an
example, systemic sclerosis (SSc) tends to remain stable during gestation [1] as
does ankylosing spondylitis (AS). In the latter case, however, it is not so simple to
evaluate disease activity, since pregnancy itself physiologically alters inflammatory
indices and often causes low back pain. Well-defined data are available for rheuma-
toid arthritis (RA), a disease that shows a spontaneous amelioration during preg-
nancy in nearly 80 % of the cases [2, 3]. Still unclear is the course of systemic
vasculitides during pregnancy: profound transformation of the immune and endo-
crine systems favoring Th-2 cytokine polarization [4–6] may explain the improve-
ment of primarily Th1-mediated vasculitides (mainly Takayasu arteritis and Behçet
disease) and the worsening of Th2-driven ones, such as granulomatosis with poly-
angiitis (Wegener’s granulomatosis) or eosinophilic granulomatosis with polyangi-
itis (Churg–Strauss syndrome).
15 Long-Term Outcome of Children of Rheumatic Disease Patients 291
The literature is controversial regarding change in systemic lupus erythematosus

(SLE) activity during pregnancy: while some authors report an increased risk for
lupus flare, others reach the opposite conclusion, finding flare rates to be unchanged
as compared to nonpregnant SLE patients [7]. It has been estimated that risk of SLE
flare during pregnancy ranges from 7 to 33 %.
Influence of Maternal Disease on Children’s Outcome
Over the last 20 years, much effort has been directed towards improvement of preg-
nancy management, permitting women with rheumatic diseases to have safe and
successful pregnancies. More recently, attention has shifted to whether rheumatic
diseases and/or medication used for the management of these disorders impacts the
subsequent development of children exposed to these factors in utero.
The frequency of preterm birth is high even in the general obstetric population,
at rates of 12–13 % in the USA and 5–9 % in Europe; in addition, incidence of pre-
term birth is increasing [8]. One of the most frequent problems related to maternal
SLE and certain other rheumatic diseases is preterm birth (birth before 37 weeks of
gestation): this affects 23–28 % of SLE pregnancies [9]. Risk factors for preterm
delivery include clinical and serological activity of the disease, high prednisone
dose, hypertension [5], and thyroid dysfunction [10]. Preterm birth is mainly due to
the preterm premature rupture of membranes (PPROM), but, in a number of cases,
it is medically induced to protect the health of the mother and/or of the baby (due to
onset of fetal distress or pre-eclampsia) [11]. Babies born before 28 weeks of gesta-
tion merit particular attention, because they are at highest risk for neonatal death,
medical complications, and neurodevelopmental problems, most importantly cogni-
tive impairment [12]. Low birth weight newborns (<2,500 g) and SGA (small for
gestational age) neonates are also reported in SLE pregnancies, ranging from 6 to
35 % [11, 13], and likely to be related to placental dysfunction.
Data from the study of preterm delivery in normal women can (to some extent)
be extrapolated to SLE and other rheumatic disease patients. Importantly, prematu-
rity is a critical prognostic factor for perinatal complications such as hypoxic-
ischemic brain injury or intracranial hemorrhage that can lead to long-term
neurodevelopmental disabilities, especially in infants born with a very low birth
weight (VLBL) [14]. Cognitive deficits without major motor deficits are by far the
dominant neurodevelopmental sequelae in infants with VLBW. Moreover, an
increased prevalence of cognitive impairment, poorer educational achievement, and
specific language difficulties has been repeatedly observed among school-age chil-
dren after extremely preterm birth, as compared with those born at full term [15, 16].
The rate of survival in very premature infants has gradually increased because of
progress in therapy and quality of care, but this achievement has raised issues about
the increasing rates of neurological disabilities and cognitive dysfunction [17]. In
this group, various brain lesions can occur, including periventricular leukomalacia
292 C. Nalli et al.
(PVL), a distinctive form of cerebral white matter injury that accounts for most of
the subsequent motor abnormalities, cognitive defects, and visual impairment, and
is caused by hypoxic-ischemic events.
Germinal matrix-intraventricular hemorrhage is the most common variety of
neonatal intracranial hemorrhage, and its incidence is directly related to the degree
of prematurity. Long-term outcome, including incidence of major neurological
sequelae, depends primarily on the degree of associated parenchymal injury [14].
Recently, Volpe coined the term “encephalopathy of prematurity” in order to
describe a complex amalgam of primary destructive disease (PVL accompanied by
neuronal/axonal disease) and secondary maturational and trophic disturbances [18].
Encephalopathy of prematurity is clinically associated with a high occurrence of
cognitive, behavioral, attentional, or socialization deficits in this population even
without any major motor deficits (e.g. cerebral palsy) [19].
The spectrum of visual problems in preterm infants is extremely broad; it may
include both peripheral problems (strabismus, refraction disorders, and retinopa-
thies) and problems of central origin. Cerebral visual impairment is among the most
common sequelae of a preterm birth and usually arises from hypoxic-ischemic
injury to watershed areas of the brain [20]. Cerebral visual impairment includes all
visual dysfunctions “caused by damage to, or malfunctioning of, the retrogeniculate
visual pathways (optic radiation, occipital lobe and associative visual areas) in the
absence of visual system abnormalities” or of any major ocular disease [21, 22].
Recently Fazzi et al. suggest a widespread involvement of higher visual processing
systems, involving both the ventral and dorsal streams, in preterm children with
PVL. These children displayed an uneven neuropsychological profile, with deficits
in visual object recognition, visual imagery, visual–spatial skills, and visual mem-
ory, and sparing of visual associative abilities, non-verbal intelligence, and face and
letter recognition [23, 24].
In women with rheumatic diseases, in particular SLE, fetal complications and
prematurity may be related to the presence of aPL, which are autoantibodies that are
hallmarks of and are known to be associated with thrombosis and pregnancy loss
[25]. Rare cases of thrombosis related to maternal transplacental passage of aPL
have been described in neonates born to mothers with APS: between 1987 and 2002
only 13 neonatal thromboses possibly related to acquired aPL were reported [25]. In
2003, a large prospective European study was initiated with the aim to assess the
outcome of the offspring of mothers with APS. During a 5-year follow-up, it was
shown that one-third of infants passively acquire maternal antibodies, which are
subsequently cleared during the first 6 months of life and usually become undetect-
able by the first year of life [26]; however, no cases of neonatal thrombosis were
reported in 134 children born to mothers with aPL during pregnancy [27, 28].
It is relatively common to find healthy children who are positive for aPL, mainly
anti-beta 2 glycoprotein I (b2GPI). Our group studied 57 healthy children aged 1-year
and positive for IgG anti-b2GPI who were born to 56 mothers with systemic autoim-
mune disease attending our multidisciplinary pregnancy clinic [14 SLE, 11 undif-
ferentiated connective tissue disease, 10 primary Sjögren’s syndrome, 7 primary
APS, 4 mixed connective tissue disease, 2 rheumatoid arthritis, 5 asymptomatic aPL
carriers, 3 anti-nuclear antibody (ANA) carriers]. Only 25 % of these mothers were

