TOG

The Obstetrician & Gynaecologist

The journal for continuing professional development
from the RCOG
The CPD journal from the RCOG ISSN 1467-2561/1744-4667 (online)
http://onlinetog.org http://onlinetog.org

Volume 18 Number 2 2016

Contents

Editorial Education
83 Mark Roberts 143 The fallopian tube as the origin of non-uterine pelvic high-grade
serous carcinoma
Ieera Madan Aggarwal, Yu Hui Lim, Timothy Yong Kuei Lim
Editor's Pick
89 Spotlight on… mental health
Tahir Mahmood CPD
154 CPD questions for volume 18 number 2
157 CPD questions for BJOG paper. A systematic review and network
Reviews meta-analysis comparing the use of Foley catheters, misoprostol
91 Natural killer cells and reproductive health and dinoprostone for cervical ripening in induction of labour
SBA Hsu Phern Chong, Siobhan M Quenby 157 CPD questions for BJOG paper. Donor oocyte conception and
99 Preimplantation genetic diagnosis: an overview and recent pregnancy complications: a systematic review and meta-analysis
SBA advances
Jara Ben-Nagi, Paul Serhal, Sioban SenGupta, Karen Doye, 160 TOG Ratings
Dagan Wells
107 Unexplained subfertility: diagnosis and management
SBA Anupa Nandi, Roy Homburg Letters and Emails
162 Re: The Obstetrician & Gynaecologist Volume 17, Issue 4
117 The role of transabdominal cervical cerclage techniques in Albert Zinn
SBA maternity care (includes author’s reply)
Donald Gibb, Ertan Saridogan
127 Acute kidney injury in pregnancy and the use of non-steroidal
SBA
163 UKOSS update
anti-inflammatory drugs
Kate S Wiles, Anita Banerjee
137 INTERGROWTH-21st: a new paradigm for fetal growth in the And finally…
21st century 164 Do it yourself
Jane E Hirst, Aris T Papageorghiou, for the International
Fetal and Newborn Growth Consortium for the 21st Century
(INTERGROWTH-21st)
The Obstetrician & Gynaecologist 10.1111/tog.12292 http://onlinetog.org
Editorial
TOG is on the move. . .or at least it is if you have the app that
has just been launched. Check the App Reviews later in this
issue, which cover the apps for TOG and our sister journal
BJOG. Download them for free in the usual way (for iOS and
Android) and you will have quick access to content that is easy
to use and then you can keep up-to-date on the beach. The
format allows quick access to PDF and Enhanced HTML
“Anywhere” articles. Personally I love it, so they’re not just for
our younger members.
The “Editors Pick” by Tahir Mahmood was specially
commissioned to support the International Women’s Day in
March 2016. This is in line with the RCOG celebration this
year, which is themed ‘Joining up care in maternal mental
health’. As noted in the January 2016 TOG Issue, with the
report on MBBRACE-UK 2015, mental health is a significant
factor contributing to maternal mortality. One in eleven of the
women who died during or within six weeks of pregnancy was
due to mental health-related causes and up to a year after birth
almost a quarter of all maternal deaths were related to mental
health problems. This “Spotlight on. . .mental health” from
past issues is linked to a Virtual Issue and can be found on the
TOG page in Wiley Online Library (onlinetog.org), under the
‘FIND ISSUES’ panel (bit.ly/Virtual-Issues).
The functions of uterine natural killer cells and their
relationship to reproductive dysfunction is new to many of us
but it has been long postulated that immunology may hold the
key to unexplained recurrent miscarriage, implantation failure
and pre-eclampsia. Siobhan Quenby and Hsu Chong outline
the current evidence as a promising future area of research.
Perhaps this will explain the fascinating data that show higher
artificial reproduction technique pregnancy rates with prior
uterine instrumentation.
Putting ethical considerations aside, and there are quite a
few that Jara Ben Nagi and colleagues appropriately mention,
preimplantation genetic diagnosis appears to have many
advantages over traditional methods used post implantation,
that ultimately lead to termination of affected pregnancies. As a
specialty, we all need to understand these brave new
developments and are grateful to the authors for presenting
this excellent article.
When is unexplained subfertility truly unexplained or due
to subtle but often known contributing factors influencing
fertility? Anupa Nandi and Roy Homburg describe these
(including immunological causes, again) and the investigations
that are appropriate, before critically assessing the balance
between conservative management and active treatment. This
is not just a debate of clinical efficacy but also cost effectiveness
and is a timely, detailed response to Section 1.8 of 2013 NICE
Guidance (nice.org.uk/guidance/cg156).
As a gynaecological surgeon I was surprised that
transabdominal cerclage, perhaps with a laparoscopic
approach, had not become more widely used when the vaginal
approach was not possible. Indications being a severely
disrupted cervix and failed previous vaginal approach. Donald
Gibb and Ertan Saridogan explain that this is due to
insufficient data. They highlight the importance of case
selection, specialist surgical expertise and the need for national
audit and collaboration. The surgical approaches are well
Editor-in-Chief
Mark Roberts
ª 2016 Royal College of Obstetricians and Gynaecologists
Editorial
described and further reading on this subject includes 2007 Editorial board
NICE Guidance (nice.org.uk/guidance/ipg228). Mark Roberts MD MRCOG
Kate Wiles and Anita Banerjee present the aetiology and Royal Victoria Infirmary,
management of acute kidney disease in pregnancy and outline Newcastle Upon Tyne
the potential risk of prescribing NSAIDs in pregnancy, in the Mohamed Abdel-Fattah FRCOG
postpartum period and especially after major postpartum University of Aberdeen, Aberdeen
haemorrhage. The text is a valuable reference for medical and Philippa Corson MRCOG
obstetric clinicians faced with a pregnant or postpartum North Middlesex Hospital, London
(Trainee Representative)
woman with a new elevated serum creatinine titre, when causes
Kate Harding FRCOG (CPD Editor)
can be multifactorial, and delayed or inappropriate
Guy’s and St Thomas’ NHS Foundation
management can be detrimental. Trust, London
As incoming Editor-in-Chief, I inherited this Stuart Jack MRCOG
commissioned article on fetal growth then to become aware of Royal Infirmary, Edinburgh
the controversies around this topic later. In my days of Euan Kevelighan FRCOG (CPD Editor)
obstetrics, many years ago, we simply requested fetal Singleton Hospital, Swansea
assessment, whether serial ultrasound, amniotic fluid index or Justin Konje FMCOG (Nig) FWACS MRCOG
uterine artery Doppler, for “small for dates” based on University of Leicester, Leicester
symphysis fundal height. Checking the extensive RCOG Green- (Lead CPD Editor)
top Guideline 31 published in 2013 there have been some Kate Langford MA MD MBA FRCOG
changes at least. Certainly the publication of Guy’s and St Thomas’ NHS Foundation
Trust, London
INTERGROWTH-21st, which outlines growth standards,
condenses the series of publications in BJOG for TOG readers Jo Morrison BM BCh MA MRCOG DPhil (Oxon)
Musgrove Park Hospital, Taunton
and considers a world health perspective on the small-for-
Nicola Mullin MFFP FRCOG
gestational-age fetus. I remind the reader to also consider the
Countess of Chester Hospital NHS
work on customised growth charts; many will be familiar with Foundation Trust, Chester
the Growth Assessment Protocol (GAP) based on GROW Surabhi Nanda MRCOG
software that is now being used in many UK units. Liverpool Women’s NHS Foundation Trust,
The concept that the fallopian tube may be the origin of Liverpool
pelvic non-uterine high-grade serous carcinoma (HGSC) Thomas Tang MD MRCOG
seems to have suddenly arrived with a tidal wave of support. Regional Fertility Centre, Royal Maternity
Those of us regularly undertaking risk reducing salpingo- Hospital, Belfast
oophorectomy for BRCA gene mutations had often noted tubal Ephia Yasmin MRCOG
University College London Hospitals NHS
intra-epithelial dysplasia reported on histology specimens
Foundation Trust, London
without understanding the significance. Ieera Aggarwal and
colleagues explain the evidence on this topic and the International advisory board
association with P53 mutation. Still to determine is the exact Ben CP Chan FRCOG
origin of HGSC in patients without tubal intra-epithelial Hong Kong Maternal & Fetal Medicine Clinic
carcinoma and the optimum timing of risk reducing surgery. Ki-Hong Chang MD PhD
The proposal for staged salpingectomy, and later, Ajou University School of Medicine, Korea
oophorectomy, reducing early symptoms of estrogen Amr El-Shalakany MSc MD FRCOG
deficiency, appears attractive but, while more of us are Ain Shams University Maternity Hospital,
Cairo, Egypt
performing opportunistic salpingectomies, we are yet to reach
a consensus on prevention strategies. Kristen A Matteson MD MPH
Brown Medical School, Providence, USA
Once again Marian Knight gives us the UKOSS update, this
Henry Murray MRCOG
time outlining the summary facts for postpartum haemorrhage
Australia
requiring transfusion of 8 or more units of red cells. You can
Dimitrios Koleskas MRCOG
easily imagine this coming up in an exam! To close this issue, Euroclinic, Athens, Greece
the Emeritus Professor Drife gives us his “And finally. . .Do it
N Rajamaheswari MD DGO MCh (Urology)
yourself”. As soon as this is released online I am planning to Director, Urogynaecology Research Center
show it to my wife and my secretary, both will find it amusing Pvt Ltd, India
but I suspect that I will still need to buy the bouquet when I Duru Shah MD FCPS FICS FICOG DGO DFP FICMCH
(i.e. when my wife and I) do it myself. Read his article and you Jaslok Hospital, Sir Hurkinsondas Hospital
will understand. Then finally from me. . .. remember to check and Breach Candy Research Centers, India
the TOG App, give it a go, you might like it! David Shaker FRCSEd FRCOG FRANZCOG
University of Queensland, Rockhampton
Base Hospital and Mater Private Hospital,
Australia
Dirk Timmerman MD PhD
University Hospitals Leuven, Belgium
83
tog_18_2_aims_A&S 3/28/2016 2:51 PM Page vi
The Obstetrician & Gynaecologist
Aims and scope
The Obstetrician & Gynaecologist (TOG) is an editorially
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Obstetricians and Gynaecologists (RCOG). It aims to provide
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with an up-to-date, peer-reviewed information resource
delivered through current, educational articles.
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87
 DOI: 10.1111/tog.12284 2016;18:89–90
The Obstetrician & Gynaecologist
http://onlinetog.org
Spotlight on. . . mental health
Tahir Mahmood CBE MD FRCPE FACOG FRCOG Consultant Obstetrician and Gynaecologist Victoria Hospital, Kirkcaldy, Scotland, KY25NE,
UK and President European Board & College of Obstetrics and Gynaecology (EBCOG) Email: tahirmahmood1@nhs.net
There is a complex interplay between physical, psychosocial,
and emotional factors and mental state. A multifactorial
unpleasant, emotional experience of a psychological
(cognitive, behavioural, emotional), social and/or spiritual
nature may interfere with the ability to cope effectively with a
disease, its physical symptoms and its treatment. A precise
definition of what constitutes a psychosexual problem or
dysfunction is difficult to define. They are not only reported
by women who have undergone extensive surgery for their
cancers or suffer from other benign gynaecological
conditions, but are often reported by women presenting
with other non-pathological gynaecological and obstetric
issues such as continuing pelvic pain despite negative
laparoscopy, persistent vaginal discharge, vulvodynia,
vaginismus, associated nonconsumption and tokophobia.
The articles selected in this series, put together especially for
International Women’s Day, provide a broad overview of
mental health.
Obstetrics and mental health
Women experience major depression twice as often as men,
mainly during the reproductive years. This is unrelated to
culture, race or class. Conlon and Lynch (TOG 2008;10:151–
155) point out that approximately 10% of pregnant women
will experience clinically significant depressive symptoms
during pregnancy. Lowes et al. (TOG 2012;14:179–187) point
out that anorexia nervosa, although usually recognised as a
self-limiting eating disorder among young adolescent
females, has the highest maternal mortality rate during
pregnancy among all psychiatric disorders, along with a
six-fold increase in perinatal mortality. Anorexia is associated
with other psychological problems, such as depression,
anxiety and obsessive-compulsive disorder (40%), that
make women with anorexia more vulnerable to postnatal
depression. More than 100 women die annually in the USA,
with the most immediate cause of death being suicide.
Postpartum psychosis
Oates (TOG 2008;10:145–150 and TOG 2008;10:231–235)
and Di Florio et al. (TOG 2013;15:145–150) highlight that all
types of psychiatric disorders can complicate the postpartum
period, arising either denovo or as a recurrence or relapse of
ª 2016 Royal College of Obstetricians and Gynaecologists
Editor's Pick
a pre-existing condition. They point out that postpartum
disorders, such as puerperal psychosis and depressive illness,
warrant special attention. The first 90 days of the postpartum
period are associated with an altered risk of psychosis and
severe depressive illness.
All women, especially primiparous women and those
suffering from bipolar disorders (severe affective disorders),
should be screened antenatally for the known risk factors.
There is increased risk among primiparous women; it is
multifactorial and a combination of biological, generic and
hormonal changes postpartum may act as a trigger. Women
with a history of serious psychiatric illness, peripartum or
otherwise, should be assessed by a psychiatrist in the
antenatal period to ensure that a management plan
involving all of the disciplines relevant to their care can be
drawn up.
I recommend that clinical practice guidelines should be
based on 2007 NICE Guidance and the RCOG Good Practice
Paper - Management of women with mental health issues
during pregnancy and the postnatal period.
Gynaecological problems and mental
health
Gynaecological cancers
The diagnosis of cancer casts a huge emotional disruption, a
negative impact on sexual function and reduces quality of
life. Even among cancer survivors, there is a negative impact
on women’s physiological wellbeing. Kew et al. (TOG
2002;4:193–196) point out that psychosexual functioning
does not usually improve with time, even among survivors.
Mitchell (TOG 2011;13:22–28) urges that ‘distress screening
tools’ be implemented to identify unmet needs. A coherent
strategy is required to deal with the psychosexual dysfunction
in women after treatment for a gynaecological malignancy.
Urinary incontinence
Sinclair and Ramsay (TOG 2011;13:143–148) reported that
women with urinary incontinence experience sexual
dysfunction, a greater psychological morbidity (particularly
major depression, which has been shown to be more
common in incontinent women, adding to the cycle of low
self-esteem), increased social withdrawal and, ultimately, a
reduction in quality of life.
89
 Editor’s pick
Female infertility
An increasing number of couples are seeking assistance with
advanced reproductive techniques and the couples may
experience a roller coaster of emotions, including despair,
hope, anger and anxiety, sadness, isolation and grief.
Unsuccessful treatment can have long-term impacts on
relationships with a partner and friends, and women may
suffer from more severe symptoms of depression. Joy and
McCrystal (TOG 2015;17:83–89), and Bryson and Traub
(TOG 2002;4:201–204) propose that infertility services
should also focus on a patient’s changing psychosocial
needs “by providing effective, holistic and patient-centred
counselling services”.
Medically unexplained symptoms in gynaecology
Burnel (TOG 2011;13:154–160), and Cowan and Frodsham
(TOG 2015;17:47–53) point out that approximately 20% of
women attending general gynaecological outpatient clinic
have psychosexual symptoms; they present as chronic pelvic
pain, deep dyspareunia, vulvodynia, hypoactive sexual desire
disorder and repeated requests for gynaecological surgery.
The relationship between medically unexplained symptoms
(MUS) and other forms of psychiatric disorders is probably
complex and there is an increased lifetime risk of depression.
It is important to note that this association operates in both
directions: people with an episode of depression are more
likely to develop an episode of MUS and those with MUS are
more likely to develop an episode of depression.
Psychosexual disorders in women
Coulson and Crowley (TOG 2007;9:217–222) elucidate that
sexual difficulties are not uncommon among both
90
heterosexual and homosexual women; they were reported
by 43% of women. The problems of female sexual difficulties
result from a combination of biological, psychological and
interpersonal factors, and are poorly understood. Quite
often, covert presentation of a sexual difficulty can take the
form of complaints about pelvic pain, distress about periods,
and general dissatisfaction with a contraceptive. Rymer et al.
(TOG 2010;12:237–243) reviewed the multifactorial aetiology
of hypoactive sexual desire disorder, which can affect women
of all ages, but the incidence is high among surgically-
induced menopausal women. An increased professional
awareness of hypoactive sexual desire disorder and
knowledge about effective therapeutic intervention
is warranted.
Training for the specialists of the future
Women expect tomorrow’s specialists to provide
psychosexual medical services but there is little or no
training in this area for medical students, obstetrics and
gynaecology trainees and specialists. An improvement in the
education of healthcare professionals working with these
patients, and an increase in the number of staff available, will
be required in order to ensure that these women receive the
support that they need. Furthermore, clinicians also need to
know the key concepts as described in the Mental Capacity
Act 2005. This subject has been ably covered by Nicholas and
Nicholas (TOG 2010;12:29–34).
A virtual issue of all TOG articles on mental health is
available at http://onlinetog.org.
ª 2016 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12256
The Obstetrician & Gynaecologist
http://onlinetog.org
Natural killer cells and reproductive health
a b,
Hsu Phern Chong MRCOG PhD, Siobhan M Quenby
a
NIHR Clinical Lecturer and Specialist Registrar in Obstetrics and Gynaecology, Division of Reproductive Medicine, Warwick Medical School,
Clinical Sciences Research Laboratories, Clifford Bridge Road, Coventry CV2 2DX, UK
b
Professor of Obstetrics and Honorary Consultant Obstetrician, Division of Reproductive Medicine, Warwick Medical School, Clinical Sciences
Research Laboratories, Clifford Bridge Road, Coventry CV2 2DX, UK
*Correspondence: Siobhan M Quenby. Email: s.quenby@warwick.ac.uk
Accepted on 22 July 2015
Key content
 Uterine and peripheral natural killer cells have distinct functions.
 Uterine natural killer cells play an important role in
decidualisation and implantation.
 There is evidence to suggest that disorders in uterine natural killer
cell physiology may lead to reproductive problems, such as
recurrent miscarriage, recurrent implantation failure and
pre-eclampsia.
 Current evidence does not support routine testing of uterine
natural killer cells and more research is needed.
Learning objectives
 Distinguish between peripheral and uterine natural killer cells.
Please cite this paper as: Chong HP, Quenby SM. Natural killer cells and reproductive health. The Obstetrician & Gynaecologist 2016;18:91–7. DOI: 10.1111/
tog.12256
Introduction
A number of maternal physiological adaptations are required
to facilitate continuing fetal development and survival.
Advances in the field of immunology have furthered our
understanding of these adaptations. For example, expression
of human leucocyte antigens (HLAs) differs in the placenta
and fetus.1,2 This is a highly logical adaptation since the
placenta is the first foreign tissue that comes into contact
with the decidua. Additionally, specific alterations in the
behaviour and repertoire of T-lymphocytes contribute to
tolerance of the fetus.3 The purpose of this review is to
describe the evolution of knowledge concerning a unique
subset of immune cells, uterine natural killer (uNK) cells, in
physiological and pathological reproductive states. For the
purposes of this review, we will describe natural killer cells
found in the peripheral circulation as peripheral natural killer
cells (pNK), and those found in the endometrium as uNK.
Origins of uterine natural killer cells
Central to host defence mechanisms, natural killer cells play a
vital role in the innate immune response. They are subtyped
ª 2016 Royal College of Obstetricians and Gynaecologists
2016;18:91–7
Review
PhD FRCOG *
 Counsel women with recurrent pregnancy loss about natural killer
cell testing.
Ethical issues

Investigation and treatment of women with recurrent miscarriage
or recurrent implantation failure is complex. The psychological
implications of these conditions may result in a myriad of
investigations and treatments of questionable benefit.
Keywords: natural killer cells / recurrent implantation failure /
recurrent miscarriage
by virtue of their expression of the CD56 and CD16 cell
surface antigens (Figure 1). The majority of pNK cells exhibit
CD16 but have fewer CD56 surface antigens; thus they are
typically described as CD56dim/CD16+. CD16 is responsible
for cell lysis.1 The primary function of pNK cells is to
recognise foreign antigens that are potentially detrimental to
the host organism. Recognition of foreign antigens initiates a
cascade of events that result in the eventual destruction
and/or removal of the foreign antigen.
Vertebrates distinguish native and foreign proteins
through the expression of a group of cell surface molecules
called HLAs, which are encoded by major histocompatibility
complex (MHC) genes.4 Digestion of intracellular proteins
generated by the invading organism results in peptides or
amino acids that bind to specific portions of HLA.4 This type
of antigen presentation sensitises natural killer cells and killer
T-lymphocytes resulting in the activation of cellular (i.e. non-
antibody-related) immunity and, consequently, apoptosis
and cytolysis of the presenting cell. Thus, these molecules
play a critical role in transplantation genetics and are
sometimes referred to as ‘transplantation antigens’.
HLA-A, HLA-B and HLA-C are responsible for triggering
this response and are often referred to as ‘classical’ MHC
91
 Natural killer cells and reproductive health

epithelial endometrial cells for implantation.17 Furthermore,

progesterone can also bind directly to the GR on uNK cells.15
Thus, differential regulation of uNK cells in the endometrium
exists and contrasts with that of pNK cells, which remains
unchanged in the proliferative and secretory phases of the
menstrual cycle.
The interest in natural killer cells in pregnancy loss was
borne out of the hypothesis that rejection of the fetus occurs
at the feto-maternal interface, leading to miscarriage or
recurrent implantation failure.18 If natural killer cells have
cytotoxic and cytolytic activity then it was proposed that this
would have an adverse effect on the fetus.
Figure 1. Hallmarks of uterine natural killer (uNK) cells. uNK cells
express CD56 cell surface markers and killer cell immunoglobulin-like
receptors (KIRs). Progesterone acts genomically on the intracellular Physiological response during the
glucocorticoid receptor (GR) as well as the progesterone receptor (P4) menstrual cycle
on surrounding stromal tissue to induce decidualisation. KIRs interact
with extravillous cytotrophoblast human leucocyte antigens. In humans, the endometrium undergoes a transformation
during the secretory phase to become the decidua, which is
capable of sustaining pregnancy. The human endometrium is
molecules.2 They are expressed on all nucleated cells with the unique in being able to undergo spontaneous decidualisation.
exception of extravillous cytotrophoblasts. Natural killer cells Under the influence of progesterone, endometrial stromal
express killer cell immunoglobulin (Ig)-like receptors (KIRs) cells proliferate and secrete cytokines and angiogenic factors
on their cell surface, which recognise and bind to the classical essential for decidualisation (Figure 2). Angiogenic factors
HLAs.2 Non-classical MHC molecules such as HLA-E, HLA- such as vascular endothelial growth factor-A (VEGF-A),
F and HLA-G present extracellular proteins that have been placental growth factor (PlGF) and angiopoietin-1 (Ang-1)
internalised into the cells.5 Both classical and non-classical induce proliferation, maturation and stabilisation of the
HLAs are inherited in a Mendelian fashion, with the entire
haplotype (i.e. combinations of classical and non-classical
HLAs) being inherited from each parent.6
uNK cells were first recognised as a unique cell type
present in abundance during the mid-secretory phase of
women with normal menses, and in the decidua of
terminated pregnancies.7 The cells were described as large
endometrial lymphocytes and were found to express the
CD56bright cell surface antigen.8 They were eventually named
uterine natural killer cells, based on a similar method used to
identify pNK cells.9 In the context of reproductive
physiology, the term ‘uterine natural killer cell’ is a
misnomer; their cytolytic activity is in fact much reduced
because of a lack of CD16.7,10 Instead, uNK cells release a
wide range of cytokines and angiogenic factors that are now
understood to play a critical role in decidualisation,
implantation and recognition of the embryo.11,12
Additionally, binding of HLA-G by the KIR2DL4 receptor
triggers release of pro-inflammatory and pro-angiogenic
cytokines.13 Interestingly, unlike their peripheral Figure 2. Decidualisation in the human endometrium. The human
counterparts, uNK cells lack the progesterone receptor endometrium undergoes spontaneous transformation to one capable
(PR).14 Instead, the actions of progesterone on uNK cells of sustaining a pregnancy (decidualisation). These changes are
are mediated via the glucocorticoid receptor (GR).15 mediated by progesterone. Secretion of angiogenic factors induces
spiral artery remodelling and migration and proliferation of uterine
Progesterone enhances the expression and activity of natural killer (uNK) cells (blue circles) in the endometrial stroma (yellow
11BHSD type 1 in decidualising human endometrial cells). The exact source of uNKs is unknown. Ang-1 = Angiopoietin 1,
stromal cells, thus increasing the conversion of cortisone to IL-15 = interleukin-15, PlGF = placental growth factor, VEGF = vascular
cortisol.16 Cortisol has a direct effect on the preparation of endothelial growth factor.

92 ª 2016 Royal College of Obstetricians and Gynaecologists

 Chong and Quenby

spiral arteries.19 Interleukin-15 (IL-15) messenger RNA
(mRNA) activity and protein expression are upregulated in
endometrial stromal cells.19 IL-15 binds to IL-15 receptors on
uNK cells, which induces proliferation of the uNK cells.19 As
a result, uNK cells are the predominant leucocyte and
account for at least 30% of the endometrial stroma during
the late secretory phase of the menstrual cycle,20 where they
can be found surrounding spiral arteries (but not veins)21
and glands. Progesterone binding to GR on uNK cells induces
interferon-gamma (IFNG), which further promotes
angiogenesis and uNK cell proliferation.1 Whether
increased numbers of uNK cells initiate or are the effect of
decidualisation is unclear.
Physiological response in pregnancy
By undergoing decidualisation, the endometrium becomes
receptive to the blastocyst.22 Implantation involves a series of
cellular processes by which the embryo is embedded into the
decidua. The outer cell mass layer of the blastocyst makes
contact with the epithelial cells of the decidua, then attaches
to and invades the endometrial stroma.23 If successful
implantation occurs, differentiation of the outer cell mass
into trophoblastic cells occurs; they subsequently secrete
human chorionic gonadotrophin (hCG), which is detectable
in maternal serum.24 As the syncytiotrophoblast progressively
invades the endometrial stroma, angiogenic factors, such as
IFNG, that are secreted by uNK cells activate the production
of nitric oxide, a potent vasodilator and inhibitor of smooth
muscle proliferation. Thus, the preferential exchange of
nutrients and oxygen in favour of the embryo is facilitated.1
This invasion is not detected by maternal immune cells,
partly because of the lack of classical HLA molecules as
mentioned previously. The extravillous trophoblast consists
of cytotrophoblast cells, interstitial and endovascular
trophoblast cells and placental-bed giant cells.25 They are
unique because they express only certain types of HLAs:
HLA-C, HLA-E and HLA-G (Figure 3). Binding of the
classical MHC molecule HLA-C to uNK cells occurs via
activating or inhibitory KIRs. Binding of the non-classical
HLA-E to CD94/NKG receptors on uNK cells is thought to
inhibit uNK cytotoxicity and mediate uNK–trophoblast
interactions.13 Binding of HLA-G to KIR2DL4 on uNK
cells blocks the lytic activity of uNK cells and increases
pro-angiogenic cytokines.24, 26 Thus, uNK cells may be
regarded as regulators of the depth of syncytiotrophoblast
invasion. The reader is directed to an excellent review and
illustration of placentation across a selection of mammalian
species by Moffett and Loke.24
The role of uNK in reproductive disorders
Recurrent miscarriage
The Royal College of Obstetricians and Gynaecologists
(RCOG) defines recurrent miscarriage (RM) as having lost
three or more consecutive pregnancies before 24 weeks of

Figure 3. Extravillous cytotrophoblast cells and uNK cell interaction. Extravillous cytotrophoblast (EVT) cells express non-classical human leucocyte
antigens (HLAs), which interact with killer cell immunoglobulin-like receptors (KIRs) found on uterine natural killer (uNK) cells. Consequently uNK
cell cytotoxicity is inhibited and angiogenic cytokine production increases. For example, nitric oxide production is mediated via interferon gamma
(black arrow) produced by uNK cells, resulting in vasodilation and inhibition of smooth muscle proliferation. Thus the depth of syncitiotrophoblast
invasion is regulated. B = blastocyst cavity, CT = cytotrophoblast, GR = glucocorticoid receptor, P4 = progesterone receptor.

ª 2016 Royal College of Obstetricians and Gynaecologists 93

 Natural killer cells and reproductive health
gestation.27 The incidence of RM is estimated to be between
1% and 3%, depending on the definition used.28 The causes
of RM are varied and can be categorised into maternal and
fetal causes. Maternal causes include pre-existing medical
conditions such as anti-phospholipid syndrome, polycystic
ovarian syndrome, and uterine causes such as malformations
of the uterus and fibroids. Fetal causes include chromosomal
abnormalities that may be congenital or arise de novo.
The interest in natural killer cells as a cause of RM
stemmed from a growing body of evidence demonstrating
natural killer cells as a biosensor of foreign antigens. The
emergence of uNK cell testing was the result of evidence
demonstrating the crucial role of uNK cells in decidualisation
and implantation. Alterations in the ‘form, fit and function’
of uNK cells were proposed as a mechanism to explain
miscarriage in women without pre-existing medical causes, as
well as those for whom a fetal cause could not be found.
In a study of the endometria of women with RM versus
controls, Lachapelle et al.29 identified a decrease in the
abundance of CD56bright/CD16– cells and an increase in the
CD56dim/CD16+ (i.e. pro-cytolytic) cell type. Women with
RM had higher uNK cell counts than controls.30 Although a
systematic review investigating the role of pNK and uNK cells
in RM failed to identify any differences in RM patients versus
controls, a key finding of this review was the lack of
standardisation for uNK cell estimation in the endometrium.
Studies included in the systematic review measured pNK by
virtue of a total proportion of natural killer cell activity, as
determined by flow cytometry or a specialised assay. The
normal range varied from one study to another.31 uNK cells
were measured using immunohistochemistry or flow
cytometry. Again, the normal range varied from one study
to another. Thus, this review was limited by the significant
heterogeneity of included trials and highlighted a lack of
good quality primary studies. In contrast to uNK cells, pNK
cells have no role in decidualisation or implantation, thus
testing for pNK cells in RM would appear to be of
little benefit.
Recurrent implantation failure
Implantation failure is typically diagnosed when there is
evidence that implantation has not taken place. It is nearly
impossible to quantify the incidence of this in spontaneous
conceptions; however, it is a diagnosis that is commonly
made following assisted reproductive techniques (ART).
There is a lack of standardisation in the definition of
recurrent implantation failure (RIF). The most commonly
used definition is “three or more failed treatment cycles”
followed by “two or more failed cycles”.32 An impaired
decidualised response prohibiting implantation is a
proposed cause.32
Some researchers have drawn similarities between patients
with RIF and RM, although their definitions would indicate
94
distinct entities. However, given the role of uNK cells in
decidualisation and implantation, it would seem biologically
plausible that uNK cells might have a role in RIF.
Nevertheless, a systematic review comparing women with
RIF versus controls did not identify a difference in pNK or
uNK cells in the endometrium.31 Again, study heterogeneity
prohibited any meaningful meta-analysis of the study
results.31 Thus, testing for pNK or uNK cells in the context
of RIF requires further research in the form of an adequately
powered, prospective, blinded observational study.
Impaired placentation
The concept of maternal rejection of paternal antigens is not
new, and in fact this purported ‘incompatibility’ sparked
trials investigating paternal leucocyte immunisation. There is
now clear evidence that this treatment does not increase the
pregnancy rate.33 However, some studies have now
demonstrated a plausible link between pre-eclampsia, the
paternal HLA-C molecule and uNK cells. The MHC
molecules are coded for by hundreds of alleles, which allow
innumerable conformational changes in the peptide-binding
portion. These polygenic and polymorphic changes are
critical for recognition of the myriad foreign peptides that
challenge the host immune system. Recent evidence suggests
that certain combinations of the paternally derived HLA-C
molecule may be associated with pre-eclampsia.6,21 The
absence of activating KIRs on maternal uNK cells and the
HLA-C2 allotype in the fetus have been demonstrated to
increase the incidence of pre-eclampsia.6 It was proposed that
the absence of this activating KIR resulted in impaired
trophoblast invasion and spiral artery remodelling; hallmarks
of pre-eclampsia.24
Management of patients
Recurrent miscarriage
Women with RM are a diverse population. As such,
treatment should be tailored to the cause, if found. For the
majority of women with unexplained RM, supportive
treatment early in pregnancy will result in a successful
pregnancy, although the precise mechanism underpinning
this is unclear. There is no evidence to support measurement
of pNK cells in women with RM.9 Current evidence does not
recommend routine measurement of uNK cells in women
with RM. This is partly because of a lack of good quality
studies describing a consistent technique for measuring uNK
cells, and a lack of evidence surrounding effective treatments.
Quenby et al.34 demonstrated that treatment with
prednisolone reduced the uNK cell count in women with
RM. This randomised controlled trial (RCT) randomised
women with RM (where RM was defined as having three or
more lost pregnancies) and a uNK cell count greater than 5%
to either treatment with prednisolone or a placebo. However,
ª 2016 Royal College of Obstetricians and Gynaecologists

the effects of treatment with prednisolone were not
significant; this could be explained by the sample size.
Further RCTs involving a larger cohort are required to
confirm this. That 57% of women with three or more
consecutive miscarriages involved in the study did not have
an elevated uNK cell count demonstrates the complex nature
of assessing the role of uNK cells in patients with RM.34
Kuroda et al.16 demonstrated a difference in glucocorticoid
signalling in patients with RM, and a higher proportion
of uNK cells close to the luminal epithelium. uNK cells
are normally found in surrounding perivascular cells and
glands in the endometrial stroma.20 Thus, it was proposed
that elevated uNK cells in patients with RM might be a
reflection of relative glucocorticoid deficiency in the
endometrial stroma, rather than a cause. Conversely,
steroid deficiency could be a reflection of impaired
decidualisation, in which uNK cells may be directly
involved.13 Treatment with corticosteroids aims to correct
this deficiency and therefore distribution of uNK cells in the
endometrial stroma.
Recurrent implantation failure
A 2012 systematic review demonstrated a beneficial effect of
endometrial injury inflicted either by hysteroscopy (and/or
curettage) or by pipelle biopsy in the cycle preceding embryo
transfer.35 The meta-analysis of four RCTs demonstrated a
higher cumulative pregnancy rate (risk ratio 1.71 [95% CI
1.40–2.09]). The precise mechanism behind an increase in the
cumulative pregnancy rate is unclear, especially when not all
women in the treatment group actually underwent curettage
or biopsy. However, the meta-analysis of a total of 411
patients in the treatment groups with 572 controls did not
demonstrate significant statistical heterogeneity, indicating
that the results are unlikely to be influenced by differences
between the trials. Three of the RCTs included women with
two or more unsuccessful cycles.35 One of the RCTs included
women with one or more unsuccessful cycles.35 The
proinflammatory response caused simply by
instrumentation of the uterus could result in recruitment
of immune regulatory cells,36 either transiently or
permanently. It is also unclear how long this effect is
expected to last, given the lack of studies comparing
endometrium harvested from one menstrual cycle to the
next, and beyond. We are unaware of studies investigating
the biochemical or clinical pregnancy rates after delaying
embryo transfer by more than one cycle following
instrumentation of the uterus.
Pre-eclampsia
A recently published large observational study demonstrated
an increased risk of pre-eclampsia in women who had three
ª 2016 Royal College of Obstetricians and Gynaecologists
Chong and Quenby
or more recurrent miscarriages.37 Given the role of uNK cells
in spiral artery remodelling, treatment aimed at reducing
oxidative stress could reduce the risk of pre-eclampsia.
Certainly, in vitro experiments demonstrated a beneficial
effect of antioxidants on syncytiotrophoblasts and spiral
artery remodelling.38 However, this failed to translate into
clinical benefit as a large RCT investigating treatment with
high-dose vitamin C and E did not demonstrate a reduction
in pre-eclampsia, and was associated with a reduction in
birthweight.39 A systematic review of nine trials confirmed
that high-dose vitamin C and E supplementation did not
reduce the risk of pre-eclampsia.40 This is, in part,
unsurprising as supplementation with these antioxidants
were only begun from the 20th week of pregnancy, well past
the period of spiral artery remodelling.
Wong et al.41 investigated the correlation between uNK
cell count and pre-eclampsia in 71 women with a history of
RM (three or more lost pregnancies) who subsequently had a
live birth. There was no significant difference in the incidence
of pre-eclampsia between women with a high uNK cell count
(defined as 13.9% of stromal cells staining positive for
CD56).41 Thus, on balance, screening for gestational
hypertension in women with a history of unexplained
recurrent miscarriage alone is unjustified on the basis of an
absence of preventative strategies.
Current controversies and avenues for
further research
A key gap in the current knowledge of uNK cells relates to
their origin. A number of hypotheses have been proposed.21
As a small cohort of pNK cells are CD56brightCD16–, it was
proposed that these pNK cells migrate into the
endometrium.42 It has also been suggested that uNK cells
are the result of cellular differentiation directly from bone
marrow stem cells. However, it has not been possible to
demonstrate the migration of bone marrow stem cells to the
endometrium. In fact, bone marrow stem cells are not known
to leave their site of origin. A more likely explanation is that
uNK cells are derived from a cohort of stem cells residing in
the endometrium itself.21 However, this is as yet unproven.
An area of controversy relates to the method by which
uNK cells are measured.31,43 Commonly described methods
include cell counting using formalin-fixed tissue stained for
CD56 cells and fluorescent activated cell-sorting. The reader
will note that a key limitation of both these techniques lies
with the availability of a specific antibody for uNK cells.
Furthermore, the threshold for normality differs, as does the
way in which uNK cell numbers are estimated by cell
counting in histological sections. Efforts are underway to
ascertain the most consistent method.
Because of the complex interactions between the blastocyst
and the epithelial layer of the endometrium, it is also unclear
95
 Natural killer cells and reproductive health
if recurrent miscarriage or implantation failure is the result of
aberrant uNK cell migration into the endometrium, or
signalling from the abnormal embryo. Evidence in favour of
the latter comes from a study of uNK cells using flow
cytometry in missed miscarriages.44 The decidua of
karyotypically abnormal pregnancies demonstrated a higher
uNK cell population than in karyotypically normal
miscarriages.44 However, given that the endometrium in
one cycle is dissimilar to the next, and no two embryos are
identical, testing this hypothesis would be difficult. In this
respect, the use of animal models may be useful.45
Whilst uterine instrumentation appears to improve
cumulative pregnancy rates, it is unclear if this procedure
results in regulation of the uNK cell population. To our
knowledge, no studies have investigated this directly, since
embryo transfer is undertaken in the cycle immediately after
uterine instrumentation. In this respect, research on the
impact of uterine instrumentation or ‘endometrial scratch
therapy’ on the uNK cell population would be useful. If
endometrial trauma increases the cumulative pregnancy rate,
then hypothetically, primary endometrial scratch could be
beneficial for all patients about to embark on ART and
embryo transfer and not just those experiencing RIF. The
benefits of a successful first cycle cannot be emphasised, given
the psychological, emotional and financial cost of assisted
reproduction.46 Furthermore, where the first cycle is offered
on the National Health Service (NHS), this could represent a
significant cost saving to the NHS. However, further research
is needed since the procedure can cause discomfort and is not
risk free.
Conclusion
Advances in molecular biology techniques have furthered our
knowledge and understanding of uNK cells in the context of
reproductive physiology and pathology. The causes of RM
and RIF comprise a spectrum of disorders in which uNK cells
may be partly involved. Future research in the field will
benefit women with a history of recurrent miscarriage or
recurrent implantation failure. Until such a time, uNK cell
testing should remain within the remit of research trials.
Disclosure of interests
Professor Quenby is an advisor on several international and
national committees: the European Society for Human
Reproduction and Endocrinology Early Pregnancy Special
Interest Group, the Medicines and Healthcare Products
Regulatory Agency (MHRA) Expert Advisory Panel for
Women’s Health, the Scientific Advisory Committee of the
Royal College of Obstetricians and Gynaecologists (RCOG),
the RCOG Preterm Labour Clinical Study Group, and the
RCOG Early Pregnancy Clinical Study Group. She is
currently an Associate Editor for BMC Pregnancy and
96
Childbirth and has served as an Associate Editor for
Human Reproduction.
Contribution to authorship
HPC wrote the manuscript and CPD questions. SMQ edited
the manuscript and CPD questions for content accuracy.
Both authors read and approved of the final version of
the manuscript.
Acknowledgements
Dr Hsu Phern Chong is currently funded by an NIHR
Clinical Lectureship.
Supporting Information
Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
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 DOI: 10.1111/tog.12264 2016;18:99–106
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Preimplantation genetic diagnosis: an overview and

recent advances
Jara Ben-Nagi MBBS MD MRCOG,a,* Paul Serhal MRCOG,
b
Sioban SenGupta BSc PhD,
c
Karen Doye BSc,
d

Dagan Wells PhD FRCPathe

a
Consultant Gynaecologist and Subspecialist in Reproductive Medicine, Centre for Reproductive and Genetic Health, Gray’s Inn Road, London
WC1X 8LD, UK
b
Consultant Gynaecologist and Medical Director, Centre for Reproductive and Genetic Health, Gray’s Inn Road, London WC1X 8LD, UK
c
Deputy Director, Institute for Women’s Health, University College London, Chenies Mews, London WC1E 6HX, UK
d
Lead preimplantation genetic diagnosis nurse, Centre for Reproductive and Genetic Health, Gray’s Inn Road, London WC1X 8LD, UK.
e
Associate Professor, Institute of Reproductive Sciences, Oxford Business Park, Oxford OX4 2HW, UK
*Correspondence: Jara Ben-Nagi. Email: jbennagi@gmail.com

Accepted on 9 October 2015

Key content  To learn about IVF, embryogenesis, the biopsy process and when
 Preimplantation genetic diagnosis (PGD) was developed for to transfer disease-free/carrier embryo(s).
couples at risk of transmitting a genetic disorder to their children.
Ethical issues
 Before PGD, options available to these couples were remaining
 PGD for ‘saviour sibling’: should couples be offered human
childless, prenatal diagnosis, gamete donation or adoption.
leucocyte antigen (HLA) matched treatment for a child who is in
 Couples requesting PGD have in vitro fertilisation (IVF) to
remission or who may develop the late onset condition?
produce embryos for biopsy, even if they are fertile.
 PGD for sex selection: should we offer sex selection for
Learning objectives ‘family balancing’?
 To understand indications for PGD.
Keywords: IVF / preimplantation genetic diagnosis
 To learn about the genetic work up required prior to
undergoing IVF.

Please cite this paper as: Ben-Nagi J, Serhal P, SenGupta S, Doye K, Wells D. Preimplantation genetic diagnosis: an overview and recent advances. The Obstetrician
& Gynaecologist 2016;18:99–106. DOI:10.1111/tog.12264

the process of IVF required for PGD, as well as when to

Introduction
biopsy and transfer embryos. We will also discuss ethical
Preimplantation genetic diagnosis (PGD) is an early form of debates of relevance to PGD. Preimplantation genetic
prenatal diagnosis (PND) for couples at risk of transmitting a screening (PGS), a method that uses similar technology to
genetic disorder to their children. Before PGD, the options PGD but aims to improve IVF success rates by testing
for such couples were remaining childless, PND, gamete embryos for chromosome aneuploidy, is not discussed here
donation or adoption.1 If couples opt for PND by chorionic since it lies outside the scope of this review.
villus sampling or amniocentesis and discover that the fetus is
affected by a genetic disorder, they must then decide to Indications for PGD
continue with the pregnancy or consider termination. If
couples decide to go through PGD, they will have to undergo Genetic diseases can be divided into the following categories:
in vitro fertilisation (IVF) procedures, even if they are fertile, monogenic (single gene) disease, chromosomal abnormalities,
in order to produce embryos for biopsy and testing. Only mitochondrial disorders or complex disease. Inherited disease
embryos found to be unaffected by the family’s inherited may arise at the level of the gene or the chromosome.2 There are
condition are transferred to the uterus. Consequently, the five modes of inheritance for monogenic diseases:
risks and the physical and emotional burden of PND can i) autosomal recessive
be avoided. ii) autosomal dominant
In this article, we discuss the indications for PGD and the iii) X-linked recessive
various new methods being used to make a genetic diagnosis iv) X-linked dominant
(including karyomapping and next-generation sequencing), v) Y-linked.

ª 2016 Royal College of Obstetricians and Gynaecologists 99

 Preimplantation genetic diagnosis
The first three of these are of the greatest relevance in
clinical practice. PGD can be applied to autosomal and sex-
linked disorders. Mutations can take the form of deletions,
insertions or substitutions of individual nucleotides or larger
regions of a gene. Duplications can also cause disease but
such occurrences are less common.2
Monogenic disease
In autosomal recessive conditions, individuals with a single
abnormal copy of a gene will not manifest the disease. Such a
person is known as a heterozygote or carrier. If a man and
woman in a couple are both heterozygotes, PGD may be
considered because they have a one in four chance of their child
inheriting two defective gene copies and therefore being
affected by the disease. The most common autosomal recessive
condition among Caucasians in Europe is cystic fibrosis.3
There are more than 1000 mutations responsible for cystic
fibrosis but the most common is a three-base-pair deletion
known as p.Phe508del.2 The most common autosomal
recessive condition worldwide is b-thalassaemia.4 There are
numerous distinct gene mutations causing beta-thalassaemia
and most affected individuals are carriers of two different
mutations (known as compound heterozygotes). This makes
PGD more technically challenging.
For autosomal dominant conditions, the affected
individual needs only to have one copy of the abnormal
gene for the disease to be expressed. In general, autosomal
dominant conditions tend to be less severe and life-
threatening than autosomal recessive conditions, or of later
onset. Statistically, half of the children of a patient affected
with a dominant disorder will inherit the defective gene and
therefore be affected. For some dominant disorders, the
pattern of inheritance can be complicated by incomplete
penetrance, late onset conditions and variable expression
(individuals with a mutation displaying unpredictable
differences in the severity of disease symptoms). It is
hypothesised that environmental or other factors may play
a role in disease expression.
Table 1 shows the mode of inheritance, risk of inheritance
to offspring and examples of inherited conditions. The most
common indication for PGD of a cancer predisposition
syndrome is mutation in the BRCA1 and BRCA2 genes,
associated with breast and ovarian tumours, and of variable
penetrance:5 the risk of female carriers of BRCA1 mutation
developing breast cancer or ovarian cancer before the age of
70 years is 60–80% and 30–60%, respectively, and the risk of
female carriers of BRCA2 mutations developing breast cancer
before the age of 70 years is 5–20%.
X-linked disorders occur as a result of a mutation on the X
chromosome, which may be recessively or dominantly
inherited. The majority of X-linked disorders are recessive
(Table 1). Female carriers are unaffected or can be mildly
affected as the other X chromosome carries a normal copy of
100
Table 1. Mode of inheritance, risk to offspring and examples of
inherited conditions.
Mode of Autosomal Autosomal X-linked
inheritance recessive dominant recessive
Risk to offspring 1:4 1:2 1:2 male
Example Cystic fibrosis Marfan’s disease Duchenne
Sickle cell Huntington’s muscular
anaemia disease* dystrophy
b-thalassaemia BRCA1 & Haemophilia
BRCA2**
Preimplantation Yes Yes Yes
genetic diagnosis
*late onset condition; **variable penetrance
the gene. It is expected that half of the sons produced by
female carriers will be affected with the disease, while the
other half will be unaffected. As the exact mutation for these
conditions is not always determined in particular families,
embryo sexing may be offered and only female embryos
transferred to the uterus. This avoids the possibility of an
affected male pregnancy, but has the disadvantage that half of
the discarded male embryos will be unaffected.
It should be borne in mind that some mutations occur
spontaneously (de novo) during gamete formation and are
responsible for sporadic cases (that is, the appearance of
affected individuals in families with no history of disease).
Some mutations arise after fertilisation of the oocyte and
during embryogenesis, leading to a proportion of cells
carrying the mutation (known as mosaicism).
Chromosomal abnormalities
At a chromosomal level, there are two separate entities for
chromosomal abnormalities: numerical or structural.
Numerical chromosomal abnormality (aneuploidy) arises as
a result of errors in meiotic or mitotic division. Aneuploidies
are the most frequent cause of spontaneous miscarriage and
implantation failure in couples undergoing IVF treatment.
Structural chromosome rearrangements occur as a result of
the simultaneous breakage of chromosomal segments that
then rejoin within the same or a different chromosome.
These mutations can be translocations, inversions or
deletions, or, more rarely, rearrangements such as ring
chromosomes. The carrier of a chromosome rearrangement
is phenotypically normal but problems arise during
gametogenesis. Couples in which one of the partners is a
carrier of a chromosomal rearrangement may have a history
of recurrent miscarriage or implantation failure, severe male
factor infertility or an affected child.
Human leucocyte antigen typing
Another indication of PGD is for human leucocyte antigen
(HLA) typing. The locus on chromosome 6 contains a
ª 2016 Royal College of Obstetricians and Gynaecologists