found to be aPL positive during pregnancy. All children were free of thrombotic
events. The detection of anti-b2GPI in early childhood suggests a de novo production
of antibodies, related not to the maternal background, but rather to environmental
factors (vaccines, infections or beta 2-glycoprotein I in food) acting on the children’s
immune systems. Beta 2-glycoprotein I, the main target of aPL, is a protein com-
posed of five different domains [29]. Recent literature suggests antibodies directed
against different domains of b2GPI may have different biological effects. aPL found
in healthy children carry preferential specificity for domain 4/5 of b2GPI, while
patients with APS mainly have antibodies directed to domain 1. The two types of
antibodies likely carry different pathogenic potential: antibodies versus domain 1
seem to cluster in patients with systemic autoimmune conditions, including APS, and
to be more specific for thrombotic events, while antibodies specific for domain 4/5
have been identified in subjects with no history of thrombosis or systemic autoim-
mune disease [29].
To test the hypothesis that the presence of anti-b2GPI IgG in these children was
not related to maternal autoimmune background we evaluated anti-b2GPI in 100 chil-
dren (from 3 months to 7 years of life) who were admitted to the hospital for elective
surgical procedures and whose families were free of autoimmune diseases. Antibody
levels showed different titers to be associated with different age ranges. In particular,
pre-school children displayed IgG anti-b2GPI in 48 % of cases; yet, no cases of
thrombosis were found. These data support the hypothesis that anti-b2GPI in children
are the result of environmental triggers such as viral infections and vaccines.
Neonatal lupus is a passively acquired autoimmune disease mediated by mater-
nal anti-Ro/SSA and anti-La/SSB antibodies, which can cross the placenta and
harm the fetus. The less severe form of neonatal lupus includes typical cutaneous
manifestations, usually transient, such as annular or elliptical rash of the face, scalp,
trunk, or extremities. Rash usually appears 6 weeks after delivery and disappears
without any sequelae by the age of 6–8 months. Anti Ro/SSA antibodies can also
damage fetal cardiac conduction tissue resulting in conduction abnormalities,
termed first-, second-, or third-degree (complete) congenital heart block (CHB).
Due to important bradycardia, children born with complete CHB usually require
early implantation of a pacemaker. Studies evaluating the long-term outcome of
these children note no negative effects on neurodevelopment and suggest a normal
quality of life.
Few data are available regarding fetal morbidity in RA pregnancies: outcomes in
women with well-controlled RA are comparable to those in the general population.
However, women affected by RA (or other inflammatory arthritis) who experience
a higher level of disease activity during the third trimester and/or are taking a mod-
erate to high amount of glucocorticoids are at risk for SGA babies and for preterm
delivery [30, 31], with all the associated potential for subsequent neurodevelopmen-
tal sequeli. A recent study found a high rate of preterm birth in these pregnancies,
but no association between this complication and disease activity at conception or
during pregnancy was noticed [32]. According to the few available case reports,
ankylosing spondylitis has no significant effects on pregnancy outcome [33, 34].
294 C. Nalli et al.
Table 15.1 Potential effects of transplacental passage of maternal antibodies during pregnancy
(modified from Parke) [41]
Maternal antibody Fetal outcome
Anti-Ro/SSA, anti-La/SSB Neonatal lupus: transient cutaneous rash, congenital heart block
(various degrees), asymptomatic elevation of liver enzymes,
cytopenia
Antiphospholipid antibodies Fetal wastage, placental insufficiency, prematurity and preterm
birth, fetal/neonatal clinical thrombotic events (rare)
Thyroid antibodies Hypothyroidism, hyperthyroidism
Systemic vasculitides are uncommon diseases and few cases of pregnancies are
reported in literature. The most frequent fetal complications due to maternal disease
are low weight at birth and IUGR, and, less often, preterm delivery and fetal loss
[35]. The incidence of fetal complications seems to be higher in mothers with more
severe disease and with a higher number of damaged vessels. In children of mothers
with ANCA-associated vasculitides, two cases of microscopic polyangiitis-like
syndrome were described in the newborns, potentially due to the passage of mater-
nal ANCA through the placenta. In one case, the syndrome was characterized by
purpuric rash that spontaneously disappeared within 3 days; the other case devel-
oped pulmonary hemorrhage and kidney involvement successfully treated with
high-dose steroid therapy and exchange transfusion. It has been suggested that
maternal treatment with immunosuppressive therapy may prevent the onset of this
syndrome in the child [36–38]. Several cases of transient neonatal Behçet’s disease
have reported, probably due to diffusion of lesional lymphocytes in the placenta, but
more data are needed [39]. Generally, the outcome of pregnancy from systemic
vasculitides seems to be favorable in the majority of cases if pregnancy is planned
during a remission period of the disease.
Thyroid autoimmunity is often part of the picture of systemic autoimmune dis-
eases. The transplacental passage of maternal anti-thyroid antibodies can influence
fetal clinical outcome. Transplacental passage of thyroid stimulating immunoglobu-
lin can result in thyrotoxicosis in the fetus after 20 weeks gestation, when the fetal
thyroid can respond to the stimulus. Both fetal hypo- and hyperthyroidism may
occur, especially during the first trimester of gestation. Maternal hypothyroidism is
associated with impaired fetal neurological development and delayed mental and
motor development [40] (Table 15.1).
Influence of Maternal Therapy on Pregnancy Outcome
The management of rheumatic diseases often requires immunosuppressive therapy

during pregnancy. Drugs can cross the placental barrier and enter into the fetal cir-
culation. Obviously, it is desirable to minimize fetal exposure and to avoid known
teratogens and mutagens. As a result, pregnancy should be planned for a period of
remission in which no drugs (or drugs compatible with pregnancy) are used. It is
advisable for these women to consult with a multidisciplinary management team in
which different experts (rheumatologist, obstetric expert, neonatologist, psycholo-
gist, and neuropsychiatrist) cooperate to handle and integrate the patients’ needs.
While a full discussion on medication use during pregnancy is discussed elsewhere,
below we will highlight some of the important documented effects of specific agents
on childhood development.
Several studies have investigated the effects of antenatal steroids on adverse neo-
natal neurologic short- and long-term outcomes with conflicting results. Spinillo
et al. described an increased risk of leukomalacia and neurodevelopmental abnor-
malities in preterm babies (born between 24 and 34 weeks gestation) exposed to
multiple doses of dexamethasone (DEX); in the same population, betametasone may
be safer [42]. Lee et al. studied neurodevelopmental outcome in a large population of
extremely low birth weight infants exposed prenatally to DEX, betamethasone, or no
steroid (control group). Prenatal betamethasone exposure was associated with
reduced risks of hearing impairment and neurodevelopmental impairment when
compared with no prenatal steroid exposure, whereas prenatal dexamethasone was
associated with a less favorable outcome [43]. In 2004 a group of 13 children exposed
to DEX antenatally (cumulative dosage range 20–260 mg) were tested with different
scales according to their age. All of them were found to have a normal intelligence
quotient (IQ > 90) [44]; these results need to be confirmed with a larger series.
A large 2003 case–control study evaluated 133 pregnancies in patients taking
hydroxychloroquine (HCQ) throughout pregnancy: no significant differences were
found either in pregnancy or in neonatal outcome. Follow-up data of these children
were collected at a mean age of 26 months: no visual, hearing, growth or develop-
mental abnormalities were reported by pediatricians. In addition, no conduction
abnormalities were reported [45]. Motta et al. found no ocular or neurodevelopmen-
tal abnormalities in 40 infants at 1, 3, 6, and 12 months of life born to mothers who
were taking HCQ (200 mg/daily) during pregnancy and lactation [46]. Considering
that HCQ may accumulate in the retina of patients taking this drug, this rare col-
lateral effect was evaluated in children born to mothers taking HCQ during preg-
nancy. The ophthalmologic evaluation in several studies did not show retinal
abnormalities [47, 48].
Available data on newly introduced drugs are sparse and limited because, for
ethical reasons, it is not possible to include pregnant patients in randomized clinical
trials. However, experience with pregnancies inadvertently exposed to biological
drugs is slowly accumulating. Biological manufacturers recommend stopping these
medications during pregnancy and lactation and both the US Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) do not consider
biologic therapies to be safe during pregnancy or lactation [49–51]. Anti-tumor
necrosis factor (anti-TNF) agents and anakinra are classified as pregnancy FDA cat-
egory B, while rituximab, abatacept, and tocilizumab are pregnancy FDA category
C. These drugs are transported through the placenta and reach important levels in
exposed newborns. As an example, the concentration of infliximab in cord blood is
about 160 % that found in maternal blood because the antibodies containing the Fc
296 C. Nalli et al.
component of IgG1 are actively transported through the placenta. Other biological
agents show less transplacental passage: 4–7 % with etanercept and 3.9 % with cer-
tolizumab [52]. No data were found concerning use of tocilizumab and golimumab
during gestation; abatacept and anakinra experiences are very limited (2 and 10
pregnancies, respectively) [52]. On the contrary, a significant number of pregnancies
exposed to infliximab, etanercept, and adalimumab are reported in the literature.
Even though the available data are too limited to claim safety of these drugs during
gestation, the existing evidence suggests that the overall risk of anti-TNF agents is
relatively low. It is often difficult to understand whether fetal complications (preterm
births, IUGR, small for gestation age babies) are due to the effect of biological drugs
or to maternal disease activity.
Some reassuring data are available on the effects of immunosuppressive drugs on
the developing fetal immune system. Airò et al. studied 17 babies born with com-
plete CHB who were treated in utero with high-dose DEX therapy, and character-
ized the production, function and survival of T lymphocytes. They observed that
T-cell compartments in these children did not show any relevant abnormality and
were comparable to those of age-matched controls [53]. The same authors studied a
child born to a woman affected by an overlap syndrome of systemic lupus erythe-
matosus/polymyositis (PM), who presented with active myositis at the beginning of
pregnancy. Therapy with cyclosporin, corticosteroids, hydroxychloroquine, and
high-dose intravenous immunoglobulin induced a progressive remission of clinical
and laboratory signs of myositis. Although the child was born premature (33 weeks)
and small for gestational age, he had normal growth and did not show any clinical
signs of immune deficiency. Lymphocyte phenotype and function studies, as well as
response to vaccination, were also normal [54].
Cimaz et al. also performed immune function evaluations in both humoral and
cellular compartments in 14 children of patients with autoimmune disorders taking
immunosuppressants including cyclosporin during pregnancy. Overall, in utero expo-
sure did not significantly influence the children’s immune systems. Complete blood
count, immunoglobulin (Ig) serum levels, IgG subclasses, and lymphocyte subpopu-
lations were determined at about 1 year of age and no alterations compared to con-
trols were found. All children responded satisfactorily to hepatitis B vaccination [55].
Limited data are available on long-term follow-up of children exposed in utero to
immunosuppressants, in particular, for neurological outcome; further studies are
warranted to improve the current state of knowledge.
Neurodevelopmental Outcome
Behavioral and neuropsychological outcome in children born to patients with rheu-

matic disease is a matter of great interest. In fact, a number of heterogeneous factors
may interact to influence the neuropsychological development of these children.
As stated above, IgG maternal antibodies can cross the placenta after week 12 of
gestation and potentially act on the developing fetus. Maternal aPL could potentially
react directly with fetal cerebral tissue (during the fetal period the blood–brain bar-
rier is still incomplete) and continue their pathogenic effect during the early life of
the child through microthrombosis and inflammatory reactions leading to further
disruption of the blood–brain barrier. The in vitro demonstration of binding of aPL
to neuronal cell-surface antigens supports a possible direct action of autoantibodies
on the neurons of these children. These perspectives are supported by several in vivo
animal models [56]. A number of studies support a relationship between aPL posi-
tivity and neurological manifestations such as migraine, epilepsy, and movement
disorders in positive patients [57], but there are no data suggesting an increased risk
of development of these disorders in the offspring of aPL-positive patients.
In toddlers and children born to mothers with aPL positivity, intelligence levels
have been found to be normal: it may be concluded that aPL exposure during fetal
life does not impair global intelligence capacity [58–60]. However, language delay
and learning disabilities (LD) have been described in children of mothers with APS
with a higher rate than that of the age-matched peers. The transplacental passage of
maternal aPL as well as other well-known risk factors (prematurity, genetic and envi-
ronmental factors) could contribute to the occurrence of LD in this population [59].
Several studies have been performed on mothers with SLE to evaluate their chil-
dren’s long-term outcome. Maternal SLE does not appear to impair intelligence
levels independent of its association with prematurity; however, it may increase the
occurrence of LD (and particularly dyslexia) in male children [50, 60, 61].
Lahita first investigated the prevalence of learning disabilities in the children of
parents with SLE. Forty-five percent of the 55 male children of mothers with SLE
had an LD, whereas none of the 13 children of fathers with SLE were affected.
Furthermore, if the finding of LD was significantly attributable to the stress of hav-
ing a parent with chronic disease, then LD should have been found in the female
children also [61]. Over 90 % of the learning disabilities were diagnosed as dys-
lexia, however Lahita’s definition of dyslexia in the offspring of patients with
SLE—discrepancy between verbal and performance IQ—does not correspond to
the current DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders,
fourth edition text revision) definition of dyslexia which is reading achievement
substantially below that expected, given the person’s age, measured intelligence,
and age-appropriate education [59]. McAllister et al. also proposed an association
between maternal immunoreactivity, as represented by women with SLE, and
adverse child developmental outcome, particularly in male children (hyperactivity,
attention deficit, and reading difficulties) and considered the role of prematurity, but
with a different methodological weakness: the authors only asked to report the pres-
ence or absence of each developmental problem [62].
Subsequent studies performed by direct examination of the children rather than by
interviewing the parents or reviewing school records have confirmed a high incidence
of LD in offspring of women with SLE [58]. In one study, LD were related to presence
of maternal aPL and, in the other case, to maternal anti-Ro/SSA and anti-La/SSB
antibodies and disease activity during pregnancy. The latter study, by Ross et al., com-
pared children of SLE mothers to gestational-age-matched controls to eliminate the
confounding effect of prematurity on diagnosis of neurodevelopmental problems [60].
298 C. Nalli et al.
Urowitz et al. confirmed the previous findings reporting an increased rate of