number of genes that encode cell surface antigen presenting
proteins. These genes play a major role in immune system
function.6 HLA matching can be used when a family has a
seriously ill child requiring stem cell transplantation in order
to cure an acquired disease (e.g. leukaemia) or genetic
diseases (e.g. thalassaemia).7,8 In the latter indication, PGD is
used to identify embryos that are unaffected by the familial
disorder, and which are also HLA-matched to the affected
sibling in need of a transplant. The identified embryos are
then transferred to the uterus. If a pregnancy results, stem
cells are harvested from the discarded umbilical cord at birth
and used to cure the sick sibling. The chance of obtaining an
embryo that is viable, free from the disease and HLA-
compatible is small (3/16). However, this strategy has been
successfully applied in a growing number of cases.9
Mitochondrial disorders
Mitochondrial disorders arise as a result of mutations in the
mitochondrial genome and are the most common group of
inborn errors of metabolism.10 These disorders show
complete maternal inheritance. They affect at least 1 in
5000–8000 individuals.10 Disorders of this type have variable
manifestations, which can affect single tissues or multiple
systems. Genetic counselling and diagnosis for patients at risk
of transmitting a mitochondrial disorder is challenging. This
is because of a phenomenon known as ‘the bottleneck’, in
which the population of mitochondria within the developing
oocyte is greatly reduced, then re-expanded. It can lead to a
highly variable and unpredictable phenotypic impact.
However, it has been shown recently that PGD offers a
reliable means of stratifying embryos in terms of their risk of
developing a mitochondrial disorder. This would permit
embryos at low risk to be transferred.10,11 In some cases
where all oocytes have a high mutational load, alternative
strategies such as oocyte donation may be considered.
Recently, ‘three person IVF’ has been approved by the UK
House of Lords to allow fertility clinics to carry out
Figure 1. FISH for chromosome abnormalities. Robertsonian translocation carrier 45,XY,der(13q;14q)(q10;q10). These images are courtesy of
Professor Joy Delhanty.
ª 2016 Royal College of Obstetricians and Gynaecologists
Ben-Nagi et al.
mitochondrial donation. This advanced IVF therapy would
help to eliminate mitochondrial diseases by substituting the
mother’s mitochondrial DNA with that from an anonymous
female donor.
Genetic work up and methods used to
make a genetic diagnosis
The polymerase chain reaction (PCR) was one of the first
techniques to be used for the purpose of PGD. It involves
amplifying a sequence of DNA on the Y chromosome to
reveal the sex of an embryo, thus avoiding the transfer of
potentially affected males in families with an X-linked
disorder.12 DNA is released from a lysed cell and the
mutation site is amplified to a detectable level. The amplified
DNA is then analysed for the presence or absence of the
mutation. Contamination with extraneous DNA and ‘allele
dropout’ (ADO) are the biggest threats to diagnostic
accuracy. ADO is a phenomenon specific to single cell PCR
that occurs as a result of a failure to amplify one of the two
alleles in a heterozygous cell. It can result in misdiagnosis
and, potentially, the transfer of an affected embryo. Advances
in DNA amplification, including fluorescent and multiplexed
PCR, allow the inclusion of additional informative linked
markers to give an accurate result even if ADO affects the
mutation site.13–15 Harper et al.16 reported a misdiagnosis
rate of 10/3727 (0.27%) over a 10-year period (1997–2007)
after embryo transfer attributed to contamination or allele
dropout. PGD for single gene disorders has shown the
highest pregnancy rate compared with other indications
(23% per oocyte retrieval and 29% per embryo transfer).16
Until recently, fluorescence in situ hybridisation (FISH)
was the most frequently used method for the analysis of
chromosome rearrangement (Figure 1). The biopsied
embryonic cells are spread onto a slide, the DNA in the
nucleus is denatured and DNA probes, labelled with
fluorochromes specific for the region of interest on the
101
 Preimplantation genetic diagnosis
chromosome, are allowed to hybridise.17 The misdiagnosis
rate of FISH for chromosomal rearrangements was reported
as 0.1% (3/2731) per embryo transfer, 0.5% (4/825) for X-
linked testing and 0.3% (1/354) for social gender selection.16
There are several reasons for FISH-specific misdiagnosis,
resulting from the technology or embryo biology. PGD for
chromosomal abnormalities has been shown to have a higher
number of embryos that are unsuitable for transfer because of
genetic abnormality than PGD cycles conducted for the
avoidance of a single gene disorder. As a result, pregnancy
rate is 17% and 26% per oocyte retrieval and embryo
transfer, respectively.16 There is little difference in pregnancy
outcomes between male and female carriers and type
of translocation.
Comparative genomic hybridisation (CGH) was first
introduced in 2000 to identify chromosomal aberrations
and aneuploidy.18,19 Whereas FISH is only capable of looking
at a handful of chromosomes in each cell, CGH can
interrogate all of the chromosomes in a sample. The
method requires whole genome amplification of the DNA
from the test cell, which is then labelled with a fluorochrome
and compared with DNA from a chromosomally normal
control. Microarray CGH is a more recent variation of CGH
technology. Like CGH it is a generic protocol, which can be
used to detect abnormal chromosome rearrangements while
simultaneously screening for aneuploidies.20 Unlike CGH the
analysis can be completed much more rapidly, avoiding the
need to cryopreserve embryos after biopsy.20 The first
reported clinical application of microarray CGH for
translocation carriers resulted in four healthy births.21
Karyomapping is a novel technique for diagnosing
single gene disorders, which has been available in the UK
since 2013.22 Approximately 300 000 single nucleotide
polymorphisms, distributed throughout the genome, are
Figure 2. Detection of a single gene disorder by karyomapping. Fingerprinting is unique to the chromosome that carries the defective gene. The
chromosomes are examined at 300 000 different points in the vicinity of the mutation (red M).
102
genotyped in the parents and also a close relative of a known
genetic status (e.g. an affected child of the couple). Embryo
biopsies can be tested using microarray analysis, revealing
whether the parental chromosome(s) carrying the
mutation(s) has (have) been inherited (Figure 2).22
Karyomapping enables diagnosis of more than one
monogenic disorder, or of a monogenic disorder and a
chromosomal rearrangement simultaneously. Furthermore,
karyomapping has a more rapid work up time compared
with conventional methods. Natesan et al.23 compared the
accuracy of karyomapping with direct mutation detection in
218 embryo samples from 44 PGD cycles. Karyomapping was
concordant with direct mutation testing in 213/218 (97.7%)
and the nonconcordant samples were all in consanguineous
regions.23 Karyomapping also enables the detection of most
forms of aneuploidy, which would improve implantation and
birth rate following the transfer of an unaffected embryo.
However, disadvantages of aneuploidy screening include
mosaicism and self-correction, resulting in potentially
euploid embryos being discarded.
Next-generation sequencing is a relatively new technology
that can potentially be used to ascertain the number of
chromosomes in an embryo biopsy sample or to diagnose
single gene disorders. The process involves fragmenting the
genome of the biopsied cells and sequencing the resulting
fragments. By counting the number of sequences derived
from each chromosome, it is possible to determine how
many copies of the chromosome were in each cell.24 Next-
generation sequencing has the potential for high-throughput
analysis of many samples. It also has the potential to
significantly reduce the costs of genetic testing, and work up
is not required to make a genetic diagnosis. Table 2 shows
the methods used to make a genetic diagnosis for various
genetic abnormalities and the work up time for each method.
ª 2016 Royal College of Obstetricians and Gynaecologists
 Ben-Nagi et al.

Table 2. Methods used to make a genetic diagnosis for various genetic abnormalities and the work up time.

Use/method Multiplex-PCR FISH CGH Karyomapping NGS

Single gene defect Yes - - Yes Yes

Chromosomal rearrangement Yes* Yes Yes Yes -
Aneuploidy screening - Yes** Yes*** Yes*** Yes***
Work up time 3–6 months 2–3 months None 4–6 weeks None

CGH = comparative genomic hybridisation; FISH = fluorescent in situ hybridisation; NGS = next generation sequencing; PCR = polymerase
chain reaction.
*Reciprocal and Robertsonian translocation only; **5–12 pairs of chromosomes only; ***all 23 pairs of chromosomes

poor sperm parameters (Figure 3). ICSI is carried out to

Work up and the process required for
maximise fertilisation and avoid maternal and paternal
couples to have IVF for PGD
contamination, which can result in misdiagnosis. Where
Couples requesting PGD undergo IVF treatment regardless of FISH is the diagnostic technique, IVF may be used rather
whether or not they are infertile. For PGD to be successful, it than ICSI.
occurs in an assisted reproductive technology clinic and
involves a dedicated team of clinicians, nurses, embryologists,
Embryogenesis, biopsy process and when
molecular biologists, genetic nurses and counsellors.1
to transfer
Details of the procedures involved in IVF treatment is
beyond the scope of this article, but the reader may refer to On day 1 after oocyte collection, a fertilisation check takes place
Balen.25 All baseline investigations are checked before the start to confirm the presence of both pronuclei 16–18 hours
of the IVF process (Table 3). An ovarian reserve test records postfertilisation. Cleavage stage embryos (3 days
the woman’s age and counts of basal follicle stimulating postfertilisation) are examined and the number of cells is
hormone, estradiol and antral follicles. Ovarian reserve determined. In laboratories with optimum culture conditions,
decreases with advancing age as a result of a decline in the cleavage stage embryos are cultured to blastocysts (5–6 days
ovarian pool of follicles.26 Ovarian reserve test scores, in postfertilisation) (Figure 4). About 46–76% of cleavage stage
particular anti-m€ullerian hormone and antral follicle counts, are embryos are cultured to the blastocyst stage.28 A blastocyst
strong predictors of quantitative ovarian response to controlled consists of an inner and outer cell mass (trophectoderm),
ovarian stimulation.27 Many PGD centres preclude women which give rise to the fetus and placenta, respectively.
from treatment because of poor ovarian reserve, which results in A biopsy can be performed on the first and second polar
low oocyte yield, cancellation and negative outcome. This avoids body, the cleavage stage embryo or blastocyst. Polar body
later distress and disappointment.26 biopsy is minimally invasive. However, its limitation is that
Intracytoplasmic sperm injection (ICSI) is used for the only the female contribution to the embryo is tested. Embryo
PGD of all single gene disorders and for infertile men with biopsy at the cleavage stage (6–8 cells) avoids this limitation
(Figure 5). It allows retrieval of 1–2 blastomeres (cells) and
has been the most common approach for monogenic
Table 3. Baseline investigations for a couple requiring preimplantation disorders.16 However, it provides limited genetic material
genetic diagnosis.
and time for performing analysis.29 There is also a risk of
Investigation Woman Man misdiagnosis as a result of ADO, which may occur with PCR-
based protocols.30
Hepatitis B & C Yes Yes With extended embryo culture, blastocyst biopsy (retrieval
HIV Yes Yes of 5–10 trophoectodermal cells from a 5–6-day-old embryo of
Rubella Yes N/A
100–150 cells) has been performed.31–33 Blastocyst biopsy is
Ovarian reserve test Yes N/A
(FSH/E2/AMH/AFC/BMI) more favourable than the removal of 1–2 cells from a 3-day old
2D scan* Yes N/A embryo of 6–8 cells. In a paired randomised clinical trial, day 3
Semen fluid analysis N/A Yes embryo biopsy led to 30% implantation and live birth
AFC = antral follicle count; AMH = anti-m€ ullerian hormone; compared with 50% of unbiopsied controls; a relative
BMI = body mass index (kg/m2); E2 = estradiol; FSH = follicle reduction of 39%.33 In contrast, 51% of biopsied blastocysts
stimulating hormone; N/A = not applicable. and 54% of non biopsied blastocysts had sustained
*part of the ovarian reserve test to check antral follicle count and
to screen the endometrium. implantation and progressed to delivery33. In addition,
blastocyst biopsy provides more DNA material for analysis,

ª 2016 Royal College of Obstetricians and Gynaecologists 103

 Preimplantation genetic diagnosis
Figure 3. Intracytoplasmic sperm injection: a single sperm is injected into each egg.
Figure 4. Photomicrographs from left to right represent embryonic development from a fertilised egg to a cleavage stage embryo and blastocyst.
which results in increased sensitivity and specificity
of PGD.29,33
Embryo biopsy, either at the cleavage or blastocyst stage,
followed by fresh embryo transfer has traditionally been
performed in PGD for monogenic diseases and for
chromosomal rearrangements.16,34 However, the advent of
vitrification has changed the situation; systematic reviews have
shown improved pregnancy rates with transfer of frozen and
then thawed embryos compared with that of fresh
embryos.35,36 Vitrification has the additional advantage that
the biopsied cell(s) can be transported to the PGD laboratory
for diagnosis prior to embryo transfer. Furthermore,
cryopreservation of embryos and transfer in a frozen–thawed
cycle minimises the risk of late onset ovarian hyperstimulation
syndrome, avoids suboptimal endometrium in stimulated
Figure 5. Embryo biopsy at cleavage stage (Day 3).
104
cycles and is associated with improved perinatal outcomes.36
Hence, several centres have started to implement this strategy
of blastocyst biopsy, cryopreservation and frozen–thawed
embryo transfer for PGD cases.29,31
There are various factors affecting the success of PGD
outcome. These factors include the woman’s age, her ovarian
reserve and the condition requiring diagnosis. There is a
decline in the number of follicles with advancing age.37 Poor
ovarian reserve is associated with high risk of cancellation and
diminished response to ovarian stimulation. Furthermore,
advancing chronological age is associated with reduced oocyte
quality. Subsequently, there is an increase in early pregnancy
loss and reduced live birth rate.38 For monogenic disorders,
PGD results in a higher proportion of suitable embryos for
transfer than for chromosomal rearrangements. Thus, overall
pregnancy rate is higher for single gene disorders.16 Lifestyle
factors, such as smoking and raised body mass index, are
associated with a lower pregnancy rate per embryo transfer
than in nonsmokers and nonobese women.39,40
Ethics
As PGD is an early form of PND, many believe that it can be
defended from an ethical point of view.17 However, others are
against PGD procedures. Apart from the classical religious views,
some of the ethical issues raised include the moral and legal status
of the embryos created, the biased selection of embryos created,
application of PGD in late onset conditions, creation of a ‘saviour
sibling’ and sex selection for family balancing. There are numerous
ethical issues within PGD practice; these are important but
beyond the scope of this article. Here we highlight a few examples.
ª 2016 Royal College of Obstetricians and Gynaecologists

Huntington’s disease is a late onset neurodegenerative
condition in which carriers with full penetrance alleles have a
50% risk of transmitting the mutation to their children.
Critics argue that a child carrying the mutation will have
“many decades of good and unimpaired living”.41 However,
Huntington’s disease is a severe condition and the penetrance
of the mutation is complete. It is insensitive and against the
patients’ autonomy to deny them access to PGD. Although
carriers of Huntington’s disease will have 3–4 decades of
healthy living, they will have the strenuous burden of the
eventualities of the disease. PGD is a viable alternative to
PND since it avoids the emotional and moral burden of
termination of pregnancy.42
Another application of PGD, which has been considered
controversial in the past, is HLA typing, which involves
selection of an embryo that is HLA-matched to a sibling. The
child born as a result of PGD is used as a stem cell donor for
a sick sibling,17 hence, the terminology ‘saviour sibling’. This
was first described by Verlinsky and colleagues9 in 2001,
where preimplantation HLA matching combined with PGD
for Fanconi Anaemia was performed. This case demonstrated
that PGD with HLA matching is feasible for preselecting
unaffected and HLA-compatible embryos as a source for
stem cell transplantation for a sick sibling.9 There have been
ethical arguments against creating a child for treatment of
their sick sibling. Opponents question how a child would feel
knowing that they were created for the sole purpose of saving
a sick sibling. However, proponents argue that a child will be
just as loved and cared for as their sick sibling, thus will not
be made to feel as though their sole purpose in life was to
donate stem cells.43 The child may also feel proud of having
contributed to saving their sibling’s life, rather than having
low self-esteem and self-worth.17 Furthermore, parents would
naturally volunteer an existing child to be a bone marrow
donor for their sick sibling.43,44
Another contentious indication for PGD is sex selection for
‘family balancing’. This is the situation where a family could,
for example, request a daughter if they already have one or two
sons.45 This should be differentiated from sex selection for a
family’s convenience.17 Opponents of sex selection for
nonmedical purposes believe it is discriminatory against
women and girls, sexist, and will encourage countries such as
India and China to promote the selection of male embryos. In
these cultures, there is a strong social pressure to have sons,
resulting in an imbalance in the sex ratio.46 It may also lead to
a form of coercion, or even harm to women who fail to give
birth to sons.46 Others also believe it is a form of modification
of children, which is an inappropriate and unfair use of
PGD.45 Proponents of family balancing argue that it gives a
family increased autonomy and avoids sex discrimination and
a skewed sex ratio.44,45 They believe that, provided sex
selection is not based on the idea of one gender being
superior to the other, it is neither sexist nor discriminative.
ª 2016 Royal College of Obstetricians and Gynaecologists
Ben-Nagi et al.
Furthermore, it is unlikely to lead to an imbalance in the sex
ratio since there is no preference for one gender over another
in Western societies.47 However, McCarthy48 highlighted that
even proponents admit it is not a healthcare necessity and
should not be funded by the state. Most countries (Australia,
Canada, France, Germany, Japan, Netherlands and United
Kingdom) prohibit sex selection for nonmedical reasons,
arguing that it is ethically unacceptable.49
Conclusion
PGD has revolutionised PND. For many couples, it has
mitigated the psychological burden of the risk of transmission
of an inherited disorder to their children and avoids the mental
and physical trauma of termination of an affected pregnancy.
Despite women going through the IVF process and its
associated risks, they feel the benefits of PGD outweigh the
risks, albeit without a guarantee of a live birth. Recent advances
in PGD methodology, such as karyomapping, have meant that
for couples who have a known affected relative, child or
pregnancy, the work up time to be able to make a genetic
diagnosis has dramatically reduced. Furthermore, the added
advantage of aneuploidy screening will minimise the risk of
implantation failure and miscarriage. However, powered
multicentre randomised controlled trials are required in the
future to assess the primary endpoint as to whether live birth is
significantly superior with the use of new technology compared
with conventional methods.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
JBN was responsible for conception and design, acquisition
of the data and drafting of the manuscript. PS, SS, KD, DW
were responsible for critical revision. All authors read and
approved the final version of the manuscript.
Supporting Information
Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
Infographic S1. Preimplantation genetic diagnosis
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2010;2:74.
16 Harper JC, Wilton L, Traeger-Synodinos , Goossens V, Moutou C, SenGupta
SB, et al. The ESHRE PGD consortium: 10 years of data collection. Hum
Reprod Update 2012;18:234–47.
17 Sermon K, Steirteghem A, Liebaers I. Preimplantation genetic diagnosis.
Lancet 2004;363:1633–41.
18 Voulaire L, Slater H, Williamson R, Wilton L. Chromosome analysis of
blastomeres from human embryos by using comparative genomic
hybridization. Human Genet 2000;106:210–7.
19 Wells D, Delhanty JD. Comprehensive chromosomal analysis of human
preimplantation embryos using whole genome amplification and single cell
comparative genomic hybridization. Mol Hum Reprod 2000;6:1055–62.
20 Wells D, Levy B. Cytogenetics in reproductive medicine: the contribution of
comparative genomic hybridisation (CGH). Bioessays 2003;25:289–300.
21 Alfarawati S, Fagouli E, Colls P, Wells D. First births after preimplantation
genetic diagnosis of structural chromosome abnormalities using
comparative genomic hybridization and microarray analysis. Hum Reprod
2011;26:1560–74.
22 Handyside AH, Harton GL, Mariani B, Thornhill AR, Affara N, Shaw MA,
et al. Karyomapping: a universal method for genome wide analysis of
genetic disease based on mapping crossovers between parental haplotypes.
J Med Genet 2010;47:651–8.
23 Natesan SA, Bladon AJ, Coskun S, Qubbaj W, Prates R, Munne S, et al.
Genome-wide karyomapping accurately identifies the inheritance of single
gene defects in human preimplantation embryos in vitro. Genet Med
2014;16:838–45.
24 Wells D, Kaur K, Grifo J, Glassner M, Taylor JC, Fragouli E, et al. Clinical
utilisation of a rapid low pass who genome sequencing technique for the
diagnosis of aneuploidy in human embryos prior to implantation. J Med
Genet 2014;51:553–62.
25 Balen A. Assisted conception. In: Balen A, editor. Infertility in practice. 3rd
ed. London, UK: Informa Healthcare; 2008. p. 289–326.
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26 Bhide P, Shah A, Gudi A, Homburg R. The role of anti-mullerian hormone as
a predictor of ovarian function. TOG 2012;14:161–6.
27 La Marca A, Giulini S, Tirelli A, Bertucci E, Marsella T, Xella S, et al. Anti-
Mullerian hormone measurement on any day of the menstrual cycle
strongly predicts ovarian response in assisted reproductive technology. Hum
Reprod 2007;22:766–71.
28 Langley MT, Marek DM, Gardner DK, Doody KM, Doody KJ. Extended
embryo culture in human assisted reproduction treatments. Hum Reprod
2001;16:902–8.
29 Kokkali G, Traeger-Synodinos J, Vrettou C, Stavrou D, Jones GM, Cram DS,
et al. Blastocyst biopsy versus cleavage stage biopsy and blastocyst transfer
for preimplantation genetic diagnosis of beta-thalassaemia: a pilot study.
Hum Reprod 2007;22:1443–9.
30 Wilton L, Thornhill A, Traeger-Synodinos J, Sermon KD, Harper JC. The
causes of misdiagnosis and adverse outcomes in PGD. Hum Reprod
2009;24:1221–8.
31 Chang LJ, Huang CC, Tsai YY, Hung CC, Fang MY, Lin YC, et al. Blastocyst
biopsy and vitrification are effective for preimplantation genetic diagnosis
of monogenic diseases. Human Reprod 2013;28:1435–44.
32 McArthur SJ, Leigh D, Marshall JT, de Boer KA, Jansen RP. Pregnancies and
live births after trophectoderm biopsy and preimplantation genetic testing
of human blastocysts. Fertil Steril 2005;84:1628–36.
33 Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage stage biopsy
significantly impairs embryonic implantation potential while blastocyst
biopsy does not: randomized and paired clinical trial. Fertil Steril
2013;100:624–30.
34 Chang LJ, Chen SU, Tsai YY, Hung CC, Fang MY, Su YN, et al. An update of
preimplantation genetic diagnosis in gene diseases, chromosomal
translocation and aneuploidy screening. Clin Exp Reprod Med
2011;38:126–34.
35 Wood MJ. Vitrification of oocytes. TOG 2012;14:45–9.
36 Kansal Kalra S, Ratcliffe SJ, Milman L, Gracia CR, Coutifaris C, Barnhart KT.
Perinatal morbidity after in vitro fertilization is lower with frozen embryo
transfer. Fertil Steril 2011;95:548–53.
37 Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated
disappearance of ovarian follicles in mid-life: implications for forecasting
menopause. Hum Reprod 1992;7:1342–6.
38 Nybo Andersen AM, Wohlfahrt , Christens P, Olsen J, Melbye M. Maternal
age and fetal loss: population based register linkage study. BMJ
2000;230:1708–12.
39 Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T.
Effect of body mass index on IVF treatment outcome: an updated systematic
review and meta-analysis. Reprod Biomed Online 2011;23:421–39.
40 Freour T, Masson D, Dessolle L, Allaoua D, Dejoie T, Mirallie S, et al. Ovarian
reserve and in vitro fertilization cycles outcome according to women
smoking status and stimulation regimen. Arch Gynecol Obstet
2012;285:1177–82.
41 De Wert G. Preimplation genetic testing: normative reflections. In: Harper J,
editor. Preimplantation Genetic Diagnosis. 2nd ed. Cambridge: Cambridge
University Press; 2009. p. 259–273.
42 Van Rij MC, De Rademaeker M, Moutou C, Dreesen JC, De Rycke M,
Liebaers I, et al. Preimplantation genetic diagnosis (PGD) for Huntington’s
disease: the experience of three European centres. Eur J Hum Genet
2012;20:368–75.
43 Shenfield F, Pennings G, Devroey P, Sureau C, Tarlatzis B, Cohen J, et al. Taskforce
5: preimplantation genetic diagnosis. Hum Reprod 2003;18:649–51.
44 Robertson JA. Extending preimplantation genetic diagnosis: the ethical
debate. Ethical issues in new uses of preimplantation genetic diagnosis.
Hum Reprod 2003;18:465–71.
45 Pennings G. Personal desires of patients and social obligations of
geneticists: applying preimplantation genetic for non medical sex selection.
Prenat Diagn 2002;22:1123–29.
46 Visaria L. Sex Selective Abortion in India: Some empirical evidence from
Gujarat and Haryana States [http://iussp2005.princeton.edu/papers/51652].
47 Dahl E. Procreative liberty: the case for preconception sex selection. Reprod
Biomed Online 2003;74:380–4.
48 McCarthy D. Why sex selection should be legal. J Med Ethics 2001;27:302–7.
49 Knoppers BM, Bordet S, Isasi RM. Preimplantation genetic diagnosis: an
overview of socio-ethical and legal considerations. Annu Rev Genomics
Hum Genet 2006;7:201–21.
ª 2016 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12253 2016;18:107–15
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Unexplained subfertility: diagnosis and management

a, b
Anupa Nandi MRCOG, * Roy Homburg FRCOG
a
Clinical Research Fellow, Homerton Fertility Centre, Homerton University Hospitals NHS Trust, Homerton Row, London E9 6SR, UK
b
Head of Research, Professor in Reproductive Medicine, Homerton Fertility Centre, Homerton University Hospitals NHS Trust, Homerton Row,
London E9 6SR, UK
*
Correspondence: Anupa Nandi. Email: anupa.nandi@gmail.com