neurocognitive abnormalities in the offspring of mothers with SLE. Analyses of the
neuropsychological domains revealed impairment in learning, memory, and behav-
ior in 57 SLE children (with age range of 2–26 years) compared with matched
controls. It was difficult to differentiate the impact of prematurity or fetal distress
from that of maternal disease in this study however since neurocognitive abnormali-
ties were seen more frequently in small for gestational age or low weight at birth
offspring [63]. Multiple studies confirm that prematurity is an independent risk fac-
tor for neurodevelopmental disabilities, especially in very low birth weight infants;
consequently, the majority of neonatal complications of children born to mothers
with rheumatic diseases could be a direct consequence of prematurity.
The sequelae of encephalopathy of prematurity include a high occurrence of
cognitive, sensorial, behavioral, attentional, or socialization deficits even without
major motor deficits (e.g. cerebral palsy) [14–19]. However, it is important to note
that a number of the cited studies on children of mothers with SLE did focus on the
relationship between premature birth and LD occurrence and failed to show a statis-
tically significant relationship. In fact, LD were also described in term birth babies,
supporting the hypothesis of a multifactorial origin of the neurodevelopment abnor-
malities occurring in children of patients with SLE [58–61].
Interestingly, a recent study analyzed the relation between azathioprine (AZA)
therapy during pregnancy and developmental delays in offspring. Authors evaluated
60 children born to mothers with SLE who were exposed to AZA in utero: 15 (25 %)
required neuropsychiatric evaluation, in most cases for a speech delay. AZA was
significantly and independently associated with increased special educational
requirements even after controlling for confounders (including pregnancy duration,
SGA, and maternal aPL positivity) [64].
In addition to effects of autoantibodies, prematurity, and medication, another
factor to be considered is the potential influence of the mother’s chronic illness on
psychological and behavioral aspects of her children. Several studies have focused
on the impact of chronic illness on quality of life and consequent psychological
health and function [65–68]. Chronic disease may have an adverse impact on
patients’ quality of life as well as on relationships with other family members,
including the offspring. Patients with chronic disease may feel insecure about their
future and may be fearful of becoming parents. Those with musculoskeletal limita-
tions in particular may doubt their ability to care for their children. For a woman,
pregnancy and the upbringing of the newborn may generate distress and fear and the
related emotional and physical distress may impact the development of the child
[69]. It is reasonable to expect that different rheumatic diseases impact the preg-
nancy experience differently: for example, mothers with systemic sclerosis report
difficulty with parenting, which can be related to the severity of the symptoms [70].
In fact, disabilities related to maternal disease prior to conceiving are an important
prognostic factor, since lower levels of body pain are associated with a better quality
of life. There is often a discrepancy between chronic inflammatory arthritis and
other rheumatic diseases during pregnancy: in general, most women with RA expe-
rience an improvement in their clinical condition, On the contrary, patients with
connective tissue diseases, for example SLE, usually undergo more rigorous
monitoring and follow-up during pregnancy due to the risk of a flare. Differences in
expectations and intensity of monitoring may affect stress levels for these women.
RA may become a significant limitation after delivery when the disease often
flares. The mother may suffer due to physical pain as well as the difficulty of attend-
ing to the family: this poor parental ability may also influence the children’s out-
come. Chronic disease causes anxiety and worry in the entire family. Affected
mothers may experience a conflict between accepting the illness and denying their
symptoms so that they might appear healthy to the other family members. Generally,
the presence of a chronic disease in the mother and the attendant emotional distress
can interfere with parenthood and baby holding [68].
Furthermore, maternal distress and depression during the pregnancy itself may
impact pregnancy and neonatal outcome: these emotions produce a characteristic
hormonal response with increased cortisol levels and decreased dopamine and sero-
tonin levels. This hormonal environment may promote premature delivery of low
birth weight babies. A similar effect may be seen with corticosteroid treatment in
mothers with rheumatic diseases [69].
Only one study has addressed the presence of fathers with immunologic disor-
ders as a risk factor. No statistical significance was found but the authors suggested,
based on trends in the data, that daughters born to these fathers seem to have more
hyperactivity disorders and sons to have more reading problems. These findings
seem to support a genetic role for an association between immunoreactivity and
developmental problems (rather than a strictly gestational role) but no additional
studies are currently available on the paternal role [71].
Ideally, clinical follow-up of newborns of mothers with rheumatic diseases
would include a neuropsychiatry expert’s intervention to evaluate the child’s devel-
opment and identify any neurodevelopmental problems at an early stage. The first
year of life represents a critical period for psychomotor development. The consul-
tant could help the parents to recognize their own and their child’s competences.
During this period we underline the importance of baby holding and care in order
to achieve a “good enough” relationship between mother and child. By helping the
child to have a harmonious development, one achieves a positive feedback on
parental perception of their own competences and consequently reduces parental
anxieties [72].
To the best of our knowledge, no studies are available on the very long-term
outcome of this pediatric population, i.e. adolescence and youth. Information on the
recurrence of maternal or paternal autoimmune diseases in the long-term follow-up
of children is lacking. The previously cited papers focusing on the neurological
development do not mention any associated diseases in the children. Nevertheless,
common experience of pediatricians is that children born to mothers with rheumatic
disease do not generally show a significantly increased risk of developing the auto-
immune disease of their parents. In addition, offspring have uncomplicated growth
[25, 45, 53, 73] and are usually healthy with a normal intelligence level. Some
children may experience LD or behavioral problems. The limited statistical power
of the current literature does not permit us to distinguish whether the increased rate
of cognitive impairment is primarily related to the maternal autoimmune disease or
to prematurity: it is likely that both factors play some role.
300 C. Nalli et al.
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ERRATUM
The Medical Management of the Rheumatology

Patient During Pregnancy
Bonnie L. Bermas
L.R. Sammaritano and B.L. Bermas (eds.), Contraception and Pregnancy

DOI 10.1007/978-1-4939-0673-4_16
The spelling of the drug Certolizumab in Table 14.2 was incorrect. The correct drug
name should read: Certolizumab
The online version of the original chapter can be found at

http://dx.doi.org/10.1007/978-1-4939-0673-4_16
L.R. Sammaritano and B.L. Bermas (eds.), Contraception and Pregnancy E11
Index
A epidemiology, 110
Abortion, 112–113 infertility, 129, 239
Acquired immunity, 8 IVF, 241
Acute fatty liver of pregnancy (AFLP), 55–56 labor and delivery, 127
Angiotensin-converting-enzyme laboratory considerations
(ACE)-inhibitors anticardiolipin and anti-β2-
preconception and antepartum glycoprotein-I antibodies, 117
management, 166, 167 lupus anticoagulant, 116–117
renal crisis, 162–164 type of aPL and risk, 117–119
Ankylosing spondylitis (AS) long-term risk of thrombosis, 130
fertility, 149, 241–242 neonatal, 128–129
maternal disease activity, 150 non-obstetric manifestations
pregnancy outcome in SpA, 149–150 catastrophic antiphospholipid
problems in, 152 syndrome, 116
Ankylosis, 150 non-criteria manifestations, 116
Anti-β2-glycoprotein-I (aβ2GPI) vascular thrombosis, 115
antibody, 117, 292–293 obstetric manifestations
Anticardiolipin antibodies (aCL), 90, 112, 117 definitions of pregnancy loss, 112–113
Anti-Müllerian hormone (AMH) fetal demise/death, 113–114
evaluation, 234 HELLP syndrome, 115
Antineutrophil cytoplasmic antibody intrauterine growth restriction, 114
(ANCA)-associated vasculitis maternal thromboembolic disease, 114
(AAV) preeclampsia/eclampsia, 114–115
corticosteroids, 176, 177 recurrent early pregnancy loss, 113
granulomatosis with polyangiitis, 175–176 postpartum considerations
microscopic polyangiitis, 177 breastfeeding, 128
myeloperoxidase autoantibodies, 177 contraception, 128
rituximab, 175 thromboprophylaxis, 127–128
Antiphospholipid antibodies (aPL), 69–70, preconception counseling, 126
110, 116, 117, 214, 239 pregnancy monitoring and general
Antiphospholipid syndrome (APS), 88 care, 126–127
adverse pregnancy outcome, 109–110 treatment options
aPL evaluation, 125–126 aspirin, 118
classification criteria, 110–112 asymptomatic aPL, 124–125
clinical manifestations, 112 glucocorticoids, 123
contraception, 214–216 heparin, 120–122
in Patients with Rheumatic Disease, DOI 10.1007/978-1-4939-0673-4,
306 Index
Antiphospholipid syndrome (APS) (cont.) Cervical cap, 204

hydroxychloroquine, 120 Cesarean section deliveries, 89
intravenous immunoglobulin, 120, 123 Chronic inflammatory arthritides (CIA)
plasma exchange, 123 age at diagnosis, 141, 142
preeclampsia, 124 pregnancy outcomes, 145
recurrent pregnancy loss, 123–124 Churg–Strauss syndrome. See Eosinophilic
thrombosis, 124 granulomatosis with polyangiitis
Anti-Ro/SS-A and La/SS-B antibodies (EGPA)
congenital complete heart block, 100 Colchicine, 179, 282
neonatal lupus, 82, 293 Combined hormonal contraceptives
pre-pregnancy assessment, 70 absolute and relative contraindications, 208
Sjogren’s syndrome, 100–102 complications, 207
Antral follicle count (AFC), 234 effects of, 207, 209
APS. See Antiphospholipid syndrome (APS) formulations, 206–207
ART. See Assisted reproductive techniques level of estrogen, 209
(ART) risk factors, 209–210
Aspirin, 92, 118, 128, 274–276 venous thromboembolism, 209
Assisted reproductive techniques (ART) Complement, 12–13, 21–22, 89
Fertility 101, 230 Condom, 169, 204
fertility evaluation and investigation Congenital complete heart block
aging, 230–231 (CCHB), 100, 101
hormone evaluation of woman, 234 Congenital heart block (CHB)
infertile couple assessment, 232 discordance of, 257–258
initial management, 235 epidemiology, 252
macrofertility, 233 incidence of, 256
male investigation, 235 monitoring, 262–263
microfertility, 235–236 Contraception, 73, 128
office visit, 232 antiphospholipid syndrome, 214–216
ovarian reserve, 234 barrier methods, 204
fertility management emergency contraception, 211–212
ankylosing spondylitis, 241–242 hormonal contraception
APS, 239–241 estrogen-progesterone preparations,
connective tissue disease, 244–245 206–210
rheumatoid arthritis, 236–237 progestin-only preparations, 210–211
scleroderma, 242–244 intrauterine devices, 205–206
systemic lupus erythematosus, 237–240 long-acting reversible contraception, 204
Autoantibodies, 69, 177 medication interactions, 219–221
Azathioprine (AZA), 86, 93, 166, 180, 195, mycophenolate REMS, 203
278, 298 nonreversible methods, 204
perfect use effectiveness, 203
Raynaud’s phenomenon, 218
B rheumatoid arthritis, 216–218
Barrier methods, contraception, 204 sexual activity and alcohol use, 202
Behçet’s disease (BD), 179–180 SLE patients, 201–202, 212–214
Belimumab, 93 typical use effectiveness, 203
Bone marrow-derived (B) cells, 10 Contraceptive sponge, 204
Breastfeeding, 73, 128, 265–266 Copper IUD, 205, 211–212
Corticosteroids
ANCA-associated vasculitis,
C 176, 177
Calcinosis, Raynaud’s phenomenon, colonic ulcerations, 180
esophageal dysmotility, high-dose, 176, 187, 189
sclerodactyly, and telangiectasias for inflammatory myopathy, 193
(CREST) syndrome, 159 intraarticular injection, 151
Catastrophic antiphospholipid syndrome low dose, 73
(CAPS), 116 moderate-dose, 194
Index 307
prophylactic, 92 Fertility
rheumatoid arthritis and SpA, 151 evaluation and investigation
Cryoglobulinemic vasculitis, 178–179 aging and fertility, 230–231
Cyclooxygenase (COX) inhibitors, 149 hormone evaluation of woman, 234
Cyclophosphamide, 238, 280 infertile couple assessment, 232
Cyclosporine A, 278 initial management, 235
Cytokines, 13–14, 22–23 macrofertility, 233
male investigation, 235
microfertility management,
D 235–236
Decidual immune cells, 18–20 office visit, 232
dendritic cells, 21 ovarian reserve, 234
macrophages, 21 management
NK cells, 20 ankylosing spondylitis, 241–242
Depot medroxyprogesterone acetate APS, 239–241
(DMPA), 204, 211 connective tissue disease, 244–245
Diabetes, 88–89 rheumatoid arthritis, 236–237
Disease-modifying antirheumatic drug scleroderma, 242–244
(DMARD), 151 systemic lupus erythematosus,
DNA fragmentation index (DFI), 235 237–240
Fertility 101, 230
Fetal allograft, 17
E Fetal demise/death, 47, 113–114, 162
Eclampsia, 51, 114–115 Fetal monitoring and surveillance, 90–91
Embryonic development and fetal
physiology
blastocyst, 32 G
cardiac formation, 33 Gastroesophageal reflux disease, 54
fetal circulation, 34 Gastrointestinal (GI) disorders, pregnancy
fetal fat tissue deposition, 34 AFLP, 55–56
implantation, 33 dermatologic conditions, 56–57
organ developments, 34 gastroesophageal reflux disease, 54
organogenesis, 33 intrahepatic cholestatis, 55
spiral arterioles, 32 nausea and vomiting, 54
syncytiotrophoblast, 32 venous thromboembolism/pulmonary
Emergency contraception, 211–212 embolism, 56
Eosinophilic granulomatosis with polyangiitis Germinal matrix-intraventricular
(EGPA), 177–178 hemorrhage, 292
Estrogen-progesterone contraceptives Giant cell arteritis (GCA), 174
contraindications, 208 Glucocorticoids, 60, 123, 276–277
effects on reproduction system, 207 Granulomatosis with polyangiitis
intravaginal ring, 207 (GPA), 175–176
monophasic/multiphasic, 206
non-contraceptive benefits, 207
side effects, 207 H
stroke risk, 209 Hemolysis, elevated liver enzymes, low
transdermal patch, 206 platelets (HELLP) syndrome, 51,
venous thrombosis risk, 209 65, 83, 115
Expected date of delivery, 41 Heparin, 120–122
Hormonal contraception
estrogen-progesterone preparations,
F 206–210
Fecundity, 229–230 progestin-only preparations, 210–211
Female menstrual cycle, 230–231 Human leukocyte antigen (HLA), 148
308 Index
Human placenta, 18–20 Immunosuppressive agents