Accepted on 14 August 2015

Key content Learning objectives

 Unexplained subfertility is diagnosed when standard investigations
(tests for ovulation, tubal patency and semen analysis) are all
normal. Between 30% and 40% of subfertile couples fall
into this category.
 In some couples, unexplained subfertility may result from subtle
undetectable factors; in other couples, it may be associated with a
genuine absence of any abnormality.
 There is currently much controversy about the selection of
appropriate management options for such couples, especially
following the National Institute for Health and Care Excellence
(NICE) guideline published in 2013. Therefore, a clear
understanding of the available evidence is essential for the
management of couples with unexplained subfertility.
 The potential contributing factors, diagnosis and management of
unexplained subfertility are discussed.
 To summarise the available recent evidence and help the reader
obtain a clear understanding of the continuing debates in this field.
 To help clinicians in counselling couples with
unexplained subfertility.
Ethical issues
 Should couples be advised to try to conceive naturally for 2 years
(regardless of their age) before they are offered treatment, even
though fecundity declines with age?
 What does the evidence suggest should be the first line of
management for couples with unexplained subfertility: intrauterine
insemination or in vitro fertilisation?
Keywords: IUI / IVF / unexplained infertility / unexplained
subfertility

Please cite this paper as: Nandi A, Homburg R. Unexplained subfertility: diagnosis and management. The Obstetrician & Gynaecologist 2016;18:107–15. DOI:
10.1111/tog.12253

contributing factors that can be responsible for

Introduction
subfertility (Box 1).
Unexplained subfertility is usually diagnosed if a couple fails
to conceive after 1 year of regular unprotected sexual Increased age of the female partner
intercourse even though investigations for ovulation, tubal As the female partner’s age increases, there is a decline in
patency and semen analysis are normal.1,2 For as many as the total number of remaining oocytes and their quality.9
30–40% of couples experiencing subfertility, their subfertility Because of the decline in oocyte quality, there is an
remains unexplained.3,4 While the average cycle fecundity increase in the embryonic aneuploidy rate in older women,
without treatment in women with unexplained subfertility is
1.3–4.1%,5 prognosis depends on the age of the female partner,
duration of subfertility and previous obstetric history.6,7
Box 1. Potential contributing factors for subfertility
Differences of opinion exist among fertility specialists
regarding the optimal treatment for couples experiencing
1. Low ovarian reserve
unexplained subfertility.8 This review aims to discuss the 2. Increased age (over 35 years) and low oocyte quality
diagnosis and management of unexplained subfertility and 3. Lifestyle factors
highlight the continuing controversies in this field. 4. Tubal function defects
5. Fertilisation defects
6. Implantation defects
7. Metabolic disorders, immunological and genetic factors
Potential contributing factors 8. Endometriosis
The diagnosis of unexplained subfertility is made by 9. Fibroids
10. Adenomyosis
exclusion. However, there are various potential

ª 2016 Royal College of Obstetricians and Gynaecologists 107

 Unexplained subfertility: diagnosis and management
which leads to nonimplantation and subfertility.10,11 A
study by Maheshwari et al.12 showed that women over 35
years of age were more likely to have unexplained
subfertility than their younger counterparts (OR 1.8, 95%
CI 1.4–2.2).
Lifestyle factors and unexplained subfertility
Smoking
Both active and passive smoking can adversely affect the
potential to conceive by reducing the ovarian reserve and by
altering the tubal function and the uterine environment.13 In
men, smoking impairs the fertilising capacity of the sperm by
reducing the mitochondrial activity and increasing the
DNA damage.14
Weight
Both obesity (defined as a body mass index above 30) and
being underweight (defined as a body mass index below 19)
can impair fertility even in young and regularly ovulating
women.15 Obesity can alter the follicular environment and
lead to oocyte incompetence and suboptimal embryo
quality,16 impairing implantation by negatively influencing
the endometrium.17 Obesity in men can contribute to
subfertility by causing DNA damage to sperm,18 decreased
libido and erectile dysfunction.19
Excessive alcohol intake
In men, even habitual consumption of over 5 units per week
has an adverse effect on sperm quality,20 although the true
impact on male fertility is unclear. Similarly, excessive
alcohol consumption in women may affect fertility by
decreasing the implantation rate, and causing luteal phase
dysfunction and abnormal embryo development.21 However,
there is still no universal agreement on the safe limit of
alcohol consumption.22
Other factors
Other factors that may have an impact on fecundity are
psychological stress, environmental exposure to pollutants
and use of illicit drugs and caffeine.23
Ovarian reserve
Ovarian reserve is the size of the remaining follicle pool in
the ovary at any given time. This often indicates the
capacity of the ovary to produce an oocyte that can be
fertilised and that results in a successful pregnancy. The rate
of follicular depletion varies between individuals, hence the
ovarian reserve.1 A woman’s age remains the single most
important factor in determining reproductive outcome;
ovarian reserve can only predict ovarian response in an
assisted reproductive technology cycle.24 Younger women
with low ovarian reserve are more likely to have cycle
108
cancellation caused by poor oocyte yield in in vitro
fertilisation (IVF), but once oocytes are retrieved they
have almost normal pregnancy rates.25
Tubal function defects
In addition to tubal patency, tubal function is important to
achieve successful pregnancy. Optimal tubal functions, such
as adequate ciliary motion and muscular activity, are
required for sperm–oocyte interaction and transport of the
embryo to the uterine cavity for implantation.26 Milder forms
of gonorrhoea and chlamydia infection can cause tubal
function defect without causing overt occlusion.27 Impaired
tubal function in otherwise patent tubes can lead
to subfertility.
Fertilisation defects
Subtle defects in oocyte and sperm leading to defective
fertilisation are possible causes of unexplained subfertility.
Sperm defects, such as abnormal acrosomes resulting in
poor or no zona pellucida binding28 and defects in
acrosome reaction resulting in failure of sperm–zona
pellucida penetration, are possible factors leading to
subfertility.29 Sperm DNA integrity may be a prerequisite
for normal fertilisation.30 An otherwise normal semen
analysis (as per the World Health Organization criteria)
may include sperm with altered genetic material induced by
various factors, such as defects in chromatin remodelling at
the time of meiotic division, post-testicular oxidative stress,
various environmental factors or advanced male age.31 High
levels of sperm DNA fragmentation can lead to reduced
fertilisation and increased miscarriage rates.32 A variety of
in vitro tests are available to detect sperm function defects,
such as the ability of sperm to penetrate cervical mucus
surrogate, quantification of sperm–zona binding
using hemizona pellucidae and hyaluronan binding
assay.33 The methods used to detect sperm DNA
fragmentation include the sperm chromatin structure
assay, the single-cell gel electrophoresis assay and the
terminal uridine nick-end labelling assay.34 However, the
clinical utility of these tests has been undermined by
the introduction of intracytoplasmic sperm injection
(ICSI).32 Hence, these tests do not form a part of
routine investigations.2,35
Implantation defects
A receptive endometrium is undoubtedly essential for
successful implantation and pregnancy. Various
biochemical factors like cytokines, leukemia inhibitory
factor, interleukin-1 and some chemokines (e.g. CX3CL1,
CCL14) may be involved in endometrial receptivity.36,37
Alterations of these factors in the endometrium can cause
subfertility. There are no standard tests to detect
these defects.
ª 2016 Royal College of Obstetricians and Gynaecologists

Immunological, metabolic and genetic factors
Dysregulation of the immune system and increased
production of autoantibodies have been suggested as
possible causes of unexplained subfertility. Autoimmune
antibodies like anti-thyroid, anti-ovarian, antinuclear,
antiphospholipid and anti-smooth muscle antibodies have
been associated with unexplained subfertility.38 Although the
exact role of these autoantibodies in the pathogenesis of
unexplained subfertility is unclear, various theories have been
proposed, such as the reduction of fertilisation rate,
interference with early implantation and modulation of
follicle-stimulating hormone (FSH) function, thereby
influencing ovarian function.39 In addition to altered
immune response, thrombophilic gene polymorphisms
(e.g. methylenetetrahydrofolate reductase gene
polymorphism) could be a cause of unexplained
subfertility.40 The possible mechanism could be the
causation of early implantation failure; however, more
evidence is needed to confirm this.41
Oxidative stress owing to an imbalance between reactive
oxygen species and antioxidants can be caused by factors
such as obesity, smoking, alcohol, recreational drug use and
environmental exposure to various toxins. Oxidative stress
has been linked both with male subfertility (as it causes
damaged sperm42) and with female subfertility, although the
mechanism of its action in females is not clear.43
Endometriosis
About 30% of asymptomatic women with otherwise
unexplained subfertility will be diagnosed with mild
endometriosis if laparoscopy is undertaken.44 The fecundity
of women with mild endometriosis is similar to that of
women with unexplained subfertility.45 There is no evidence
that medical treatment of mild endometriosis improves
fertility, and laparoscopic ablation can improve the live birth
rate only minimally.46–48 Hence, it is debatable whether mild
endometriosis in women with unexplained subfertility is
responsible for their subfertility.
Fibroids
The role of fibroids in causing subfertility is unclear. The
submucosal component of fibroids could be associated with
reduced conception but evidence remains scarce.49 There is
insufficient evidence that myomectomy for intramural or
subserous fibroids improves pregnancy rates.50
Adenomyosis
The impact of adenomyosis or its treatment on fertility
remains unsubstantiated because of a paucity of data.51
Therefore, subfertility in women with adenomyosis remains
unexplained for now.
ª 2016 Royal College of Obstetricians and Gynaecologists
Nandi and Homburg
Investigations for unexplained subfertility
Box 2 lists the tests performed to diagnose unexplained
subfertility. However, they have limitations and even the
most sophisticated tests can fail to detect subtle causes
of subfertility.
Detection of ovulation
Although there are various strategies to detect ovulation,
none of these tests can detect the quality of the oocyte. Tests
like urinary luteinising hormone estimation, midluteal phase
progesterone levels and ultrasound monitoring of follicular
growth might detect ovulation; however, they may fail to do
so if not performed at the right time of the menstrual
cycle.2,52 The presence of a regular menstrual cycle in itself is
a fair indicator of regular ovulation, and the chances of
anovulation in a woman with a regular menstrual cycle
are low.2,53
Tubal patency test
Assessment of tubal patency can be achieved by various
methods, such as hysterosalpingogram, hysterocontrast
sonosalpingography and laparoscopy and dye tests. None
of these methods, however, can detect tubal function
defects, which can potentially contribute to a
couple’s subfertility.
Semen analysis
This remains the most important investigation of the male
partner. In 2010, new World Health Organization criteria for
semen analysis using lower reference limits were released
(Table 1).2,54 Although semen analysis results provide
evidence of the concentration, motility and morphology of
Box 2. Investigations for unexplained subfertility
1. Detection of ovulation
a. Urinary luteinising hormone estimation
b. Midluteal progesterone
c. Ultrasound monitoring of follicular growth and confirmation of
follicular rupture.
2. Tubal patency test
a. Hysterosalpingogram
b. Hysterocontrast sonosalpingography
c. Laparoscopy and dye test
3. Semen analysis
4. Pelvic ultrasound and saline infusion sonography
5. Ovarian reserve testing
6. Laparoscopy in symptomatic women
7. Hysteroscopy in known uterine anomaly or pathology
109
 Unexplained subfertility: diagnosis and management
Table 1. World Health Organization 2010 criteria for normal semen
analysis
Criteria Parameters
Volume ≥1.5 ml
pH ≥7.2
Sperm concentration ≥15 9 106/mL spermatozoa
Total sperm count ≥39 9 106 spermatozoa
Total motility ≥40%
Progressive motility ≥32%
Vitality ≥58% live spermatozoa
Morphology ≥4% with normal morphology
sperm, they do not assess sperm function,55 which potentially
affects fertility.
Ovarian reserve tests
Tests available for ovarian reserve estimate basal FSH (early
follicular phase: day 2–5 of the menstrual cycle), inhibin A
and B, anti-m€ ullerian hormone, antral follicle count and
ovarian volume. The clomiphene citrate challenge test and
the exogenous FSH ovarian reserve test56 are also used.
Although the basal FSH test is the most frequently used, it
has significant intra- and intercycle variability, which limits
its reliability. In contrast, the anti-m€
ullerian hormone test
can be applied at any time during the menstrual cycle and
both this test and the antral follicle count have good
predictive value for ovarian stimulation response.57 Although
these tests predict the response to ovarian stimulation during
IVF, they are quite limited in their accuracy to predict the
chances of spontaneous conception.58,59 According to the
American College of Obstetricians and Gynecologists, it is
reasonable to encourage a woman to attempt to conceive
sooner rather than later if her ovarian reserve is found to be
diminished, as her window of opportunity to conceive might
be shorter than anticipated.60
Diagnostic laparoscopy
Women with unexplained subfertility with tubal patency
confirmed by normal hysterosalpingogram findings can still
have peritubal adhesions and/or endometriosis, which can
lower the chances of spontaneous conception.61 However, it
is difficult to predict which women would benefit most from
surgery and the concerns are increased cost, surgical risks and
women’s anxiety about potential surgery. Both the American
Society for Reproductive Medicine and the National Institute
for Health and Care Excellence (NICE) suggest laparoscopy
only in women with symptoms of comorbidities.2,62 In 2010,
Badawy et al.63 showed in a prospective randomised
controlled trial that diagnostic laparoscopy could be
postponed until after 3–6 failed cycles of ovarian
stimulation and timed sexual intercourse. While it is
110
reasonable to postpone laparoscopy in asymptomatic
women with normal hysterosalpingogram and no previous
history of pelvic infection or surgery, it might be useful in
selected women with multiple failed ovarian stimulation with
or without intrauterine insemination (IUI).64,65
Hysteroscopy
Hysteroscopy is a reliable way to diagnose and treat uterine
cavity anomalies like fibroids, polyps, septum and
adhesions.66 Women with unexplained subfertility might
benefit from hysteroscopic removal of submucous fibroids
and polyps to improve their chances of conceiving.67 Where
facilities are available, saline infusion sonography together
with 3D ultrasound can offer a less invasive outpatient
method to assess the uterine cavity with accuracy similar to
that of hysteroscopy.68
Treatment options for unexplained
subfertility
In the absence of a definitive diagnosis, the treatment of
unexplained subfertility remains empirical.4 Although
various treatment strategies are available, evidence is
lacking to confirm the superiority of one over the
other (Box 3).
Expectant management
The chances of spontaneous conception remain high in
couples with unexplained subfertility. In a multicentre
cohort study of 437 couples with unexplained subfertility,
74% of couples conceived spontaneously.7 A Dutch
multicentre trial randomised 253 couples with unexplained
subfertility and intermediate prognosis of natural conception
within 12 months, into an expectant management group and
an intervention group receiving IUI with controlled ovarian
hyperstimulation (COH) for 6 months. Similar continuing
pregnancy rates between the two groups were found (23% for
the intervention group and 27% for the expectant management
group)69 and there was a saving of €2,616 per couple in favour
of expectant management.70 Although expectant management
is a valid option for couples with a favourable prognosis, it
Box 3. Treatments for unexplained subfertility
1. Expectant management
2. Ovulation induction (clomiphene citrate, letrozole, gonadotrophins)
3. Intrauterine insemination (IUI) with or without ovarian stimulation
4. In vitro fertilisation (IVF)
NICE Guideline recommendations 2013: Do not offer IUI routinely
for people with unexplained subfertility who have regular
unprotected sexual intercourse. Consider IVF after 2 years of expectant
management.
ª 2016 Royal College of Obstetricians and Gynaecologists

remains challenging for clinicians to choose the best candidates
for this treatment. Twenty-nine prediction models have been
developed to help clinicians in this regard. However, they have
been developed for different patient profiles and lack thorough
external validation.71 Although these models can be used for
decision making in couples similar to the populations they
were developed for, there remain concerns regarding their
generalisability across different patient profiles. Moreover,
expectant management might not be acceptable to many
couples, as further attempts of natural conception add to
already existing stress and frustration.72 This leads to
overtreatment in many of these cases.73
Tubal flushing or perturbation
A possible therapeutic benefit of tubal flushing during
hysterosalpingogram has been known to gynaecologists for
over half a century. A range of oil-soluble and water-soluble
contrast media have been used for hysterosalpingogram and
have been linked to an increased chance of pregnancy. A
2007 Cochrane review summarised 12 trials involving 2079
participants and concluded that oil-soluble contrast media
increase the odds of live birth in comparison with no
treatment (Peto OR 2.98, 95% CI 1.40–6.37), but could not
confirm any benefit of oil-soluble versus water-soluble
media because of the lack of an appropriate trial.74
Possible mechanisms of action are mechanical (removal of
tubal debris), immunological (affecting peritoneal cytokines
and preventing peritoneal mast cell phagocytosis of
spermatozoa) or an effect on the endometrium to promote
implantation.75 Oil-soluble contrast media have now been
widely replaced by water-soluble contrast media because of
better image quality, early dissipation that removes the need
for delayed films and the possibility of granuloma formation
with oil-soluble media.
Clomiphene citrate with or without intrauterine
insemination
Clomiphene citrate acts as an anti-estrogen; it increases
endogenous FSH and thereby stimulates multiple follicular
developments. Although its effectiveness has been described
in cases of oligo-ovulation, questions have been raised
regarding its usefulness in otherwise ovulatory women.76 A
Cochrane review that summarised 14 clinical trials (1159
participants) found no clinical benefit of clomiphene citrate
for unexplained subfertility.77
Intrauterine insemination
IUI plus COH is widely used in cases of unexplained
subfertility before resorting to more invasive options like
IVF. It involves placement of washed sperms into the uterine
cavity around the time of ovulation. It has been used both
with and without ovarian stimulation. Two studies have
failed to show any benefit of IUI with or without COH over
ª 2016 Royal College of Obstetricians and Gynaecologists
Nandi and Homburg
expectant management in terms of live birth rates in couples
with unexplained subfertility.69,76 A 2012 Cochrane review
demonstrated that IUI plus COH increases the live birth rate
more than two-fold compared with IUI in a natural cycle
(OR 2.07, 95% CI 1.22–3.5).78 COH may correct subtle
ovulation problems and slightly increase the number of
oocytes available for fertilisation, thereby increasing the
chances of pregnancy.79 However, a major concern with
multiple follicle development in IUI plus COH is multiple
pregnancies.80 It has been demonstrated that by using mild
ovarian hyperstimulation and strict cancellation policies,
multiple pregnancy rates can be kept to approximately 10%
without reducing pregnancy rates.81 The 2013 NICE fertility
guideline recommends not routinely offering IUI to couples
with unexplained subfertility but proceeding directly to IVF
after 2 years of subfertility2. However, the success of IUI
depends on multiple factors82 and many clinics continue to
provide IUI plus COH for patients with unexplained
subfertility despite the NICE recommendation.83
In vitro fertilisation
With advances in assisted reproductive techniques, IVF has
emerged as a safe and successful treatment option. However,
debate continues about whether it should be the sole
treatment for couples with unexplained subfertility.
The first randomised controlled trial by Goverde et al.84 in
2000, compared six cycles of IUI in a natural cycle versus six
cycles of IUI plus COH versus six cycles of IVF in 258 couples
with unexplained and mild male factor subfertility. They
found that although pregnancy rate per cycle was better with
IVF compared with IUI in natural cycle or IUI plus COH
(12.2% versus 7.45% and 8.7%, respectively), there was no
difference in cumulative pregnancy rates (38% versus 31%
and 37%, respectively). However, pregnancy rates from IVF
have continued to improve and the current UK IVF success
rates are 27–32% for women under 37 years of age.85 One
might argue that the pregnancy rate reported by Goverde
et al.84 is outdated.
Reindollar et al.,86 in a large randomised controlled trial in
2010, demonstrated the effectiveness of moving to IVF after a
course of clomiphene citrate and IUI compared with
conventional treatments of clomiphene citrate and IUI,
followed by FSH and IUI, followed by IVF. Pregnancy rates
were not only higher, but moving to IVF sooner allowed
women to conceive 3 months earlier. However, the use of
clomiphene citrate and IUI prior to IVF in this trial can be
questioned, as there is much evidence against the use of
clomiphene citrate in ovulating women.77 The same group
compared two cycles of clomiphene citrate and IUI versus
two cycles of FSH and IUI versus immediate IVF in 154
couples with older women (38–42 years) and demonstrated
superior pregnancy rates and fewer treatment cycles with
immediate IVF.87
111
 Unexplained subfertility: diagnosis and management
In 2011, Custers et al.88 randomised 116 couples with
unexplained and mild male factor subfertility and
unfavourable prognosis of natural conception, to one cycle
of IVF-eSET (elective single embryo transfer) and three cycles
of IUI plus COH. They found similar live birth rates: 24% in the
IVF-eSET group and 21% in the IUI plus COH group (relative
ratio 1.17; 95% CI 0.60–2.30). Custers and colleagues have also
found IUI plus COH to be more cost effective.89
In 2012, a Cochrane review summarised the trials for
unexplained subfertility treatment and found no evidence for
the effectiveness of IVF over IUI as a first line treatment. No
significant differences in multiple pregnancy or ovarian
hyperstimulation syndrome rate between the two treatments
were found.90
Bensdorp et al.91 shed new light on the effectiveness of
IUI and IVF for couples with subfertility in their 2015
study. In this multicentre randomised controlled trial
involving 17 centres in The Netherlands, 602 couples with
unexplained and mild male factor subfertility and
unfavourable prognosis for natural conception were
randomised to three groups: three cycles of IVF and
single embryo transfer, six cycles of IVF in a modified
natural cycle, and six cycles of IUI plus COH. The
researchers found comparable singleton live birth rates
(52% versus 43% and 47%, respectively) and comparable
Figure 1. The authors’ suggested algorithm on the best treatments for unexplained subfertility. FSH = follicle-stimulating
hormone, IUI = intrauterine insemination, IVF = in vitro fertilisation.
112
multiple pregnancy rates (6% versus 5% and 7%,
respectively) between the treatment arms.
The literature indicates that although the per-cycle success
rate of IUI is lower than that of IVF (9% versus 22%),92
cumulative IUI success rates are comparable to those of IVF.91
From the perspective of couples, IUI remains less invasive, less
stressful and less time consuming than IVF. Perinatal outcome
for singletons is better with IUI than with IVF.93 Hence, IUI
plus COH remains a very realistic treatment option.
Intracytoplasmic sperm injection
In 5–25% of cases of unexplained subfertility, no fertilisation
has been reported with conventional IVF procedures.94 This
could be due to occult abnormalities in sperm or oocytes.95,96
ICSI has been advocated for these couples.97 However,
studies have failed to show any benefits of ICSI over IVF in
terms of clinical pregnancy rates (33% IVF versus 26%
ICSI)98 or live birth rates (46.7% IVF versus 50% ICSI).99 A
2013 systematic review summarised 11 studies with a total of
901 couples and showed a higher fertilisation rate with ICSI
compared with IVF (RR 1.49, 95% CI 1.35–1.65) and the
need to treat five participants with ICSI to prevent one case
of fertilisation failure.100 Because of the paucity of data, the
review authors could not analyse the pregnancy outcome
from ICSI compared with IVF. Both the American Society for
ª 2016 Royal College of Obstetricians and Gynaecologists