Hydroxychloroquine (HCQ), 92, 120 azathioprine, 278
Hypertensive disorders, pregnancy cyclosporine A, 278
diabetes, 88–89 mycophenolate mofetil, 279
eclamptic seizure, 51 tacrolimus, 279
gestational hypertension, 49 Infertility
HELLP syndrome, 51 anti-phospholipid antibodies, 239
inadequate placentation, 50 APS, 129
magnesium seizure prophylaxis, 52 definition, 229
medications, 50 management of, 237
preeclampsia, 49 pre-scleroderma, 243
recurrent seizure, 52 prevention of, 245
reproductive endocrinology, 230
Inflammatory myopathy
I clinical features, 185
Idiopathic inflammatory myopathies (IIM). incidence, 185
See Inflammatory myopathy massive perivillous fibrin deposition in
Immunoglobulins and humoral immunity, 11 placenta, 194–195
Immunology maternal outcome, 195
acquired immunity, 8 and multiple pregnancies, 192
autoimmune diseases, 26 neonatal outcome, 192–193
cellular effectors new disease onset after pregnancy, 193
bone marrow-derived cells, 10 pregnancy outcomes
monocytes, macrophages, and dendritic disease flare, 190–192
cells, 10–11 disease onset, 187–189
natural killer cells, 10 disease remission during
neutrophils, eosinophils, and gestation, 189
basophils, 11 treatment options, 193–194
thymus-derived cells, 9–10 Innate immunity, 6–7
complement, 12–13, 21–22 Intrahepatic cholestatis, 55
cytokines, 13–14, 22–23 Intrauterine devices (IUD), 205–206
decidual immune cells, 18–20 Intrauterine growth restriction (IUGR),
dendritic cells, 21 48, 114, 161
macrophages, 21 Intravaginal ring, 206, 207
NK cells, 20 Intravenous immunoglobulin (IVIG)
fetal allograft, 17 APS, 120, 123
hormonal regulation, 25 inflammatory myopathy, 193–194
immunoglobulins and humoral immunity, 11 refractory thrombocytopenia and
implantation site and transplantation dermatomyositis, 280–281
antigens, 23–24 In-vitro fertilization (IVF), 67, 129, 236, 241
innate immunity, 6–7
lymphocyte education, 16
major histocompatibility complex, 15–16 J
menstrual and reproductive cycle Juvenile idiopathic arthritis (JIA), 141–144
implantation, 5
luteal phase, 5
maternal–fetal interface, 6–7 L
proliferative phase, 4 Labor and delivery, 127
syncytiotrophoblast, 6 Large vessel vasculitis
trophoblast cells, 6 giant cell arteritis, 174
peripheral neutrophils, 19 Takayasu arteritis, 172–174
peripheral T lymphocytes, 17–19 Leflunomide, 280
primary and secondary immune response, 8 Long-acting reversible contraception, 204
Index 309
Long term children’s outcome Maternal physiologic changes

diagnosis and management of, 289–290 cardiovascular system, 35–36
important issues, 290 gastrointestinal system, 37–38
maternal disease impacts muscloskeletal system, 38
anti-b2GPI, 292–293 renal system, 36–37
encephalopathy of prematurity, 292 respiratory system, 36
germinal matrix-intraventricular Maternal therapy, long-term children’s
hemorrhage, 292 outcome
neonatal lupus, 293 biological manufacturers, 295
potential effects of, 294 effects of antenatal steroids, 295
preterm birth, 291 immune function evaluations, 296
spectrum of visual problems, 292 immunosuppressive drugs, 296
systemic vasculitides, 294 management of, 294–295
thyroid autoimmunity, 294 Maternal thromboembolic disease, 114
maternal therapy Medical management, rheumatology patient
biological manufacturers, 295 anti-coagulants, 282
effects of antenatal steroids, 295 antimalarials, 277
immune function evaluations, 296 aspirin, 274
immunosuppressive drugs, 296 biologics, 281
management of, 294–295 colchicine, 282
neuropsychological development COX-2 inhibitors, 276
analyses, 298 cyclophosphamide, 280
AZA, 298 glucocorticoids, 276–277
chronic disease, 299 immunosuppressive agents
clinical follow-up, 299 azathioprine, 278
IgG maternal antibodies, 296–297 cyclosporine A, 278
learning disabilities, 297 mycophenolate mofetil, 279
maternal distress and depression, 299 tacrolimus, 279
musculoskeletal limitations, 298 inadvertent drug exposure, 282
SLE, 297 IVIG, 280–281
pregnancy and rheumatic diseases, lactation, 281
290–291 medications
Low-dose aspirin (LDA), 69, 70, 84, 92, 118 potential side effects and toxicities,
Lupus anticoagulant (LAC), 116–117 274, 275
Lupus manifestations and flares, 84–86 principles, 274
Lupus nephritis, 86–88 risk assessment of, 273–274
Luteinized unruptured follicle (LUF) methotrexate, 279–280
syndrome, 149 NSAIDs, 276
Lymphocyte rituximab, 281
antigen-specific, 8 sulfasalazine, 277–278
education, 16 Medium-vessel vasculitis, 174–175
natural killer cells, 10 Microfertility management, 235–236
peripheral blood, 148 Microscopic polyangiitis (MPA), 177
peripheral T, 17–19 Miscarriages, 47, 160–161
T-cell receptor γδ+ T, 21 Mixed connective tissue disease (MCTD)
features of, 100
fertility and contraception, 101
M impact of pregnancy, 104
Macrofertility, 232, 233, 235 outcomes of pregnancy, 102–103
Major histocompatibility complex (MHC), with systemic lupus erythematosus, 100
15–16, 261 treatment, 105
Massive perivillous fibrin deposition Mode of delivery, 46
(MPVFD), 194–195 Monocytes, macrophages, and dendritic
Maternal mortality, 84 cells, 10–11
310 Index
Mycophenolate mofetil, 279 Plasma exchange, 123, 179