Reproductive Medicine and the NICE practice committees
do not recommend routine ICSI for unexplained
subfertility.2,101 However, use of ICSI for at least some
oocytes (split IVF–ICSI) offers several benefits. It allows
detection of fertilisation defects, reduces the risk of failure to
fertilise and identifies couples that would need ICSI in
subsequent cycles.
Cost analyses
One of the important factors to consider is the cost of
treatments. It is difficult to perform this kind of analysis
because of differences in the cost of treatment between
different countries and different regions in the same country.
The study by Reindollar et al.86 in 2010 found a saving of
$2,624 per couple in the immediate IVF arm. However, the
cost they analysed was the insurer’s charge data, which could
be quite different from the cost of fertility treatment when it
is government funded. Similarly, a cost-effectiveness analysis
by Chambers et al.102 in 2010 showed IVF to be cost effective.
However, this study can be criticised because it was a cohort
study and the study population was drawn from private
clinics. In contrast, van Rumste et al.89 showed cost saving
with three cycles of IUI plus COH in comparison to one cycle
of IVF-eSET in a randomised controlled trial from The
Netherlands, where fertility treatments are covered by
healthcare insurance. These differences between private and
government-funded treatment reduce the generalised
applicability of this kind of analysis.
Conclusions
A range of treatment options is available for unexplained
subfertility; however, the right treatment strategy needs to be
tailored according to the individual circumstances. Factors
like the age of the female partner, duration of subfertility and
previous pregnancies should be considered in choosing the
optimal treatment protocol. One suggested algorithm is
presented in Figure 1. There is a lack of agreement between
clinicians regarding management and this is aggravated by a
lack of strong evidence, impatience on the part of
practitioners and couples and financial considerations. This
frequently leads to overtreatment in cases suitable for
expectant management or IUI with gonadotrophic ovarian
stimulation. While clomiphene with or without IUI is not
suitable for unexplained subfertility, 3–4 cycles of IUI and
ovarian stimulation with gonadotrophins could be beneficial
for many suitable couples. IVF should remain the first choice
of treatment only for those with a long duration of
subfertility, where ovarian reserve is deteriorating or when
conservative treatment has failed.
Disclosure of interests
There are no interests to disclose.
ª 2016 Royal College of Obstetricians and Gynaecologists
Nandi and Homburg
Contribution to authorship
AN carried out the literature search and wrote the draft
article. RH contributed to the final version of the article.
Supporting Information
Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
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 DOI: 10.1111/tog.12254 2016;18:117–25
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

The role of transabdominal cervical cerclage techniques in

maternity care
a, b
Donald Gibb MD MRCP FRCOG, * Ertan Saridogan PhD FRCOG
a
Consultant Obstetrician, The Birth Company, 137 Harley Street, London W1G 6BF, UK
b
Consultant Gynaecologist, University College London Hospitals, Institute for Women’s Health, 2nd Floor, North Wing, 250 Euston Road, London
NW1 2PG, UK
*Correspondence: Donald Gibb. Email: Donald@thebirthcompany.co.uk

Accepted on 14 August 2015

Key content Learning objectives

 The transabdominal cerclage procedure aims to strengthen the
cervix by placing a suture at the level of the internal os. The main
indications for transabdominal suture are a grossly disrupted
cervix, an absent vaginal cervix, and previous failed elective
vaginal cerclage.
 The transabdominal cerclage was first described in 1965 and the
laparoscopic modification was first reported in 1998. Published
reports suggest very high neonatal survival rates with
both approaches.
 Laparoscopic cerclage has the general advantages of minimal access
surgery, such as avoiding a large abdominal incision, short hospital
stay and quick recovery.
 Potential complications include bleeding from uterine vessels and
loss of pregnancy for non-interval procedures. The other reported
complications, such as suture migration, rectouterine fistula,
uterine rupture and intrauterine growth restriction, are rare.
 The place of transabdominal cerclage in preventing pregnancy loss
and preterm birth remains a subject of debate and there is a need
to audit the outcomes.
 To better understand the role of the cervix in miscarriage.
 To understand the indications for referral for transabdominal
cervical cerclage.
 To understand the obstetric and neonatal outcomes of women
after this procedure.
Ethical issues
 To consider the place of this invasive procedure, with its
consequent possible complications, in the management of
cervical weakness in women who often have poor
reproductive histories.
 To consider the lack of national and international availability of
this potentially valuable procedure.
 To consider an effective system of assessment of this procedure in a
referral context, and the future of this procedure.
Keywords: antenatal care / cervical suture / gynaecological surgery /
laparoscopy / miscarriage

Please cite this paper as: Gibb D, Saridogan E. The role of transabdominal cervical cerclage techniques in maternity care. The Obstetrician & Gynaecologist
2016;18:117–25. DOI: 10.1111/tog.12254

cases of women with repetitive midtrimester pregnancy loss,

Introduction
Cervical cerclage, sometimes referred to as cervical suture or
stitch, is a procedure carried out to prevent pregnancy loss
due to cervical weakness, by placing a suture around it. There
has been some confusion about the role of cervical cerclage in
modern perinatal care. Weakness (also called incompetence)
of the uterine cervix, which is sometimes overdiagnosed, can
cause pregnancy loss, and this can often be repetitive. A study
by the Medical Research Council (MRC) and the Royal
College of Obstetricians and Gynaecologists (RCOG)1
prompted critical thinking as to which indications should
be considered for cervical cerclage but may have resulted in
some women not having a cervical suture when it was
needed. The advent of cervical imaging by ultrasound
scanning and further critical analysis should contribute to a
better understanding. A particular challenge is presented in
and for whom no vaginal cervix can be seen (or sometimes
even felt because of previous cervical conisation or other
trauma). Benson and Durfee2 addressed this as long ago as
1965 in their report of the transabdominal open procedure
for cervical cerclage. With more recent developments in
minimal access surgery a new approach has been suggested
for this operation. We seek to clarify any lack of
understanding in this area and make the case for a national
database and audit of this unusual but valuable procedure for
women having difficulty carrying a pregnancy to term.
Late miscarriage and extreme
premature birth
The term miscarriage is preferred to abortion and cervical
weakness is preferred to incompetence. The use of

ª 2016 Royal College of Obstetricians and Gynaecologists 117

 Techniques in transabdominal cervical cerclage
‘incompetence’ should be avoided as it can have negative
connotations for women.
Late miscarriage and extreme premature birth are very
traumatic for a couple, physically and particularly
psychologically. It may lead to them delaying or even
deciding against a future pregnancy. Simplistic concepts
lead to these women being treated with transvaginal cervical
cerclage irrespective of the cause. The MRC/RCOG study1
indirectly addressed this by showing that with wide
indications for cerclage, even following one previous
pregnancy loss, cerclage made little difference to the
outcome. However, when a subgroup with three late
miscarriages was considered, a significant positive effect of
transvaginal cerclage was observed. The conditions shown in
Box 1 and Figure 1 can contribute to midtrimester
pregnancy loss.
It appears that the integrity of the cervix is partly assured
by its length. In normal pregnancy the cervix is more than
40 mm long at 18 weeks of gestation. This is manifested by
approximately 2 cm of vaginal cervix and 2 cm of
supravaginal cervix. The bladder lies anterior to the cervix
and the internal os cannot easily be reached without pushing
the bladder up when approached from the vaginal route. The
pouch of Douglas is relatively free and the uterosacral
ligaments pass into the posterolateral part of the uterus at
about the level of the internal os. Logically, a cervical
strengthening suture would be most effective at the internal
os.3 Use of a Shirodkar technique4 is more likely to achieve
this, while use of a McDonald technique5 may result in a
lower suture.
Clinical assessment
Ideally, a patient who is being considered for transabdominal
cerclage should be assessed and receive counselling before a
future pregnancy. Occasionally, women present without a
previous pregnancy loss, but more often there is a history of
repetitive midtrimester pregnancy loss. A careful history and
examination should elicit the role of any of the confounding
factors presented in Box 1 and Figure 1. Persistent placental
bleeding after 8 weeks of gestation is associated with
Box 1. Causes of midtrimester pregnancy loss.
 Bleeding
 Infection
 Uterine malformation
 Multiple pregnancy
 Polyhydramnios
 Cervical weakness (incompetence)
 Preceding chorionic villus sampling/amniocentesis (rarely)
 Fibroids (very rarely)
 Maternal illness, e.g. malaria, listeriosis
118
midtrimester membrane rupture and pregnancy loss. It is
not an indication for cervical suture in the current or future
pregnancies. Midtrimester pregnancy loss is not uncommon
in multiple pregnancy; it is possibly caused by an
overdistended uterus stretching the cervix. These patients
are sometimes told that their cervix is weak and to expect to
have a cervical suture in their next pregnancy. If their next
pregnancy is a singleton pregnancy then this may not be
necessary; they should have ultrasound assessment of cervical
length at 17 weeks of gestation. Infection may be a
confounding factor. Histopathological examination of
midtrimester loss tissue may show chorioamnionitis, but
this does not mean it was causative. There should be some
basic microbiological surveillance of a future pregnancy.
Fibroids rarely cause midtrimester loss unless particularly
large or submucous.6
Visual and digital examination of the cervix is crucial. The
mistake of taking a patient to the operating theatre and
finding that a vaginal suture is impossible must be avoided.
Visual and digital examinations will detect cervical
lacerations (Figure 2) and cervical shortening (Figure 3).
This may be complemented by a transvaginal scan of
the cervix.
Case selection: transvaginal or
transabdominal suture?
It has been said3 that the indications for transabdominal
suture are a grossly disrupted cervix (Figure 2) or an absent
vaginal cervix (Figure 3), and previous failed elective vaginal
cerclage. The first two are the most obvious indications.
Questions must be asked about how the previous failed
vaginal cerclage was done and whether there were other
circumstances leading to its failure. If there is a good portion
of the vaginal cervix present, we believe that one option is a
well-placed Shirodkar suture with bladder reflection, an
anterior knot and short trimming of the ends, which are then
buried by closure of the vaginal skin incision. There is a
paucity of data concerning the relative merits of a McDonald
suture compared with a Shirodkar suture.7 A woman who has
had a failed McDonald suture may not be willing to do the
same again; we would offer a formal Shirodkar technique,
which is higher and buried, rather than moving directly to a
transabdominal approach. We think that a suture nearer to
the internal os and more isolated from sources of infection
may be more effective.
Transabdominal open surgical
cervical cerclage
The obvious candidate for the transabdominal technique is a
woman with a severely damaged cervix and midtrimester loss
where a vaginal suture is impossible. Gibb and Salaria8 used
ª 2016 Royal College of Obstetricians and Gynaecologists

Figure 1. Multifactorial aetiology of preterm birth and miscarriage.
Figure 2. Grossly disrupted cervix.
the open surgical technique in pregnancies at King’s College
Hospital, London, UK (Figures 4 and 5). Mersilene
[Ethicon US, LCC, USA] tape RS22 was used, which has a
smaller needle than RS21. It was done following a detailed
ª 2016 Royal College of Obstetricians and Gynaecologists
Gibb and Saridogan
ultrasound scan at about 11 weeks of gestation, and when the
first trimester miscarriage risk had passed. In his personal
experience of 98 cases, the first author found the following
practical points to be useful:
1. An earlier operation (9–12 weeks of gestation) is easier,
particularly when there is a multiple pregnancy.
2. Obesity and abdominal scarring from previous surgery
make for a more difficult operation.
3. Regional anaesthesia may not be adequate, as experienced
in one case requiring conversion to general anaesthesia.
We have used general anaesthesia whereas other authors
have reported satisfactory use of regional anaesthesia.
Data for the first 50 cases were published in 1995.8
Consistent with other published studies,9–17 these data
showed a greater than 85% successful pregnancy rate, with
some women having two or even three consecutive
pregnancies in series, each delivered by caesarean section.
In complicated cases, for example where membrane rupture
or intrauterine death in the midtrimester occurred, then the
suture was removed by posterior colpotomy, thus avoiding
the need for a second laparotomy during pregnancy failure. A
further 49 cases in a referral practice have been undertaken
119
 Techniques in transabdominal cervical cerclage

Table 1. In summary, these indicate improved pregnancy

outcomes following open transabdominal cerclage in women
with previous multiple losses.
Randomised controlled trials of this technique are difficult
to implement because of the small numbers of women to
select from, and the fact that women would be unlikely to
submit to randomisation against no cerclage. One study19
currently underway is exploring previous failed elective
vaginal cerclage with a three-way randomisation to
McDonald cerclage, Shirodkar cerclage and transabdominal
cerclage. These may be in pregnancy or before pregnancy.
This trial naturally excludes women with midtrimester losses
who have no vaginal cervix on which to operate.
While the results following transabdominal cerclage are
excellent, the transfer of surgical skills to younger colleagues
is difficult for this relatively unusual procedure. There are not
enough cases at any one centre to facilitate apprenticeship.
The operation, although not technically difficult in the well-
selected patient, is an open technique during pregnancy and
Figure 3. Absent vaginal cervix, flush vaginal vault. is thus stressful for the surgeon. The threat of complications,
such as bleeding that is difficult to control and iatrogenic
between 1996 and today.18 All women except three had living pregnancy loss, is very real, though fortunately occurs rarely.
children born close to or at 38 weeks of gestation. One was It is a particularly challenging operation in women with
born at 32 weeks because of severe maternal anxiety and previous abdominopelvic surgery and in those with a
survived without deficit. Another was found to have a lethal significantly raised body mass index.
fetal abnormality at 18 weeks of gestation and had a There have been a few reports of successful transabdominal
therapeutic abortion. A third pregnancy requiring cerclage performed as a prepregnancy open procedure.20,21
hysterotomy was lost intraoperatively because of heavy Dawood and Farqhuarson22 reported on a comparison of 21
revealed vaginal bleeding on account of a central low preconceptual cases and 40 first trimester cases of open
placenta. The survival rate of normally formed babies was transabdominal cervical cerclage, concluding that
97.6%. This may be attributed to improved patient selection preconception cerclage yields a more favourable
and reaching a higher point on the learning curve. pregnancy outcome.
There is a limited number of published studies9–18 with
more than 12 cases in the series. These are summarised in
Evolution of the technique
With the advance of laparoscopic surgery, the opportunity
Table 1. Published series with more than 12 cases of open
has arisen for collaboration between obstetricians and
transabdominal suture in pregnancy.
minimal access gynaecologists to perform the cerclage
Neonatal Neonatal procedure laparoscopically. The required technique has
survival survival been modified for the laparoscopic approach and there
before after
suture suture
have been a number of publications on this. The authors of
First author Year Cases Country (%) (%) this article have followed a similar approach, and our
preliminary results with the laparoscopic approach showed
Olsen9 1982 17 Denmark 12 88 success rates similar to results published in the literature.23
Van Dongen10 1991 16 Netherlands 36 96
Novy11 1991 20 USA 20 90
Cammarano12 1995 23 USA 18 93 Laparoscopic technique
Gibb8 1995 50 UK 6 85
Anthony13 1997 13 Scotland 16 86 The first laparoscopic transabdominal cerclages were
Lotgering14 2006 101 Netherlands 24 93 reported by Scibetta et al.24 and Lesser et al.25 in 1998.
Debbs15 2007 75 USA 3 96
Umstad16 2010 58 Australia 22 100 Lesser et al.25 placed their first laparoscopic suture in a
Knudtson17 2012 15 USA 7 73 pregnant woman at 11 weeks of gestation. The operation
Gibb18 2012 43 UK 9 98 lasted 2 hours 20 minutes and there was some bleeding from
one of the uterine arteries, which was controlled with clips

120 ª 2016 Royal College of Obstetricians and Gynaecologists


Figure 4. Transabdominal cerclage: anteroposterior view.
and packing. The pregnancy continued and the baby was
delivered by caesarean section at 35 weeks of gestation
because of gestational diabetes. The suture was removed
during the operation. Scibetta et al.24 described an interval
laparoscopic cerclage procedure in an infertile woman who
had no visible ectocervix tissue because of two previous cone
biopsies for cervical adenocarcinoma. The procedure was
uncomplicated: the woman conceived following in vitro
fertilisation embryo transfer (IVF-ET) 10 weeks later and the
baby was delivered by caesarean section at 38.5 weeks
of gestation.
Since the publication of these two cases, a number of
reports have discussed the surgical and obstetric outcomes of
laparoscopic cerclage, including robotic assisted procedures.
A 2013 review26 included 25 articles published until May
2012 and identified 162 laparoscopic and three robotic
assisted cervical cerclage procedures. Of the 162 laparoscopic
procedures, 102 were interval procedures and 60 were carried
out during pregnancy. Two of the robot-assisted procedures
took place during pregnancy and one was an interval
procedure. Following all these groups of procedures, the
median gestational age at delivery was 37 weeks.
Since the cut-off date (May 2012) of the above review,
three further case series have been published. One of these
ª 2016 Royal College of Obstetricians and Gynaecologists
Gibb and Saridogan
reported 52 interval procedures from Denmark27 and the
second article,28 from two centres in Holland and the USA,
included 66 interval procedures. The third article from
Australia29 reported on 64 procedures, three of which were
during pregnancy. In the Danish study, of the 45 registered
pregnancies, 36 progressed beyond 16 weeks; 30 (83.3%) of
these were delivered by caesarean section after 36 weeks, with
a mean gestational age of 37.4 weeks. In the Dutch–American
study, 35 pregnancies were registered; 25 (71.4%) of these
delivered at or beyond 34 weeks and the total survival rate
was 90%. Three (8.6%) experienced a second trimester loss.
There were no significant complications in the Danish study
and the Dutch–American study reported three minor
complications (uterine perforation and pelvic infection). In
the Australian study, 34 out of 64 women had 35 pregnancies
following the procedure. Eleven of these were early
miscarriages, ectopic pregnancies, intrauterine demise due
to monochorionicity or termination because of trisomy 13.
The neonatal survival rate was 95.8% in the remaining 24
pregnancies. Published studies of interval and non-interval
laparoscopic cerclage with more than 12 cases are
summarised in Table 2.
The second author of this article has performed 32
laparoscopic interval procedures since 2005. There were no
121
 Techniques in transabdominal cervical cerclage

Figure 5. Transabdominal cerclage: lateral view.

Table 2. Published series of more than 12 cases of laparoscopic Surgical technique

transabdominal suture.
Laparoscopic cerclage aims to replicate the same surgical
Neonatal Neonatal approach as the open technique except that routine bladder
survival survival reflection is not carried out. The patient is placed in the
before after lithotomy position and the bladder is catheterised with a
First suture suture
author Year Cases Country (%) (%) Foley’s catheter. For interval procedures, a uterine
manipulator is inserted into the cervix; some groups insert
Cho* 2003 20 S. Korea N/K 95 an 8 mm Hegar dilator to avoid an overtight suture and
Nicolet* 2009 14 France 7 83 obstruction of the cervical canal. For procedures during
Whittle* 2009 65 Canada 8 89 pregnancy this is obviously not possible and it makes the
Riiskjaer 2012 52 Denmark N/K 83
Burger 2012 66 USA/ N/K 90 procedure much more difficult. While there are minor
Netherlands modifications to the way sutures are placed and the suture
Ades 2014 64 Australia N/K** 95 material used, the procedure usually involves placement of
N/K = not known. Mersilene tape used for transvaginal cerclage or a No. 1
*Included in the review by Nashar et al. (2013)22 Prolene [Ethicon US, LCC, USA] suture around the cervix
**Pregnancies beyond 23 weeks of gestation; 34% at the isthmic level. The uterovesical peritoneum is opened at
the isthmic level and extended slightly laterally to expose the
surgical complications and there was no conversion to uterine vessels on both sides. There is usually no need to
laparotomy. An earlier audit of these cases showed one reflect the bladder downward, except in cases of previous
midtrimester pregnancy loss and one intrauterine death. The caesarean section or other circumstances where the bladder
former was managed by removal of the suture via a posterior may have been pulled up onto the anterior uterine wall. The
colpotomy; the latter was apparently managed by suture may then be inserted either in the anteroposterior or
hysterotomy at another hospital.23 posteroanterior direction. Our approach involves using the

122 ª 2016 Royal College of Obstetricians and Gynaecologists


original curved blunt needle of the Mersilene tape to place
the suture in the anteroposterior direction. The needle is
passed between the uterine vessels and the cervicoisthmic
junction, coming out through the posterior leaf of the broad
ligament, approximately 1 cm above the uterosacral
ligament. The same approach is then repeated on the other
side and the knot is tied posteriorly, behind the
cervicoisthmic junction. Care is taken to lay the tape flat
on the uterus and to cut the ends to 1–2 cm (Figure 6). Some
groups straighten the needles so that it is easier to insert them
into the peritoneal cavity through one of the ports. They then
use the straightened needles to apply the suture in the
posteroanterior direction, starting approximately 1 cm above
the uterosacral ligaments, and tie the knot anteriorly. Some
other groups use laparoscopic port closure devices (such as
EndoCloseTM [Covidien, MN, USA]) or aneurysm needles,
inserted through the anterior abdominal wall in the
suprapubic region, to pull the Mersilene tape in the
posteroanterior direction at the isthmic level.
Anterior knots have the advantage of avoiding risk of
adhesions in the pouch of Douglas, but may increase the risk
of erosion into the bladder. Should the pregnancy fail in the
second trimester, posterior knots have the advantage of
possible removal via colpotomy to allow vaginal delivery.
(a)
(b)
Figure 6. Surgical steps of laparoscopic cerclage. a) Opened uterovesical peritoneum. b) Anterior view of laparoscopically placed suture.
c) Posterior view of laparoscopically placed suture before the knot is tied. d) Posterior view of laparoscopically placed suture after the knot is tied.
e) Closed uterovesical peritoneum at the end of procedure.
ª 2016 Royal College of Obstetricians and Gynaecologists
Gibb and Saridogan
Mersilene tape is less likely to cut through the uterine tissue
in the presence of contractions but it causes fibrosis around
and within the braided fibres so that it is more difficult to
remove when necessary. Prolene sutures are easier to insert
and remove, but they may be more likely to cut through the
uterine tissue. After the knot is tied, the uterovesical
peritoneum may be closed to cover the tape, but this is
not essential.
After completion of the procedure, the bladder catheter
can be removed and the patient can be sent home on the
same or following day.
Complications
Some of the complications of laparoscopic cerclage are the
inherent risks of laparoscopic surgery, such as visceral or
major blood vessel injury; others are specific to the cerclage
procedure. Specific complications include bleeding from
uterine vessels and loss of pregnancy for non-interval
procedures. In the largest case series, which included 31
procedures during pregnancy and 34 interval procedures,
there were two fetal losses (2/31, 6.4%) and seven
laparotomies (7/65, 10.8%).30 Bleeding from the uterine
vessels led to five of the laparotomies, while two were because
(c)
(d)
(e)
123
 Techniques in transabdominal cervical cerclage
of impaired visibility caused by morbid obesity. Six of these
patients were pregnant.
Preterm labour, midtrimester rupture of membranes and
intrauterine fetal death are challenging complications after
transabdominal cerclage. In this situation either the suture
needs to be removed or the pregnancy is terminated via
hysterotomy. The other reported complications of
transabdominal cerclage, such as suture migration,
rectouterine fistula some years later (one case we have seen
after open transabdominal suture), uterine rupture and
intrauterine growth restriction are rare and can be seen with
both laparoscopic and open approaches. In cases of posterior
knot, the suture may be removed via a posterior colpotomy.
Laparoscopic removal of the suture has also been reported.
Discussion
The place of cervical cerclage in preventing preterm birth
remains a subject of debate. A Cochrane review31 found that
vaginal cervical sutures reduced preterm birth without
significantly reducing the perinatal morbidity. It was
concluded that the decision on how to minimise the risk of
preterm birth in at-risk women should be personalised. There
are no published randomised controlled trials on the place of
transabdominal cervical suture in this field. The published
literature on transabdominal cerclage usually involves a very
specific group of women who are at risk for midtrimester loss
or preterm birth, and who are either not suitable for
transvaginal cerclage (e.g. because of a lack of vaginal cervix
due to previous surgery), or have tried the transvaginal
approaches unsuccessfully. As discussed above, both open
and laparoscopic approaches appear to offer high success
rates in this group of women who usually have very poor
obstetric history. The laparoscopic approach is relatively new
and is carried out by a few specialists. The UK National
Institute for Health and Care Excellence (NICE) classified
laparoscopic cerclage as a procedure with limited evidence
for success and an uncertain safety record. For this reason,
NICE suggested special governance and audit arrangements
when this procedure is carried out.32 We suggest setting up a
UK national register to audit the outcome of transabdominal
cerclage procedures.
Comparison of laparoscopic technique with the open
approach
There are no prospective trials comparing the laparoscopic
and open approaches. However, at least two publications
have compared the outcomes of laparoscopic cerclage
procedures, either with retrospective open controls or
against the published results in the literature. The report by
Whittle et al.30 showed an 89% fetal salvage rate after
laparoscopic cerclage, while a 60–100% success rate was
found in the literature using the open technique. Another
124
report by Carter et al.33 reported 75% success after
laparoscopic cerclage, compared with 71% after open
cerclage. Both these reports concluded that the laparoscopic
approach compared favourably to the abdominal approach.
The laparoscopic approach has the advantages of shorter
hospital stay, quicker recovery and better cosmesis. It may
also have a lower risk of surgical complications compared
with the open technique.28
Interval versus non-interval procedures
As discussed above, interval procedures are easier and avoid
the risk of fetal loss. If laparoscopic skills are available, then
planned open interval laparotomy has no value. Laparoscopic
planned procedures rarely require non-planned laparotomy,
while the reported conversion rates for non-interval
laparoscopic procedures are approximately 10%. The
procedure requires active, and often acute, anteversion and
retroversion of the uterus by an assistant with an instrument
placed in the cervical canal. This is not desirable during
pregnancy. For this reason it is preferable to carry out
laparoscopic cerclage as an interval procedure before a
woman becomes pregnant.
Two possible disadvantages of interval procedures are first
trimester miscarriages and post-procedure infertility. In our
experience, the women we operated on do not encounter
infertility, as these are usually otherwise fertile women.
Nonetheless, it would appear sensible to limit dissection of
the paracervical tissues to minimise the possibility of adhesion
formation on the pelvis. First trimester miscarriages are usually
possible to manage expectantly or by surgical evacuation, as the
presence of a suture does not prevent insertion of a suction
cannula large enough for this gestational age.
Conclusion
Transabdominal cerclage, both open and laparoscopic,
provides excellent outcomes in well-selected patients.
Laparoscopic cerclage before pregnancy probably offers
similar chances of success compared with the open approach
and has the general advantages of minimal access surgery. It is
likely to replace the open approach in the future. The operation
is easier to perform as an interval procedure and avoids the
risks of fetal loss and conversion to laparotomy. It is important
that the woman be referred for assessment before she becomes
pregnant. Selection criteria must be strict. A history of
midtrimester pregnancy loss, the circumstances of previous
failed cerclage and a seriously deficient cervix are key criteria.
The alternative option of transvaginal cerclage in pregnancy
should be considered. There is a problem with this in that the
person with the skills to perform each procedure is likely to be
different. Currently, obstetricians perform transvaginal
cerclage and in-pregnancy open cerclage; gynaecological
surgeons – sometimes oncologists – tend to perform interval
ª 2016 Royal College of Obstetricians and Gynaecologists

open cerclage; and minimal access surgeons perform
laparoscopic cerclage. Collaboration is essential.
There is a need for a national register to monitor outcomes
of this procedure, which should be relatively
rarely performed.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
DG proposed the idea. DG contributed the main part relating
to the open technique and ES contributed the part related to
laparoscopic technique. Both contributed to the discussion
and conclusions. Both authors approved the final version.
Acknowledgements
The authors thank colleagues in this country and abroad who
have referred patients or asked them to help with their cases
and have therefore contributed to the data.
Supporting Information
Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
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30 Whittle WL, Singh SS, Allen L, Glaude L, Thomas J, Windrim R, et al.
Laparoscopic cervico-isthmic cerclage: surgical technique and obstetric
outcomes. Am J Obstet Gynecol 2009;201:364.
31 Alfirevic Z, Stampalija T, Roberts D, Jorgensen AL. Cervical stitch (cerclage)
for preventing preterm birth in singleton pregnancy. Cochrane Database
Syst Rev 2012;(18):CD008991.
32 National Institute for Health and Care Excellence. Laparoscopic cerclage for
prevention of recurrent pregnancy loss due to cervical incompetence. NICE
interventional procedure guideline No 228. Manchester: NICE; 2007.
33 Carter JF, Soper DE, Goetzl LM, Van Dorsten JP. Abdominal cerclage for the
treatment of recurrent cervical insufficiency: laparoscopy or laparotomy?
Am J Obstet Gynecol 2009;201:111.e1–4.
125
 DOI: 10.1111/tog.12257
The Obstetrician & Gynaecologist
http://onlinetog.org
Acute kidney injury in pregnancy and the use of
non-steroidal anti-inflammatory drugs
a,
Kate S Wiles MSc MRCP, * Anita Banerjee FRCP
a
NIHR Doctoral Research Fellow, Department of Women’s Health, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road,
London SE1 7EH, UK
b
Obstetric Physician, Department of Women’s Health, Guy’s and St. Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK
*Correspondence: Kate S Wiles. Email: kate.wiles@kcl.ac.uk
Accepted on 11 September 2015
Key content
 Serum creatinine falls in normal pregnancy and a new serum
creatinine level above 90 micromol/l in pregnancy should trigger
investigation for acute kidney injury.
 Causes of acute kidney injury in pregnancy include pre-
eclampsia, HELLP (haemolysis, elevated liver enzymes and low
platelet count), microangiopathic haemolytic anaemia, acute fatty
liver of pregnancy, lupus nephritis, renal tract obstruction and
drug use.
 Non-steroidal anti-inflammatory drugs (NSAIDs) can cause acute
kidney injury as well as cardiovascular and gastrointestinal
adverse effects.
 NSAIDs should be avoided in pre-eclampsia, volume depletion,
acute kidney injury and chronic kidney disease.
 When NSAIDs are used, ibuprofen has the best safety profile. It
should be used at the lowest effective dose and discontinued as
soon as possible.
Please cite this paper as: Wiles KS, Banerjee A. Acute kidney injury in pregnancy and the use of non-steroidal anti-inflammatory drugs. The Obstetrician &
Gynaecologist 2016;18:127–35. DOI: 10.1111/tog.12257
Introduction
Physiological adaptations to the kidney in pregnancy are both
functional and structural, resulting in increased renal blood
flow and glomerular filtration rate. These changes mean that
plasma creatinine and urine volumes cannot be interpreted in
pregnancy in the same way as in the nonpregnant state.
Therefore, although international consensus definitions of
acute kidney injury (AKI) exist, these have not been validated
in, and cannot be extrapolated for, pregnancy. The use of
estimated glomerular filtration rate is also not valid in
pregnancy, and serum creatinine and change in creatinine are
the only parameters that can be used for gestational
assessment of renal function. However, serum creatinine
values must be interpreted in the context of pregnancy-driven
physiological changes to the renal system. Serum creatinine
falls by 35 micromol/l in pregnancy,1 leading to an average
creatinine in pregnancy of 53 micromol/l.2 A ‘normal’
laboratory value for creatinine can therefore mask renal
ª 2016 Royal College of Obstetricians and Gynaecologists
2016;18:127–35
Review
b
Learning objectives
 To be able to diagnose acute kidney injury in pregnancy and
understand the importance of supportive treatment.
 To gain an overview of the possible causes of acute kidney injury in
pregnancy and their management.
 To appreciate the adverse effect profile of NSAIDs and be able to
modify prescribing for high-risk patients.
Ethical issues

When prescribing in pregnancy and the postpartum period the
risks and benefits of treatment must be considered for each
individual patient.
 Acute kidney injury in pregnancy is more prevalent in low and
middle income countries where there is often a lower provision of
supportive renal care.
Keywords: acute kidney injury / anti-inflammatory agents / non-
steroidal anti-inflammatory drugs / pregnancy
impairment and a new creatinine of greater than 90
micromol/l should be considered diagnostic of kidney injury
in pregnancy.3 In the context of pre-existing chronic kidney
disease (CKD), there is also no consensus definition for
superimposed AKI. However, a rise in creatinine above
prepregnancy levels cannot be explained by the normal
physiological changes of pregnancy and should be investigated
as possible kidney injury. Urine output parameters can be
difficult to interpret in pregnancy, especially in the context of
pre-eclampsia when oliguria is common.
Aetiology of AKI in pregnancy
AKI is associated with an increased morbidity and mortality
regardless of the underlying cause,4 and whenever AKI
develops in pregnancy, it is a serious complication. More
than one aetiology of AKI can co-exist in the same patient, for
example postpartum haemorrhage and use of non-steroidal
anti-inflammatory drugs (NSAIDs). Audit data5 reveal that
127
 AKI in pregnancy

AKI complicates 1.4% of obstetric admissions in the UK and  medication review

that the most common cause is pre-eclampsia. Most cases
occur in women without pre-existing renal disease and over
40% of AKI goes unrecognised by the treating clinical team.
Such data highlight a need for better diagnosis and
management of AKI in the obstetric population. Causes of
AKI in pregnancy and the puerperium are detailed in Table 1.
Management of AKI in pregnancy: general
principles
Fundamental to the management of AKI is supportive
treatment in order to maintain renal perfusion. However,
assessment of the fluid state of the pregnant woman is
complicated by physiological reductions in blood and oncotic
pressure. In addition, pregnant women can compensate for
hypovolaemia and hypotension, and may present with signs
much later than expected. The significance of tachycardia in
track and trigger systems is critical and central to early
recognition of AKI.
The clinical approach to a pregnant woman with
AKI involves:
 fluid status assessment
 consideration of fluid replacement (see section
on pre-eclampsia)
 appropriate diagnostic work-up
 early involvement of a nephrologist for patients who do
not respond to initial management.
Drug doses may need to be adjusted for a decrease in
glomerular filtration rate below 30 ml/minute including
antibiotics, anticoagulants, insulin and opiates. The use of
NSAIDs, which often form part of a standard postpartum
analgesic protocol, is contraindicated in AKI and
discussed later.
Renal replacement may be indicted in severe AKI that fails
to respond to management or in women with chronic kidney
disease for whom superimposed AKI is more significant.
Indications for renal replacement in pregnancy mirror those
in the nonpregnant population and include metabolic
acidosis, hyperkalaemia and fluid overload refractory to
medical treatment. In addition, urea is teratogenic and a
serum urea above 17 mmol/l despite medical management is
a pregnancy-specific indicator for renal replacement therapy.
If AKI leads to hyperkalaemia, calcium salts for cardiac

Table 1. Causes of acute kidney injury in pregnancy

Gestation Diagnosis Clinical features

Early Hyperemesis gravidarum Nausea, vomiting, ptyalism

Septic abortion/miscarriage Abdominal pain and vaginal bleeding. Can present with septic shock
Acute retention Retroflexed uterus

Mid–late Pre-eclampsia and HELLP
Ureteral obstruction
Placental abruption
Acute fatty liver of pregnancy
Microangiopathic haemolytic
anaemia (TTP/HUS)
New-onset hypertension and proteinuria after 20 weeks of gestation. HELLP is a variant of
severe pre-eclampsia
Increased risk if single kidney (including transplant), autonomic neuropathy (MS, type 1 DM),
polyhydramnios, multiple pregnancy, obstructed labour
Vaginal bleeding, abdominal pain, uterine tenderness
Malaise, anorexia, vomiting, polydipsia, jaundice. Elevated transaminases, hypoglycaemia and
lactic acidosis
Platelet consumption leading to haemolysis and end-organ damage, e.g. renal failure, neurological
symptoms. Presents in second and third trimesters and postpartum.

Peripartum Chorioamnionitis Tachycardia, fever, uterine tenderness, abnormal lochia, prolonged rupture of membranes
Postpartum haemorrhage Haemodynamic instability
Ureteric injury Operative delivery, fever, leucocytosis, pain, persistent ileus
NSAIDs Hyperkalaemia, exacerbation of hypertension, fluid retention

Any Urosepsis
Lupus nephritis
Glomerulonephritis
Interstitial nephritis
Renal stone disease
Intravascular volume depletion
Dysuria, back or flank pain, renal angle tenderness, signs of systemic inflammatory response
Proteinuria  haematuria. May have systemic symptoms: malaise, joint pain, hair loss,
rash, pancytopenia
Primary renal disease may present for the first time in pregnancy. Persistent proteinuria
(PCR >30 mg/mmol) before 20 weeks of gestation warrants renal referral
New drug exposure including antibiotics, NSAID, proton-pump inhibitors, H2 antagonists. May have
systemic signs including rash and fever
Renal colic. Increased risk of AKI if single kidney
Sepsis due to any cause, vomiting, cardiac failure, DKA

DKA = diabetic ketoacidosis; HELLP = haemolysis, elevated liver enzymes and low platelet count; HUS = haemolytic uraemic syndrome; MS = multiple
sclerosis; NSAIDs = non-steroidal anti-inflammatory drugs; PCR = protein/creatinine ratio; Type 1 DM = type 1 diabetes mellitus; TTP = thrombotic
thrombocytopenic purpura.

128 ª 2016 Royal College of Obstetricians and Gynaecologists


stabilisation can be safely given in pregnancy. Insulin with
glucose can also be used as a temporising measure to increase
the intracellular potassium shift while definitive treatment of
the AKI is undertaken.
Specific conditions and their management
Pre-eclampsia
Pre-eclampsia leads to AKI in only 1.5–2% of cases.6
However, because pre-eclampsia itself is common, this
means that it is the most prevalent cause of AKI in
pregnancy as well as the commonest glomerular disease in
the world.7 Renal biopsy reveals endothelial cell swelling,
termed glomerular endotheliosis, the degree of which
correlates with disease severity.8 Reduced permeability of
the glomerular capillary wall leads to a fall in glomerular
filtration and AKI.
The presence or absence of AKI in pre-eclampsia does not
affect the obstetric management of the condition, although it
is used as a marker of severity. In fact, only incomplete,
retrospective data show an association between a serum
creatinine of more than 110 micromol/l and maternal
outcome, and there is no link with neonatal outcome.9
However, magnesium sulphate is renally excreted. Therefore,
if the urine output falls to below 20 ml/hour, or if the
creatinine is higher than 90 micromol/l, a 50% dose
reduction in magnesium sulphate infusion should be
considered from 1 g/hour to 0.5 g/hour. However, in severe
pre-eclampsia or eclampsia, the usual loading bolus dose of
4 g is given. In the context of AKI, monitoring of the serum
magnesium level should be undertaken every four to six
hours, or whenever there is clinical concern regarding
toxicity. Serum magnesium concentrations may not
correlate with toxicity but a level of 2–3.5 mmol/l is advised.
Fluid management is important in pre-eclampsia. The
oliguria of pre-eclampsia does not automatically infer volume
depletion, a fluid challenge does not improve uteroplacental
perfusion,10 and there is no evidence that volume expansion
is beneficial.11 In fact, intravenous hydration in women with
pre-eclampsia is associated with pulmonary oedema and
increased maternal mortality. Women with pre-eclampsia
should therefore be ‘kept dry’ to avoid these risks and a fluid
restriction of 80 ml/hour is recommended peripartum.12
Before the natural postpartum diuresis at 36–48 hours
postpartum, oliguria is common and should not be
aggressively managed, even in the context of AKI. There is
no evidence that treating to a target urine output will prevent
the rare development of overt renal failure and a urine output
greater than 40 ml in 4 hours is sufficient in the immediate
postpartum period.12 Referral to critical care may be needed
in pre-eclampsia with AKI where invasive monitoring can be
used to guide complex fluid management.
ª 2016 Royal College of Obstetricians and Gynaecologists
Wiles and Banerjee
HELLP syndrome
HELLP syndrome is a constellation of haemolysis, elevated
liver enzymes and low platelets, and is a variant of severe pre-
eclampsia. The incidence of renal impairment is higher in
HELLP than in pre-eclampsia, with AKI complicating 3–15%
of cases.13 The risk of AKI in HELLP increases if abruption,
disseminated intravascular coagulation, sepsis, haemorrhage
or intrauterine death occur and AKI in the context of HELLP
worsens prognosis. Isolated biopsy reports describe the
glomerular endotheliosis of pre-eclampsia with additional
thrombotic microangiopathy. The resulting renal tissue
ischaemia is more severe and acute tubular necrosis can
also be seen.14
AKI in HELLP can be severe enough to necessitate
temporary renal replacement therapy, but most patients
will recover renal function unless there is underlying CKD.2
Although HELLP parameters may deteriorate for 48 hours
postpartum,15 recovery of haematological and biochemical
abnormalities should be expected. Where laboratory
abnormalities do not remit after delivery, and if platelet
consumption and AKI predominate the clinical picture, a
differential diagnosis of thrombotic thrombocytopenia
purpura (TTP) and/or haemolytic uraemic syndrome
(HUS) should be considered.
The management of HELLP is supportive and mirrors
that of pre-eclampsia. A double-blind randomised
controlled trial showed that the use of steroids did not
alter hospital stay, recovery of laboratory parameters or
complication rates.16 Although the renal pathology is that
of a thrombotic microangiopathy, there are no prospective
trial data to either support or refute the use
of plasmapheresis.
Thrombotic microangiopathy: TTP and HUS
Pregnancy-associated thrombotic microangiopathy is rare,
occurring in 1 in 25 000 pregnancies.17 Thrombi in the
microvasculature lead to a consumptive thrombocytopenia,
mechanical haemolysis and end-organ damage. Thrombotic
microangiopathy has traditionally been divided into two
different clinical phenotypes: TTP with primarily
neurological symptoms and HUS with predominant renal
dysfunction. However, the phenotypes have significant
clinical overlap. An improved understanding of the
molecular pathophysiology now facilitates a more precise
subclassification of disease based on abnormalities in either
ADAMTS13 (a disintegrin and metalloproteinase with a
thrombospondin type I motif member 13) in TTP or
complement pathway dysregulation in HUS.
Von Willebrand factor is a homeostatic protein that
induces the formation of platelet plugs. It usually undergoes
rapid breakdown by the ADAMTS13 protein. Where the
ADAMTS13 protein is deficient, deposition of platelet-rich
129
 AKI in pregnancy
thrombi occurs in the microcirculation leading to TTP.
Levels of ADAMTS13 decrease in normal pregnancy during
the second and third trimester, and pregnancy-associated
TTP manifests during these trimesters or in the postpartum
period.18 AKI develops in 30–80% of cases of pregnancy-
associated TTP, which is a much higher rate than in TTP
outside of pregnancy.14
Pregnancy can also act as a trigger for complement
dysregulation and HUS. Pathological overactivation of
complement leads to endothelial damage and renal injury.
Pregnancy-associated HUS is an ‘atypical’ disease and
distinct from diarrhoea-associated HUS, which is more
common in the general population. Eighty six percent of
women with pregnancy-associated HUS have a detectable
complement gene mutation, which leads to uncontrolled
activation.19 Renal disease with this ‘atypical’ pathology is
significant and 76% of patients with microangiopathy and
complement abnormalities progress to end-stage renal
failure.19 Most cases of pregnancy-associated HUS occur in
the postpartum period when placental expression of
complement regulatory proteins is lost.19
Both TTP and HUS can be difficult to distinguish from
HELLP. Twenty percent of women with pregnancy-
associated TTP are diagnosed with co-existing pre-
eclampsia/HELLP,14 as thrombocytopenia, haemolysis, renal
dysfunction and neurological symptoms are part of the
clinical picture of both conditions. In addition, complement
dysfunction is described in HELLP as well as HUS.20
However, clotting abnormalities are more common (20%)
in HELLP and so elevated antithrombin and fibrinogen levels
should raise the clinical suspicion of TTP.14 Table 2
highlights some of the clinical features that may aid in
distinguishing HELLP from HUS/TTP.
Table 2. Distinguishing features of HELLP versus HUS/TTP
Feature HELLP
Incidence 1 in 100 pregnancies
(10–20% of severe pre-eclampsia)
Gestation Prepartum (70%)
Postpartum (30%)
Thrombocytopenia <10x109/l, rare
Abnormal liver function Transaminitis
Acute kidney injury 3–15%
Coagulopathy 20%
ADAMTS 13 Reduced level in HELLP without co-existent TTP
Complement abnormalities Detected in HELLP
ESRF = end-stage renal failure; HELLP = haemolysis, elevated liver enzymes and low platelet count; HUS = haemolytic uraemic syndrome; TTP =
thrombotic thrombocytopenic purpura.
Adapted from Turner N, Lameire N, Goldsmith D, Winearls C, Himmelfarb J, Remuzzi G. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford:
Oxford University Press; 2015.
130
Where thrombotic microangiopathy is considered as a
potential diagnosis, specialist advice should be sought
promptly because treatment is complex and morbidity and
mortality are significant. TTP and HUS are managed with
fresh frozen plasma infusion and/or plasma exchange. This
will replace the deficiency of normal anticoagulant factors
and/or neutralise circulating antibodies. Plasma exchange in
TTP has reduced maternal mortality from over 50% to less
than 10%.18 However, microangiopathy of placental
arterioles is hypothesised to contribute to a high perinatal
mortality rate of 30–80%.6 In addition, eculizumab is
licensed for the treatment of atypical HUS. Eculizumab
inhibits activation of the complement pathway via an antiC5
blocking antibody.21 At present eculizumab is recommended
for any patient with atypical HUS in whom the ADAMTS13
activity is confirmed to be more than 10% pending further
investigation, as it is recognised that early treatment with
eculizumab reduces morbidity. Data on eculizumab in
pregnancy are limited but comparable biological agents
have been used without teratogenic effects and use in
paroxysmal nocturnal haemoglobinuria is described
in pregnancy.22
Acute fatty liver of pregnancy
Acute fatty liver of pregnancy is a rare obstetric emergency
with 5 cases per 100 000 maternities in the UK.23 The
disorder has been linked to fetal homozygosity for disorders
of beta-fatty acid oxidation leading to an excessive fatty acid
load in the mother, who is an obligate heterozygote for the
same mutation.24
AKI is a common complication of acute fatty liver of
pregnancy, with 14% of patients in the UK developing renal
impairment and 3.5% requiring renal replacement therapy.23
HUS/TTP
1 in 25 000 pregnancies
TTP: 2nd/3rd trimester and postpartum
HUS: >75% postpartum
Profound thrombocytopenia more common
Normal liver function, prehepatic hyperbilirubinaemia
30–80% in pregnancy-associated TTP
76% ESRF with complement abnormalities
None
Elevated antithrombin and fibrinogen may be seen
Deficiency in TTP
Cause HUS
ª 2016 Royal College of Obstetricians and Gynaecologists