Mycophenolate REMS, 203 Polyarteritis nodosa (PAN), 174–175
Myeloperoxidase (MPO) autoantibodies, 177 Postpartum course, 73
Myositis. See Inflammatory myopathy Postpartum thromboprophylaxis, 127–128
Myositis-specific autoantibodies Preconception counseling, 79–80, 126
(MSA’s), 185–186 Preeclampsia, 49, 65, 82–84, 114–115, 124
Preexisting renal disease, 66
Pregnancy
N complications
Natural killer (NK) cells, 10 hypertensive disorders, 48–52
Nausea and vomiting, 54 intrauterine growth restriction, 48
Neonatal APS, 128–129 pregnancy loss, 47–48
Neonatal lupus, 82 preterm birth, 52–54
cardiac manifestations, 255–256 embryonic development and fetal
clinical management of physiology
antibody testing, 263 blastocyst, 32
breastfeeding, 265–266 cardiac formation, 33
diagnosis, 262 fetal circulation, 34
long-term follow-up, 266 fetal fat tissue deposition, 34
monitoring, for CHB, 262–263 implantation, 33
prophylaxis and treatment, 263–265 organ developments, 34
screening, 262 organogenesis, 33
cutaneous, 253 spiral arterioles, 32
environmental contribution, 260 syncytiotrophoblast, 32
epidemiology, 252 GI disorders
genetic approach, 260–261 acute fatty liver, 55–56
hematologic manifestations, 254–255 dermatologic conditions, 56–57
hepatic abnormalities, 253–254 gastroesophageal reflux disease, 54
mechanisms intrahepatic cholestatis, 55
anti-SSA/Ro-SSB/La antibodies, nausea and vomiting, 54
257–258 venous thromboembolism/pulmonary
apoptosis, antibodies, and tissue embolism, 56
inflammation and injury, 258 immunology (see Immunology)
direct calcium channel effects, 258–259 maternal physiologic changes
morbidity and mortality of, 257 cardiovascular system, 35–36
neuropsychological impairment, 255 gastrointestinal system, 37–38
Sjogren’s syndrome, 100, 101 muscloskeletal system, 38
target antigens, 259–260 renal system, 36–37
Nonreversible contraception, 204 respiratory system, 36
Nonsteroidal inflammatory drugs obstetric approach, 57–60
(NSAIDs), 149, 274–276 rheumatic disease (see Rheumatic disease
pregnancy)
routine features and prenatal care
O diagnosis, 41
Obesity, 209 expected date of delivery, 41
Ovarian hyperstimulation syndrome initial prenatal visits and laboratory
(OHSS), 129, 240–241 tests, 41–44
Ovarian reserve, 234 mode of delivery, 46
preconceptional considerations, 38–40
subsequent prenatal visits and care,
P 44–46
Pemphigoid gestationis (PG), 57 Pregnancy loss
Peripheral neutrophils, 19 definitions of, 112–113
Peripheral T lymphocytes, 17–19 fetal deaths, 47
Index 311
miscarriages, 47 etiology, 139

placental disease, 48 fertility
recurrent early, 113 age at diagnosis, 141–143
SLE, 80–81 factors, 141
treatment, 123–124 inter pregnancy interval, 143, 144
Pre-pregnancy assessment. See Rheumatic population-based study, 141
disease pregnancy probability of, 141, 142
Preterm birth relative fertility rates, 143
betamethasone, 54 infertility management, 236–237
factors, 52–53 management of pregnancy
iatrogenic delivery, 53 disease activity, 152
multifetal gestation, 53 drug therapy, 151
preterm labor, 52 follow-up, 152
SLE, 81 problems in, 152
Progestin-only contraceptives, 210–211 maternal disease activity postpartum,
Pruitic urticarial papules and plaques of 147–148
pregnancy (PUPPP), 56 newborn of, 146
Prurigo of pregnancy, 56 pre-conceptual counseling, 153–154
Pulmonary arterial hypertension (PAH), pregnancy-induced amelioration, 148–149
65–66, 164 pregnancy outcomes, 145–146
Rituximab, 175, 281
R
Raynaud’s phenomenon, 100, 165, 218 S
Recurrent pregnancy loss, 113, 123–124 Schirmers test, 100
Renal crisis, 162–164 Scleroderma
Reproductive endocrinology, 230 contraception management, 168–169
Rheumatic disease pregnancy and fertility, 160, 242–244
antiphospholipid antibodies, 69–70 fetal cells, 160
anti-Ro/SS-A and La/SS-B antibodies, 70 impact of pregnancy, 164–165
autoantibodies, 69 intrapartum management, 167–168
counseling, 70 limited and diffuse cutaneous types, 160
contraception, 73 preconception and antepartum
delivery options, 72 management
fertility issues, 71 ACE-inhibitors, 166, 167
postpartum course, 73 antibody profile, 165, 166
pregnancy risk and outcome, 71–73 degree of organ involvement, 166
medication review, 68–69 immunosuppressive medications, 166
physiology of pregnancy, 64–65 with women, 165
risk of disease activity, 67–68 pregnancy outcomes
severe disease damage fetal death, 162
in-vitro fertilization, 67 intrauterine growth restriction, 161
lupus nephritis, 67 miscarriages, 160–161
preexisting renal disease, 66 preterm delivery, 161–162
pulmonary arterial hypertension, prevalence and manifestations, 159
65–66 renal crisis
rheumatic disease-related organ ACE inhibitors, 162–164
damage, 65, 67 antibody profiles, 163
Rheumatoid arthritis (RA) hypertension, 163, 164
characteristics, 139, 140 preeclampsia, 163
contraception, 144, 216–218 serum creatinine, 163
effect of pregnancy, 146–147 skin thickening, 159
312 Index
Sjögren’s syndrome (SS) moderate lupus activity, 93