Histological examination of the kidney in acute fatty liver of
pregnancy reveals tubular free fatty acid deposition, which
links with the pathogenesis in the liver.25
The main differential diagnosis of acute fatty liver of
pregnancy is HELLP because low platelets and deranged liver
function are part of the clinical picture of both conditions.
However, low serum glucose, raised serum ammonia and
prodromal vomiting are more suggestive of acute fatty liver
of pregnancy.
Management includes early diagnosis, supportive care and
prompt delivery. In most women there is recovery of liver
function and resolution of AKI after delivery.26
Systemic lupus erythematosus
Systemic lupus erythematosus is an autoimmune disease that
affects women of childbearing age. Between 20% and 49% of
women have renal involvement and therefore lupus nephritis
has the potential to present for the first time in pregnancy
with AKI, proteinuria and hypertension. Distinction from
pre-eclampsia is difficult and specialist advice may be
required. Increased lupus activity is described in
pregnancy,27 and meta-analysis data give a 16% incidence
of renal disease activation in pregnancy.28 A review of 17
studies of pregnancies affected by systemic lupus
erythematosus found that 10% of women with known
lupus nephritis develop acute renal failure in pregnancy.
Women with lupus remain vulnerable to a postpartum flare
of systemic lupus erythematosus29 and should therefore
remain under close monitoring after delivery. Prednisolone,
hydroxychloroquine and tacrolimus can be safely used to
treat lupus nephritis in pregnancy. Mycophenolate mofetil is,
however, teratogenic and should be substituted with
azathioprine prepregnancy.
Obstructive nephropathy
Obstructive nephropathy is rare in pregnancy. However,
women with a single functioning kidney, including women
with a renal transplant, are more susceptible to AKI when
obstruction occurs. Autonomic neuropathy affecting bladder
emptying needs to be considered in women with diabetes
with microvascular complications and in multiple sclerosis,
and intermittent self-catheterisation may be required.
Obstruction can also complicate urosepsis, for example, as
a result of abscess formation or pyonephrosis. A retroflexed
uterus can lead to acute urinary retention in the first
trimester. Postpartum urinary retention occurs in up to 15%
of patients and has physiological, neurological and
mechanical causes.30 In the catheterised woman, excluding
a blockage of the catheter is the first diagnostic step in AKI.
Renal stones are rare in pregnancy despite an increased
excretion of lithogenic substances by the kidney. Women
may present with renal colic or infective symptoms where
this is either a superimposed complication or the trigger for
ª 2016 Royal College of Obstetricians and Gynaecologists
Wiles and Banerjee
stone formation. Most patients will respond to expectant
management with analgesia, hydration and treatment of any
underlying infection. If intervention is required, uteroscopic
stone removal should be considered first-line.31
Diagnosis of renal tract obstruction is made difficult in
pregnancy because the pelvicalyceal system and ureter dilate
from as early as 6–10 weeks of gestation without clinical
significance. Pathological obstruction is suggested on
ultrasound if the ureter is dilated distal to the pelvic brim,
if the obstruction does not decompress by positioning the
woman on all fours and if ureteric jets are absent even in the
contralateral position.32 AKI and infection are indications for
intervention in pregnancy with either percutaneous
nephrostomy or delivery if near term.
Drugs
Drugs are the most common cause of acute interstitial
nephritis and kidney injury.33 Drugs should therefore always
be considered a potential cause of AKI and a temporal
relationship between a new drug and a change in renal
function should always be investigated. Drugs that have been
associated with interstitial nephritis and may be newly
prescribed in pregnancy include penicillins, cephalosporins,
proton-pump inhibitors and H2 receptor antagonists.
In the postpartum period, the most widely prescribed
potentially nephrotoxic drugs are the NSAIDs.
Non-steroidal anti-inflammatory drugs
NSAIDs are among the most widely used drugs in the
world.34 National Institute for Health and Care Excellence
guidelines35 recommend the use of NSAIDs in the
postpartum period for perineal pain when paracetamol
provides insufficient relief of symptoms. A meta-analysis
has shown that rectal NSAIDs given after episiotomy are
associated with less discomfort in the 24 hours after
delivery.36 In addition, NSAIDs can be used before 30
weeks of gestation if they offer an effective analgesic effect
that cannot be provided by either paracetamol or opiate
derivatives, for example, for pleuritic pain, fibroid
degeneration or musculoskeletal pain.
The mechanism of action of NSAIDs is through inhibition
of prostaglandin biosynthesis. This is mediated by preventing
the prostaglandin precursor arachidonic acid from binding to
the cyclooxygenase (COX) enzyme. Inhibition of COX
produces the therapeutic effects of NSAIDs because
prostaglandin messenger molecules are not produced and
the inflammatory drive is lost. Inhibition of prostaglandin E2
and prostacyclin (PGI2) leads to analgesic, antipyretic and
anti-inflammatory effects. However, COX is a constitutively
expressed enzyme, with a role in maintaining normal
homeostasis in the cardiovascular system, gut and kidney.
131
 AKI in pregnancy

Interruption to normal physiology therefore leads to the fold risk of acute renal failure.39 However, such adverse
recognised adverse effects of NSAIDs (Table 3). effects remain rare. Overall, significant effects are estimated
Two isoforms of COX are recognised: COX-1 and COX-2. to occur in 1–5% of exposed patients, with acute renal failure
However, selective inhibition does not improve the adverse developing in 0.5–1.0% of patients taking NSAIDs.37
effect profile of the drugs. All NSAIDs, regardless of Nonetheless, the ubiquity of NSAIDs on postnatal analgesic
selectivity, are associated with cardiovascular, protocols in the UK means that a small incidence of adverse
gastrointestinal and renal adverse effects.37 effects can translate into adverse events for a significant
number of women. In addition, up to 20% of patients with
NSAIDs and the kidney pre-existing risk factors will develop complications from
All NSAIDs have dose-dependent adverse effects in the NSAIDs.40 NSAIDs are therefore contraindicated in women
kidney. The renal adverse effects of NSAIDs and their with renal risk factors including volume depletion, pre-
mechanisms are listed in Table 4.37,38 existing CKD, and antenatal or peripartum AKI. The risk of
It has been demonstrated that within the first month of AKI must also be considered when more than one potentially
exposure to NSAIDs in a general population there is a two- nephrotoxic drug is used in combination, for example,
NSAIDs and gentamicin.
Particular reference should also be made to patients with
Table 3. Adverse effect profile of NSAIDs pre-eclampsia. The pharmacodynamic effects of NSAIDs in the
System Adverse effect of NSAIDs
kidney include sodium retention, hypertension and fluid
overload. This is effectively an exacerbation of the pre-
Cardiovascular Hypertension eclamptic state. Pre-eclampsia, even in the context of normal
Heart failure renal function, is an important contraindication to NSAID use.
Myocardial infarction

Gastrointestinal Dyspepsia Which NSAID is ‘best’ for the kidney?

Ulceration Commonly used NSAIDs and their pharmacokinetic
Bleeding properties are outlined in Table 5.37,41 The predominant
Colonic strictures
renal excretion of NSAIDs should be noted (Table 5). This is
Renal Acute kidney injury important because when renal function is impaired, as a
Hyperkalaemia
result of either acute or chronic kidney disease, this will
Sodium retention and oedema
Interstitial nephritis impair excretion of NSAIDs, and lead to a higher effective
Papillary necrosis dose and exacerbation of toxicity.
Haematological Reduced platelet aggregation Comparative data regarding the most ‘renal-friendly’
NSAIDs are limited. Naproxen has been shown to carry the
NSAIDs = non-steroidal anti-inflammatory drugs.
highest risk of acute renal failure.42 Indomethacin has been
associated with more nephrotoxicity than other NSAIDs in
terms of nephritis and hyperkalaemia, and fenoprofen has been
Table 4. Renal adverse effects of NSAIDs37,38 associated with the highest risk of nephrosis.37 Animal studies
have shown that meloxicam has very little renal effect, possibly
Renal manifestation Mechanism(s)
because of its unique structure, that limits renal distribution of
Acute kidney injury Inhibition of vasodilatory prostaglandins the drug.37 However, safety data in terms of the vascular effects
leading to decreased renal blood flow of meloxicam are limited and, given that vascular hazard
Drug reaction leading to interstitial appears to be related to COX-2 selectivity,42 this may be
nephritis
significant. Breastfeeding data for meloxicam do not exist.
Vasoconstriction and hypoxia leading to
papillary necrosis
Non-renal effects
Hyperkalaemia (10–46% Inhibition of prostaglandin-mediated
In 2013, a meta-analysis was published including 754 NSAID
of patients)37 K+ excretion
Renal tubular acidosis type IV trials and over 200 000 patient-years.42 This found that
vascular events were increased by approximately one-third by
Hypertension and fluid Increased sodium co-transport in
retention ascending loop of Henle
both diclofenac and the COX-2 selective inhibitors, mainly
due to an increase in major coronary events. A dose-
Glomerulopathy: minimal Unclear. Hypothesised indolent
dependent pattern was apparent. Almost all major vascular,
change and membranous inflammatory reaction leading to
nephropathy lymphokine production and proteinuria38 coronary and gastrointestinal events occurred in association
with either COX-2 selective inhibitors or with high doses of
NSAIDs = non-steroidal anti-inflammatory drugs.
traditional, non-selective NSAIDs, including ibuprofen

132 ª 2016 Royal College of Obstetricians and Gynaecologists

 Wiles and Banerjee

context of its apparent higher vascular risk. For most women,

Table 5. Pharmacokinetics of commonly used NSAIDs37,41
use of NSAIDs is low-dose, short-term and any adverse
Clinical Predominant Renal effects will reverse on stopping NSAID therapy. A regimen of
dose Half-life COX clearance ibuprofen 400 mg three times a day offers analgesic efficacy
Drug (mg/day) (hours) selectivity (%)
with less evidence of harm than doses above 1200 mg/day. It
Ibuprofen 1200–3200 2 Non-selective 45–79
is estimated that breastfed infants are exposed to 0.0008% of
Diclofenac 100–150 2 Non-selective 65 the maternal weight-adjusted dose, which represents 0.06%
Naproxen 500–1000 12–17 Non-selective 95 of the accepted infant dose, with no adverse effects reported
Indomethacin 75–150 4.5 Non-selective 60 in the neonate.46
Ketoprofen 200–300 2.1 Non-selective 80
Fenoprofen 800–3200 3 Non-selective Predominant Special consideration should be given to those women who
renal are at high risk of adverse effects as an adverse reaction has
clearance of the potential to cause significant morbidity, with
metabolites
unpredictable reversibility. From a renal perspective,
Celecoxib 200 11 Selective 27
Etoricoxib 60 22 Selective 75 NSAIDs should be avoided in women with CKD who may
Meloxicam 7.5–15 15–20 Selective 50 not tolerate a further reduction in glomerular filtration rate
caused by NSAIDs. Disease processes in pregnancy leading to
COX = cyclooxygenase; NSAIDs = non-steroidal anti-inflammatory
drugs. AKI may reverse on delivery, but NSAIDs should be avoided
until renal function has normalised and there is no longer a
risk of further deterioration in renal function. The incidence
2400 mg/day, diclofenac 150 mg/day, or naproxen 1000 mg/ of AKI in pre-eclampsia is low but NSAIDs are
day. However, this analysis focused largely on chronic NSAID contraindicated in all women with pre-eclampsia, regardless
exposure, with only limited evidence of increased risk in the of renal function because of the risk of augmenting the
first six months of NSAID use. In addition, the average age of pathology of pre-eclampsia through sodium retention,
participants was 61 years. Such data may not therefore have hypertension and fluid overload. The adverse effects of
direct applicability to the obstetric patient who is likely to be NSAIDs mean that they are also contraindicated in those
prescribed lower-dose medication for a short and finite period. with impaired cardiac function and the possibility of harm
Although the vascular risk factors of the obstetric patient should be considered in those with significant risk factors for
should be considered, retrospective data are reassuring, vascular events. Care should be taken when prescribing
suggesting ibuprofen at a dose of less than 1200 mg/day does NSAIDs in women with major postpartum haemorrhage or
not have a demonstrable association with either heart failure or intrapartum sepsis with hypovolaemia without reviewing
myocardial infarction.43 recent renal profile laboratory results.
In conjunction with prostaglandins, thromboxane is also a Paracetamol is safe for both the mother and breastfeeding
downstream product of COX. Thromboxane-A2 plays a role infant. However, when paracetamol is insufficient and
in platelet aggregation and aspirin exerts its antiplatelet effect NSAIDs cannot be used, there can be difficulty establishing
via inhibition of thromboxane. Because thromboxane an alternative postpartum analgesic regimen. The
production is similarly inhibited by NSAIDs, this leads to a gastrointestinal adverse effects of codeine, including nausea,
theoretical concern regarding impaired clotting function in emesis and constipation, can add significantly to the
the postpartum period, particularly in the surgical patient postpartum symptom burden, particularly following
treated with NSAID analgesia. However, aspirin differs from caesarean delivery. In order to provide effective analgesia,
other NSAIDs in that its effect is irreversible for the life of the codeine is metabolised by cyctochrome p450 isoenzyme 2D6
platelet. In contrast, the platelet effect of ‘analgesic-NSAIDs’, (CYP2D6) to morphine. This enzyme is highly polymorphic,
such as ibuprofen and diclofenac, is both reversible (note the with variable metaboliser speeds in the population. This
short half-life in Table 5) and dose-dependent. Studies of means the administration of a known quantity of codeine
small numbers of perioperative patients have shown that effectively equates to the administration of an unknown
ibuprofen has no inhibitory effect on platelet aggregation in quantity of morphine, with potential concerns being raised
women44 and similarly, that diclofenac is not associated with about exposure to breastfed infants. However, a retrospective
a clinical increase in postoperative bleeding.45 study of nearly 8000 offspring over a 10-year period has
shown no increased health risk associated with neonatal
NSAIDs: postpartum guidance exposure to maternal postpartum codeine.47 If parenteral
NSAIDs constitute useful postpartum analgesics with a low analgesia is required then fentanyl has the advantage of being
incidence of adverse effects in the healthy population. predominantly cleared by the liver, with no active
Ibuprofen should be the first-line NSAID. There is no metabolites. Therefore, metabolism is not affected by either
advantage to diclofenac over ibuprofen, especially in the acute or chronic impairment of renal function.

ª 2016 Royal College of Obstetricians and Gynaecologists 133

 AKI in pregnancy
Conclusion
AKI in pregnancy has different aetiologies and can be
multifactorial. Recognition of deteriorating renal function is
important and appropriate initial management will improve
outcome. A multidisciplinary team approach that encompasses
appropriate fluid assessment, review of medication and the
diagnosis and management of the underlying cause of the AKI is
essential. Outside of pregnancy, AKI is associated with an
increased risk of future CKD, end-stage renal disease and
mortality.48 However, the long-term effects of AKI in pregnancy
remain unknown.
When prescribing NSAIDs the risk–benefit profile for the
individual woman must be considered. Where the woman is
vulnerable, either in terms of renal function or vascular risk,
NSAIDs should not be administered in a protocol-led
manner. It should be remembered that there is a significant
lag-time between a nephrological insult and change in serum
creatinine. In addition, serum creatinine is an insensitive tool
in the diagnosis of renal parenchymal injury. Use of NSAIDs
cannot therefore be recommended in women at risk, even
when serum creatinine is being monitored; this includes
women with AKI, CKD and uncorrected volume depletion.
The renal effects of NSAIDs produce a clinical picture which
mirrors that of pre-eclampsia. Pre-eclampsia, even in the
context of normal renal function, is therefore a
contraindication to NSAID use. NSAID analgesia should be
given at the lowest effective dose and discontinued as soon as
possible in all postpartum women.
Disclosure of interests
None
Contribution to authorship
KW was responsible for conception, design, analysis, and
drafting and revision of the manuscript. AB was responsible
for revision of the manuscript. Both authors gave approval of
the final manuscript for publication.
Supporting Information
Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
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135
 DOI: 10.1111/tog.12281 2016;18:137–41
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

INTERGROWTH-21st: a new paradigm for fetal growth in

the 21st century
Jane E Hirst FRANZCOG PhD,a,* Aris T Papageorghiou FRCOG MD,b for the International Fetal and Newborn
Growth Consortium for the 21st Century (INTERGROWTH-21st)
a
Nuffield Medical Fellow, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Level 3 Women’s Centre, John Radcliffe
Hospital, Oxford OX3 9DU, UK
b
Associate Professor in Fetal Medicine and Clinical Research Director, Oxford Maternal & Perinatal Health Institute (OMPHI), University of
Oxford, Nuffield Department of Obstetrics & Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK
*Correspondence: Jane E Hirst. Email: jane.hirst@obs-gyn.ox.ac.uk

Accepted on 30 November 2015

Key content Learning objectives

 There are currently more than 100 different population-based and
customised charts in use, hence definitions of small-for-
gestational-age (SGA) are inconsistent.
 Over 130 countries have adopted the World Health Organization
Child Growth Standards. These standards recognise that all
children can achieve similar growth if environment, nutrition and
health are optimal.
 The INTERGROWTH-21st Project was a large-scale, multicountry
study that measured fetal growth of babies in utero and at birth in
mothers in whom environmental, social, medical and pregnancy
conditions were optimal.
 International standards for fetal measurement and the assessment
of newborn size at birth will enable continuity of measurement
from the pregnancy to childhood.
 Understand that 97% of variation in fetal growth is caused by
factors unrelated to ethnicity.
 When conditions for growth are optimal, fetal growth is strikingly
similar around the world.
Ethical issues
 Consider poor fetal growth as a human rights issue: what is the
legacy for individuals and societies where undernutrition has
occurred in the first 1000 days of life?
 Recognise that, as obstetricians, we have a duty to help the most
disadvantaged. The practice of ‘customising’ for ethnicity could
normalise suboptimal growth.
Keywords: disadvantaged populations / fetal growth / growth
restriction / human rights / public health

Please cite this paper as: Hirst JE, Papageorghiou AT. INTERGROWTH-21st: a new paradigm for fetal growth in the 21st century. The Obstetrician & Gynaecologist
2016;18:137–41. DOI: 10.1111/tog.12281

overweight and obesity in many countries, including

Introduction
Despite decades of research, our understanding of abnormal
fetal growth remains frustratingly limited. Worldwide, it is
estimated that 27% of all babies are born small-for-
gestational-age (SGA), when growth is compared against a
single reference chart.1 SGA is defined as birthweight in the
lowest 10th centile for gestational age and sex,2 and is
commonly used as a proxy for fetal growth restriction (FGR).
Poor fetal growth is associated with a large proportion of
stillbirths;3 however, FGR is a complex multifactorial
syndrome, meaning that generic solutions are unlikely to
exist. Conversely, most cases of excessive fetal growth result
from overnutrition that is secondary to either obesity and/or
diabetes. Global estimates of the number of overnourished
babies are not available. However, with rates of maternal
obesity greater than ever before,4 fetal overnutrition is an
important factor contributing to the epidemic of childhood
the UK.5,6
Both poor and excessive fetal growth have lifelong
consequences for metabolic, cardiovascular, physical and
intellectual development.7–9 As doctors caring for pregnant
women and their babies, our responsibility for their wellbeing
must extend beyond the perinatal period. Our actions, or lack
thereof, play an important role in determining the future
health of the child and society as a whole.
Disparities between fetal and newborn growth
monitoring
Identifying babies who have experienced poor or excessive
growth is challenging. A large number of different fetal and
newborn growth charts are currently used in clinical practice
and research. This occurs in part because of a general
acceptance in the obstetric community that charts should be
derived from local populations, given that mean birthweights

ª 2016 Royal College of Obstetricians and Gynaecologists 137

 INTERGROWTH-21st and fetal growth
differ substantially around the world. In multi-ethnic societies
such as the UK, customised growth charts have been
developed to account for disparities observed between babies
across ethnic groups.10 Both reference and customised charts
are designed such that the prevalence of SGA/FGR will always
be close to the 10th centile, despite the prevalence of most
other perinatal complications differing markedly between
populations. In other areas of medicine the use of normative
standards, rather than population-based references, are
recommended.11 Standards describe the distribution of a
parameter under healthy physiological conditions and do not
change across place or time, an approach that has yet to be
adopted in fetal growth and newborn monitoring. If adopted,
there would be substantial public health advantages, as it
would facilitate valid comparisons of growth and nutritional
states across individuals and populations.
For most practitioners, the choice of fetal growth chart is
determined either by the institution, local professional
society, imaging software program, or the default installed
by the ultrasound manufacturer. The INTERGROWTH-21st
Consortium conducted three systematic reviews to evaluate
the quality of currently used fetal growth and newborn size
charts. Of the 83 published fetal growth charts identified,12
several were found to contain significant potential sources of
methodological bias: inclusion and exclusion criteria were
inconsistent across all studies, descriptions of gestational age
assessment were frequently poor, and no study described a
comprehensive protocol to standardise image capture or
quality control. These and other sources of bias resulted in
wide variation in centile thresholds: for example, the 10th
centile for abdominal circumference (AC) at 36 weeks of
gestation ranged 276 – 292 mm.12
The quality of studies using crown–rump length (CRL) to
estimate gestational age was also assessed13 and similar
potential sources of methodological bias were identified.
Among 29 charts in use, five were based on retrospectively
collected data and 21 (72%) included both low and high-risk
women. Descriptions of population demographics were
generally poor, inclusion and exclusion criteria were not
consistently defined, and no study described how image
quality control or standardisation was achieved.
When considering the methodological quality of studies to
produce newborn size at birth charts,14 only 20 of the 105
studies identified met more than 50% of the 29
predetermined methodological quality criteria. The major
limitations were similar to those identified for fetal charts:
studies were retrospective, the reliability of gestational age
estimation was uncertain, and descriptions of populations
and measuring equipment were poor. Among the top-scoring
charts, there were large differences in centile thresholds; for
example, the 10th centile for birthweight varied by 345 g in
girls and 313 g in boys at term, representing a difference of
approximately 1 standard deviation.
138
Growth monitoring in children: a unified
global approach
Since the 1970s it has been recognised that size and growth in
children are more the result of environmental, health and
nutritional exposures than ethnic heritage.15 In 1996,
Mercedes de Onis and colleagues at the World Health
Organization (WHO) established the Multicentre Growth
Reference Study (MGRS), a globally representative cohort of
8406 healthy infants selected from six countries (Brazil,
Ghana, India, Norway, Oman and the USA). These babies
were: (i) born at term to healthy mothers; (ii) free from
social, medical or nutritional constraints, and (iii) exclusively
breastfed for the first 6 months of life.16 Growth was followed
longitudinally from birth until 5 years of age. Under these
conditions, linear growth was shown to be very similar
between children from different countries.17
These landmark findings led to the release of the WHO Child
Growth Standards in 2006, which were subsequently adopted
in over 130 countries, including the UK.18 The WHO Child
Growth Standards are universal and prescriptive, meaning that
they describe how all children should grow when conditions
are optimal, rather than how growth has occurred at a
particular time and place. Paediatricians can detect, quantify
and compare nutritional problems in children around the
world. The growth phenotypes of stunting, wasting and
overweight are uniformly defined and are valid global
indicators to track the health and nutritional state of children
and whole populations.
The INTERGROWTH-21st Project
In 2008, the INTERGROWTH-21st Consortium was formed
to answer the question as to whether fetal growth and
newborn size at birth are sufficiently similar between sites to
justify international fetal growth and newborn size at
birth standards.18
The INTERGROWTH-21st Project was implemented in
eight countries from 2009 to 2014. All study protocols and
primary findings are available online.19 Briefly, eight diverse
urban populations living in demarcated geographical or
political areas were selected where: environments were free
from major known pollutants; altitude was less than 1600 m;
most women accessed antenatal and delivery care in
institutions; mean birthweight was greater than 3100 g;
rates of low birthweight (<2500 g) were less than 10%, and
perinatal mortality was less than 20 per 1000 births. The
study sites were: Pelotas, Brazil; Shunyi County, Beijing,
China; Central Nagpur District, India; Turin, Italy; Parklands
Suburb, Nairobi; Muscat, Oman; Oxford, UK; and Seattle,
USA.20–28 Within these populations, mothers were screened
for eligibility to enter the Fetal Growth Longitudinal Study
(FGLS), a component of the INTERGROWTH-21st Project,
ª 2016 Royal College of Obstetricians and Gynaecologists