anti-Ro/SS-A and anti-La/SS-B no lupus activity, 92
antibodies, 100 severe lupus activity, 93–94
autoimmune disease, 252 fertility evaluation, 238–239
childrens with NL, 266 maternal complications
congenital complete heart block, 100 Cesarean section deliveries, 89
contraception, 101 diabetes and hypertension, 88–89
fertility, 100–101 lupus manifestations and flares, 84–86
impact of pregnancy, 104 lupus nephritis, 86–88
manifestations of, 99, 100 mortality, 84
pregnancy outcomes, 101–102 thrombosis, 88
prevalence rate of, 99 medical evaluation, infertility, 238
Schirmers test, 100 ovulation induction and IVF, 239–240
screening, 262 preconception counseling, 79–80
treatment of, 105 pregnancy outcomes
SLE. See Systemic lupus erythematosus (SLE) neonatal lupus, 82
Small for gestational age (SGA), 81–82 preeclampsia, 82–84
Small vessel vasculitis pregnancy loss, 80–81
antineutrophil cytoplasmic antibody- preterm birth, 81
associated vasculitis, 175–177 small for gestational age, 81–82
cryoglobulinemic vasculitis, 178–179 screening, 262
eosinophilic granulomatosis with Systemic sclerosis. See Scleroderma
polyangiitis, 177–178
Spondyloarthropathies (SpA)
characteristics of, 139, 140 T
contraception, 144 Tacrolimus, 279
fertility Takayasu arteritis (TAK)
age at diagnosis, 141–143 cesarean section, 174
factors, 141 disease activity, 173
inter pregnancy interval, 143, 144 epidural/spinal anesthesia, 173
population-based study, 141 hypertension, 173
relative fertility rates, 143 prevalence of, 172, 173
joint inflammation, 139 stenosis and occlusion, 173
management of pregnancy symptoms, 172, 173
disease activity, 152 Thrombosis, 88, 124, 130
drug therapy, 151 Thymus-derived (T) cells, 9–10
follow-up, 152 Transplantation antigens, 23–24
problems in, 152
pre-conceptual counseling, 153–154
pregnancy outcomes, 149–150 U
prevalence of, 139, 140 Undifferentiated connective tissue disease
Spontaneous abortions, 47 (UCTD)
SSA/Ro-SSB/La system, 259–260 features of, 100
Sulfasalazine, 242, 277–278 fertility and contraception, 101
Systemic lupus erythematosus (SLE), 291 impact of pregnancy, 104
autoimmune disease, 252 outcomes of pregnancy, 103
children with NL, 266 treatment, 105
contraception in, 201–202, 212–214
diagnosis of, 257
diagnostic investigations and monitoring V
fetal monitoring and surveillance, Vascular thrombosis, 115
90–91 Vasculitis
general principles of treatment, 91–92 large vessel
laboratory testing, 89–90 giant cell arteritis, 174
mild lupus activity, 92–93 Takayasu arteritis, 172–174
Index 313
neuropathic manifestations, 172 systemic vasculitis, 171, 172

polyarteritis nodosa, 174–175 variable vessel vasculitis, 179–180
rheumatoid vasculitis, 172 Venous thromboembolism/pulmonary
small vessel embolism, 56
antineutrophil cytoplasmic antibody-
associated vasculitis, 175–177
cryoglobulinemic vasculitis, W
178–179 Wegener’s granulomatosis. See
eosinophilic granulomatosis with Granulomatosis with
polyangiitis, 177–178 polyangiitis (GPA)

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Contraception and

Pregnancy in Patients with

Contraception and Pregnancy

ISBN 978-1-4939-0672-7 ISBN 978-1-4939-0673-4 (eBook)

Library of Congress Control Number: 2014940170

© Springer Science+Business Media New York 2014

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Rheumatologic diseases disproportionally impact women during their reproductive

New York, NY, USA Lisa R. Sammaritano

Part I Basics of Pregnancy

1 Immunology of Pregnancy ..................................................................... 3

Part II Pregnancy in Specific Rheumatic Diseases

4 Systemic Lupus Erthematosus ............................................................... 79

10 Myositis and Pregnancy ......................................................................... 185

Part III Additional Reproductive Issues

11 Contraception in Rheumatic Disease Patients ..................................... 201

Laura Andreoli Rheumatology and Clinical Immunology, Department of Clinical

Peter M. Izmirly Department of Rheumatology, New York University School of

Virginia D. Steen Department of Medicine/Rheumatology, Medstar Georgetown

Danny J. Schust and Amanda J. Stephens

ADCC Antibody-dependent cellular cytotoxicity

D.J. Schust, M.D. (*) • A.J. Stephens, M.D.

L.R. Sammaritano and B.L. Bermas (eds.), Contraception and Pregnancy 3

Through numerous pathways, the immune system works to protect an individual

The Menstrual and Reproductive Cycle

cytotrophoblast. Initially, the syncytiotrophoblast invades into the decidua and

Basic Principles of Immune Response

effector molecules, including inflammatory response molecules, antimicrobial pep-

Primary and Secondary Immune Responses

Cellular Effectors of an Immune Response

Leukocytes, including lymphocytes, monocytes, macrophages, dendritic cells, neu-

Adaptive immune system

B (Bone Marrow-Derived) Cells

NK (Natural Killer) Cells

Monocytes, Macrophages, and Dendritic Cells

Other Effector Cells

Soluble Components of Immune Responses

Immunoglobulins and Humoral Immunity

Fig. 1.2 The complement

The complement components represent an important effector arm of immune pro-

The lectin pathway is similar to the classical pathway; however, mannose-binding

In conjunction with immunoglobulins and the components of the complement cas-

Basis of Immune Specificity and Immune Cell Education

The ability to determine self from non-self is an imperative function of lympho-

The Fetal Allograft

The maintenance of a successful pregnancy requires an intricate coordination and

Cellular Immune Effectors in Pregnancy

Peripheral Immune Cells During Pregnancy

Peripheral T cells exhibit decreased mitogen responses and diminished proliferative

characterized progesterone-induced binding factor (PIBF) by lymphocytes [35].

During pregnancy, NK cells undergo dramatic and important alterations in surface

Decidual Immune Cells

endometrium are leukocytes. This number increases to 20 % in the decidua of the

Special Decidual Immune Cell Subpopulations

Macrophages, T-Cell Receptor γδ+ T Lymphocytes, and Dendritic Cells

Macrophages increase early in pregnancy, then stabilize throughout the remainder

Soluble Immune Effectors and Pregnancy

retardation, preeclampsia) or pregnancy loss. Several complement regulatory pro-

Cytokines and the Cytokine-Shift Hypothesis

Few individual cytokines appear to be absolutely necessary for pregnancy mainte-

The Implantation Site and Transplantation Antigens

The implanting human blastocyst is characterized by an inner cell mass represent-

Pregnancy as a State of Immune Modulation