which aimed to monitor growth and development from early
pregnancy until infancy.
In FGLS, fetal biometry was measured every 5 weeks until
birth by ultrasound, using a highly standardised, blinded and
scientifically rigorous protocol designed to minimise intra-
and interobserver bias.29,30 At birth, the same rigour was
applied to measure the weight, length and head
circumference of all babies born in the entire population.31
The statistical approaches to determine whether the
measurements from the eight study sites could be pooled
to produce standards were the same as those used in the
WHO MGRS.32 Skeletal (that is, fat-free) measurements were
compared across sites since they are less likely to be skewed
by overnutrition. Measurements selected were CRL in the
first trimester, fetal head circumference from 14 weeks until
delivery, and birth head circumference and length. The
variability of measurements between sites was compared by
examining the crude values from each country; by
conducting sensitivity analysis to assess the effect on the
overall trend of removing one country at a time; by
comparing the standardised site differences, that is assessing
whether or not the standard deviations of measurements for
each country were within 0.5 of the overall standard
deviation; and by conducting analysis of variance to
determine the amount of variation in growth caused by
intersite differences.
This analysis demonstrated that between 1.9% and 3.5% of
the variation observed between linear fetal growth and
newborn size at birth was attributable to intersite
differences.33 Therefore, as previously observed with infant
and child growth patterns, fetal growth and newborn size at
birth are remarkably similar around the world when
constraints on growth are minimal. Height-for-age z scores
(HAZ) describe a child’s height in terms of standard
deviations above or below the mean at a particular age,
When the FGLS babies were measured at 12 months of age,
the HAZ scores aligned almost exactly with the distribution
observed in the MGRS children.33
Implications of the INTERGROWTH-21st
Project
Standards describing optimal gestational age assessment, fetal
growth and newborn size at birth have now been
published.34–36 These represent a step change in our ability
to assess the nutritional status of babies across the world: for
the first time, growth and development can be monitored
globally using an integrative approach from the first trimester
of pregnancy until 5 years of age. Given the scientific rigour
and scale of the INTERGROWTH-21st Project, it is
anticipated that the new standards will be widely adopted.
However, with vested interests and strongly held views
regarding the influence of ethnicity on fetal growth, barriers
ª 2016 Royal College of Obstetricians and Gynaecologists
Hirst and Papageorghiou
to adoption are anticipated in some countries, including
the UK.37
The INTERGROWTH-21st findings challenge the current
acceptance of customised fetal growth charts in the UK and
elsewhere. While in FGLS the mean birthweight of the babies
born in India was less than those born in the UK (2.9 kg
versus 3.5 kg at 40 weeks of gestation), these data did not
violate the a priori null hypothesis, that is that there were no
significant differences in linear growth across populations
when the nutritional and healthcare needs of mothers were
met. It was never envisaged that data from one country
should be used to evaluate another population or vice versa.
The question is not how the length or weight of fetuses or
newborn babies from one country compare with those of
another population; the question instead is how each of these
compares with the international standards. In addition,
evidence from Europe, East Asia and South America supports
the hypothesis that populations become taller with
nutritional and social advancement.38 This transition is
occurring in India, albeit at a slower rate, particularly in
girls.39 Hence, we believe that INTERGROWTH-21st presents
powerful empirical evidence that observed differences
between populations at birth are probably caused by
underlying social, nutritional and healthcare differences
rather than ethnicity, which is a social not a
biological construct.
Obstetricians must therefore make a choice, especially in
countries with increasingly diverse mixed ancestry
populations. Customising for ethnicity or related factors
(for example, short maternal height, which reflects early life
nutritional exposures, including those in utero) risks
perpetuating the cycle of low expectations in minority and
disadvantaged groups with potentially lifelong consequences:
for example, accepting that transgenerational stunting is
physiological. Finally, customising for maternal weight, or
using reference charts derived from populations with high
rates of obesity, will mean that rates of overnutrition in
pregnancy are underrecognised, thus perpetuating the cycle
of obesity in the offspring.
The way forward
The challenge will be to reach consensus on how to evaluate
fetuses and newborns so as to (i) detect individual babies at
risk of adverse short and long-term outcomes, and (ii)
identify women and populations for which action on
nutrition, health care and social equity are most needed.
The INTERGROWTH-21st standards provide a robust,
universal toolkit developed to meet both of these needs.
Conclusion
Opposition to new scientific truths is well established. Max
Planck, who developed quantum theory, once said: “A new
139
 INTERGROWTH-21st and fetal growth
scientific truth does not triumph by convincing its opponents
and making them see the light, but rather because its opponents
eventually die, and a new generation grows up that is familiar
with it.” However, we need to act now. The findings of the
INTERGROWTH-21st Project represent an important
paradigm shift in our understanding of human growth and
development, demonstrating that a universal pattern of healthy
growth exists from the first trimester of pregnancy until 5 years
of age. The colour of a woman’s skin plays no role in
determining the variation in growth compared with social
conditions, health and nutritional state. Adjusting growth
expectations for ethnicity has no biological basis and risks
normalising suboptimal growth in disadvantaged groups.
Failure to appreciate the effects of poor or excessive nutrition
in utero will have lifelong implications for health.
Disclosure of interests
ATP is an Executive Scientific Editor of BJOG. JEH and ATP
are members of the INTERGROWTH-21st Consortium.
Contribution to authorship
The ideas for the concepts outlined in this manuscript,
acquisition of data, analysis of results, and assurance of
scientific integrity are provided by the INTERGROWTH-21st
Consortium, of which JEH and ATP are members. JEH
drafted the manuscript and provided a substantial
contribution to the synthesis of data. ATP provided
content and critical review. On behalf of the
INTERGROWTH-21st Consortium, JEH and ATP read and
approved the final version of the manuscript and take full
responsibility for the integrity of the work.
Acknowledgements
A full list of Members of the International Fetal and Newborn
Growth Consortium for the 21st Century (INTERGROWTH-
21st) and its Committees appears in the supplementary
information of this article.
References
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and regional estimates of term and preterm babies born small for
gestational age in 138 low-income and middle-income countries in 2010.
Lancet Glob Health 2013;1:e26–36.
2 Royal College of Obstetricians and Gynaecologists. The Investigation and
Managment of the Small-for-gestational-age Fetus. RCOG Green-top
Guideline No. 31. London: RCOG; 2013.
3 Froen JF, Gardosi JO, Thurmann A, Francis A, Stray-Pedersen B. Restricted
fetal growth in sudden intrauterine unexplained death. Acta Obstet
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4 Huda SS, Brodie LE, Sattar N. Obesity in pregnancy: prevalence and
metabolic consequences. Semin Fetal Neonatal Med 2010;15:70–6.
5 Mook-Kanamori DO, Durmus B, Sovio U, Hofman A, Raat H, Steegers EA,
et al. Fetal and infant growth and the risk of obesity during early childhood:
the Generation R Study. Eur J Endocrinol 2011;165:623–30.
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8 Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming
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9 Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al. Maternal
and child undernutrition: consequences for adult health and human
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12 Ioannou C, Talbot K, Ohuma E, Sarris I, Villar J, Conde-Agudelo , et al.
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13 Napolitano R, Dhami J, Ohuma E, Ioannou C, Conde-Agudelo A, Kennedy
SH, et al. Pregnancy dating by fetal crown–rump length: a systematic review
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14 Giuliani F, Ohuma E, Spada E, Bertino E, Al Dhaheri AS, Altman DG, et al.
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creating neonatal anthropometric charts. Acta Paediatr 2015;104:987–96.
15 Habicht JP, Martorell R, Yarbrough C, Malina RM, Klein RE. Height and
weight standards for preschool children. How relevant are ethnic
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17 The World Health Organization Multicentre Growth Reference Study Group.
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18 de Onis M, Onyango A, Borghi E, Siyam A, Blo €ssner M, Lutter C, et al.
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Health Nutr 2012;15:1603–10.
19 The International Fetal and Newborn Growth Consortium for the 21st
Century [https://intergrowth21.tghn.org/].
20 Villar J, Altman D, Purwar M, Noble JA, Knight HE, Ruyan P, et al. The
objectives, design and implementation of the INTERGROWTH-21st Project.
BJOG 2013;120 Suppl 2:9–26.
21 Silveira MF, Barros FC, Sclowitz IK, Domingues MR, Mota DM, Fonseca SS,
et al. Implementation of the INTERGROWTH-21st Project in Brazil. BJOG
2013;120 Suppl 2:81–6.
22 Pan Y, Wu MH, Wang JH, Pang RY, Knight HE, Cheikh Ismail L, for the
International Fetal and Newborn Consortium for the 21st Century
(INTERGROWTH-21st). Implementation of the INTERGROWTH-21st Project
in China. BJOG 2013;120 Suppl 2:87–93.
23 Purwar M, Kunnawar N, Deshmukh S, Singh A, Mulik I, Taori V, et al.
Implementation of the INTERGROWTH-21st Project in India. BJOG
2013;120 Suppl 2:94–9.
24 Giuliani F, Bertino E, Oberto M, Di Nicola P, Gilli G, Knight HE, et al.
Implementation of the INTERGROWTH-21st Project in Italy. BJOG 2013;120
Suppl 2:100–4.
25 Jaffer YA, Al Abri J, Abdawani J, Knight HE, Cheikh Ismail L, for the
International Fetal and Newborn Consortium for the 21st Century
(INTERGROWTH-21st). Implementation of the INTERGROWTH-21st Project
in Oman. BJOG 2013;120 Suppl 2:111–6.
26 Roseman F, Knight HE, Giuliani F, Lloyd S, Di Nicola P, Laister A, et al.
Implementation of the INTERGROWTH-21st Project in the UK. BJOG
2013;120 Suppl 2:117–22.
27 Dighe MK, Frederick IO, Andersen HF, Gravett MG, Abbott SE, Carter AA,
et al. Implementation of the INTERGROWTH-21st Project in the United
States. BJOG 2013;120 Suppl 2:123–8.
28 Carvalho M, Vinayak S, Ochieng R, Choksey V, Musee N, Stones W, et al.
Implementation of the INTERGROWTH-21st Project in Kenya. BJOG
2013;120 Suppl 2:105–10.
29 Sarris I, Ioannou C, Ohuma EO, Altman DG, Hoch L, Cosgrove C, et al.
Standardisation and quality control of ultrasound measurements taken in
the INTERGROWTH-21st Project. BJOG 2013;120 Suppl 2:33–7.
30 Papageorghiou AT, Sarris I, Ioannou C, Todros T, Carvalho M, Pilu G, et al.
Ultrasound methodology used to construct the fetal growth standards in
the INTERGROWTH-21st Project. BJOG 2013;120 Suppl 2:27–32.
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31 Cheikh Ismail L, Knight HE, Bhutta Z, Chumlea WC, for the International
Fetal and Newborn Growth Consortium for the 21st Century
(INTERGROWTH-21st). Anthropometric protocols for the construction of
new international fetal and newborn growth standards: the
INTERGROWTH-21st Project. BJOG 2013;120 Suppl 2:42–7.
32 Altman DG, Ohuma EO, for the International Fetal and Newborn Growth
Consortium for the 21st Century (INTERGROWTH-21st). Statistical
considerations for the development of prescriptive fetal and newborn
growth standards in the INTERGROWTH-21st Project. BJOG 2013;120
Suppl 2:71–6.
33 Villar J, Papageorghiou AT, Pang R, Ohuma EO, Cheikh Ismail L, Barros FC,
et al. The likeness of fetal growth and newborn size across non-isolated
populations in the INTERGROWTH-21st Project: the Fetal Growth
Longitudinal Study and Newborn Cross-Sectional Study. Lancet Diabetes
Endocrinol 2014;2:781–92.
34 Papageorghiou AT, Kennedy SH, Salomon LJ, Ohuma EO, Cheikh Ismail L,
Barros FC, et al. International standards for early fetal size and pregnancy
dating based on ultrasound measurement of crown–rump length in the
first trimester. Ultrasound Obstet Gynecol 2014;44:641–8.
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Hirst and Papageorghiou
35 Papageorghiou AT, Ohuma EO, Altman DG, Todros T, Cheikh Ismail L,
Lambert A, et al. International standards for fetal growth based on serial
ultrasound measurements: the Fetal Growth Longitudinal Study of the
INTERGROWTH-21st Project. Lancet 2014;384:869–79.
36 Villar J, Cheikh Ismail L, Victora CG, Ohuma EO, Bertino E, Altman DG, et al.
International standards for newborn weight, length, and head
circumference by gestational age and sex: the Newborn Cross-Sectional
Study of the INTERGROWTH-21st Project. Lancet 2014;384:857–68.
37 Chatfield A, Caglia JM, Dhillon S, Hirst J, Cheikh Ismail L, Abawi K, et al.
Translating research into practice: the introduction of the INTERGROWTH-
21st package of clinical standards, tools and guidelines into policies,
programmes and services. BJOG 2013;120 Suppl 2:139–42.
38 de Onis M, Blossner M, Borghi E. Prevalence and trends of stunting among
pre-school children, 1990–2020. Public Health Nutr 2012;15:142–8.
39 Deaton A, Dreze J. Food and nutrition in India: facts and interpretations.
Economic and Political Weekly 2009;45:42–65.
141
 DOI: 10.1111/tog.12285 2016;18:154–8
The Obstetrician & Gynaecologist
CPD
http://onlinetog.org

CPD questions for volume 18 number 2

CPD credits can be claimed for the following questions With regard to NK cells,
online via the TOG CPD submission system in the RCOG
9. both peripheral and uterine NK cells express
CPD ePortfolio. You must be a registered CPD participant of
receptors known as the killer
the RCOG CPD programme (available in the UK and
immunoglobulin-like receptors (KIRs). ThFh
worldwide) in order to submit your answers. Please log in to
10. uterine NK cells are cytotoxic. ThFh
the RCOG website (www.rcog.org.uk) to access your
11. progesterone receptors are responsible for the
CPD ePortfolio.
activation of uterine NK cells. ThFh
Participants can claim 2 credits per set of questions if at
12. peripheral NK cells fluctuate throughout the
least 70% of questions have been answered correctly. At least
menstrual cycle. ThFh
50 credits must be obtained in this way over the 5-year cycle.
13. peripheral NK cells exhibit CD16. ThFh
Please direct all questions or problems to the CPD Office.
14. CD16 is responsible for cell lysis. ThFh
Tel: +44(0) 20 7772 6307 or email: cpd@rcog.org.uk
15. women with recurrent miscarriage should
The blue symbol denotes which source the questions refer
have tests to estimate uterine NK cells in
to including the RCOG journals, TOG and BJOG, and RCOG
the endometrium. ThFh
guidance, such as Green-top Guidelines (GTG) and Scientific
16. an elevated uterine NK cell count is a
Impact Papers (SIPs). All of the above sources are available to
recognised cause of recurrent miscarriage. ThFh
RCOG members and fellows via the RCOG website.
17. treatment with prednisolone significantly
RCOG Members, Fellows and Registered Trainees have full
improves outcome in most women with
access to TOG content via the TOG app (available for iOS
recurrent miscarriage. ThFh
and Android).
With regard to recurrent implantation failure,
TOG Natural killer cells and reproductive 18. endometrial ‘injury’ in the cycle prior to
health embryo transfer is harmful. ThFh
Regarding immunity and recognition of foreign antigens, With regard to pre-eclampsia,
1. placental and fetal tissue express identical 19. a high uterine NK cell count in the endometrium
human leucocyte antigens (HLAs). ThFh inwomenwithrecurrentmiscarriageispredictive
2. the group of cell surface molecules that of pre-eclampsia in the next pregnancy. ThFh
recognise foreign proteins is called the major 20. high dose antioxidant supplementation has
histocompatibility complex (MHC). ThFh been shown to reduce the risk of pre-eclampsia. T h F h
3. HLA-A, HLA-B and HLA-C are classical
MHC molecules. ThFh
4. T-lympocytes are responsible for TOG Preimplantation genetic diagnosis: an
humoral immunity. ThFh overview and recent advances
In implantation and embryogenesis, Monogenic diseases relevant in clinical practice are
5. endometrial epithelial cells secrete angiogenic 1. X-linked dominant. ThFh
factors required for decidualisation. ThFh 2. Autosomal recessive. ThFh
6. nitric oxide is a potent vasodilator. ThFh 3. Y-linked. ThFh
7. the outer cell mass eventually differentiates to
With regard to cystic fibrosis,
form the trophoblast. ThFh
8. peripheral natural killer (NK) cells play an 4. if a couple are both carriers, their offspring has
important role in spiral artery remodelling. ThFh a 50% chance of having the condition. ThFh

154 ª 2016 Royal College of Obstetricians and Gynaecologists

 CPD

5. the most common responsible mutation 3. alteration in IL-1 levels has been shown
is D508. ThFh to lead to defects in endometrial
receptivity. ThFh
With regard to mitochondrial disorders,
4. strong evidence is now available to suggest
6. they show complete paternal inheritance. ThFh that submucosal fibroids are a recognised
7. they cause inborn errors of metabolism. ThFh cause of subfertility. ThFh
8. they affect at least 1:50 000–80 000. ThFh
With regard to endometriosis and unexplained
9. they have a predictable manifestation. ThFh
subfertility,
10. three-person in vitro fertilisation to help
eliminate these involves substitution of the 5. approximately 30% of subfertile women have
father’s mitochondrial DNA with that from mild endometriosis at laparoscopy. ThFh
a donor. ThFh 6. there is good evidence to suggest that surgical
treatment of mild endometriosis significantly
Regarding methodology used to make a genetic diagnosis,
improves live birth rates. ThFh
11. polymerase chain reaction is a new technique 7. the ESHRE Capri workshop group suggested
used to identify chromosomal rearrangement. ThFh that laparoscopy should be done in otherwise
12. misdiagnosis from an allele drop out is asymptomatic women with
recognised as a cause of transfer of an unexplained infertility. ThFh
affected embryo. ThFh 8. it is recommended that the minimal disease is
13. fluorescent in situ hybridisation is a tool used diathermised or excised to improve
to identify chromosomal rearrangements. ThFh fertility rates. ThFh
14. comparative genomic hybridisation
interrogates a handful of chromosomes. ThFh In women with infertility and mild endometriosis,
15. preimplantation genetic diagnosis for single 9. fecundity rates are lower than those in women
gene disorders has the highest pregnancy rates without endometriosis. ThFh
compared with that for other indications. ThFh
With regard to fertility investigation work-up,
Regarding embryogenesis, embryo biopsy and transfer,
10. the World Health Organization semen analysis
16. about 10% of cleavage stage embryos culture criteria include normal lower limit of sperm
to blastocysts. ThFh concentration is 15 million/ml. ThFh
17. higher number of cells are retrieved from
blastocyst biopsy compared with cleavage With regard to the prognosis of unexplained
stage biopsy. ThFh subfertility,
18. day 3 embryo biopsy is associated with a lower
11. the average cycle fecundity
implantation rate compared with
without treatment in these women is
unbiopsied controls. ThFh
5.1–7.3%. ThFh
19. frozen embryo transfer is associated with a
12. the prognosis is better if the duration of
lower pregnancy rate than fresh transfer. ThFh
subfertility is less than 3 years. ThFh
20. frozen embryo transfer increases the risk of
ovarian hyperstimulation syndrome. ThFh With regard to the increased age of the female partner in
unexplained subfertility,
TOGUnexplained subfertility: diagnosis and 13. women over the age of 35 years have a higher
management chance of unexplained subfertility compared
with younger women. ThFh
With regard to the incidence of unexplained infertility,
With regard to unexplained subfertility,
1. it has been reported in up to 20% of
subfertile couples. ThFh 14. the fecundity of women identified as having
unexplained subfertility is similar to that of
With regard to possible contributory factors of
those with mild endometriosis. ThFh
unexplained infertility,
15. there is now strong evidence to suggest an
2. a defect in acrosome reaction is unlikely to association between adenomyosis
affect fertilisation if the sperm count is normal. ThFh and subfertility. ThFh

ª 2016 Royal College of Obstetricians and Gynaecologists 155

 CPD

In relation to the treatment of unexplained subfertility, 10. Mersilene tape is suitable suture to use. ThFh
11. in vitro fertilisation and embryo transfer is not
16. the first-line treatment option for unexplained
possible after laparoscopic cerclage. ThFh
subfertility is clomiphene citrate for
ovulation induction. ThFh Indications for a transabdominal cerclage include;
With regard to smoking and fertility, 12. an absent vaginal cervix in a woman who has
had midtrimester miscarriages. ThFh
17. it causes a reduction in mitochondrial DNA
13. a failed elective vaginal cerclage. ThFh
damage in men. ThFh
14. a grossly disrupted cervix in a woman who
With regard to the assessment of ovarian reserve prior to recently lost a pregnancy at 20 weeks of gestation. ThFh
infertility treatment, 15. a previous midtrimester loss and a severely
damaged cervix. ThFh
18. anti-m€ullerian hormone has an advantage
in that it is independent of the time when it is With regard to transabdominal cerclage,
performed in relation to menstruation. ThFh
16. there is evidence that the prepregnancy type is
19. antral follicle count is as good as anti-
just as effective as the pregnancy type. ThFh
m€ullerian hormone in predicting the success
17. when pregnancy fails after the first trimester, a
of ovarian stimulation. ThFh
colpotomy is the best way to remove the stitch
20. a low anti-m€ ullerian hormone level is a poor
irrespective of the placement of the knot. ThFh
predictor of spontaneous conception. ThFh
Complications of the laparoscopic cerclage procedure
include:
TOG The role of transabdominal cervical 18. ruptured uterus. ThFh
cerclage techniques in maternity care 19. rectouterine fistula. ThFh
20. suture migration. ThFh
Regarding cervical cerclage,
1. the Medical Research Council and Royal
College of Obstetricians and Gynaecologists TOG Acute kidney injury in pregnancy and
study showed that transvaginal cerclage was the use of non-steroidal anti-inflammatory
effective in women with three previous drugs
late miscarriages. ThFh
With regard to the physiological changes in the renal
Cervical weakness is associated with system in pregnancy;
2. persistent vaginal bleeding. ThFh 1. creatinine levels fall by approximately
3. previous cone biopsy. ThFh 50 mmol/l. ThFh
2. the use of estimated glomerular filtration rate
With regard to open transabdominal cervical cerclage,
is valid. ThFh
4. the suture is able to support several 3. treatment of hyperkalaemia with insulin and
sequential pregnancies. ThFh dextrose is contraindicated. ThFh
5. the confirmation of an early missed
With regard to acute kidney injury (AKI) in pregnancy,
miscarriage is considered an indication for
its removal. ThFh 4. postpartum haemorrhage is the most
common cause. ThFh
Regarding laparoscopic cerclage,
5. it complicates up to 1.5% of obstetric
6. term pregnancy rates following the procedure admissions in the UK. ThFh
are between 25% and 50%. ThFh 6. approximately 2 in 5 cases are unrecognised. ThFh
7. interval procedures are safer and easier 7. the most common cause is
compared with non-interval (during obstetric haemorrhage. ThFh
pregnancy) procedures. ThFh 8. most cases occur in women with pre-existing
8. caesarean delivery is always indicated after renal disease. ThFh
the procedure. ThFh 9. consideration should be given to reducing
9. the fetal survival rates are comparable to drug dosages in those with a glomerular
open cerclage. ThFh filatration rate of <30 ml/min. ThFh

156 ª 2016 Royal College of Obstetricians and Gynaecologists

 CPD

Concerning thrombotic microangiopathies
haemolytic uraemic syndrome/thrombotic
cytopenia purpura),
10. they are associated with abnormalities in the
breakdown of Von Willebrand factor.
11. thrombocytopenia is usually more severe
than that seen in HELLP syndrome
(haemolysis, elevated liver enzymes,
low platelets).
12. coagulopathy is more common than in severe
pre-eclampsia.
In pre-eclampsia,
13. AKI develops in approximately 2% of cases.
14. magnesium sulphate should not be given
when AKI is present.
Postpartum non-steroidal anti-inflammatory drugs
(NSAIDs)
15. are a recognised cause of de novo AKI.
16. that selectively inhibit COX2 are safer in AKI.
17. act on the kidney to cause potassium retention.
18. are safe in women with antepartum
pre-eclampsia.
19. are contraindicated in breastfeeding women.
20. are recommended by the National Institute
for Health and Care Excellence for
perineal pain relief when paracetamol
is insufficient.
BJOG A systematic review and network meta-
analysis comparing the use of Foley
catheters, misoprostol and dinoprostone
for cervical ripening in induction of labour
Women receiving oral misoprostol for induction of labour
1. are less likely to have a caesarean section than
those receiving dinoprostone.
2. are more likely to achieve vaginal delivery
within 24 hours than those receiving
vaginal misoprostol.
3. have a lower risk of hyperstimulation with
fetal heart rate changes than women who
receive vaginal misoprostol for
cervical ripening.
Induction of labour with a Foley catheter
4. is associated with less pain than
pharmacological methods.
5. is associated with strong evidence of increased
risk of chorioamnionitis.
(that is, With regard to induction of labour in women with intact
thrombo- membranes in the third trimester,
6. misoprostol is not licensed for induction of
labour in many countries. ThFh
ThFh 7. patients using Foley catheters need more
stringent monitoring of uterine contractions. ThFh
8. the use of a Foley catheter is an appropriate
method for home induction of labour. ThFh
ThFh 9. the most efficient methods are associated with
the greatest risk of hyperstimulation. ThFh
ThFh 10. the rate of induction of labour for singleton
pregnancies doubled between 1990 and 2012
in the USA. ThFh
ThFh
Reference
ThFh 1. Chen W, Xue J, Peprah MK, Wen SW, Walker M, Gao Y,
Tang Y. A systematic review and network meta-analysis
comparing the use of Foley catheters, misoprostol, and
dinoprostone for cervical ripening in the induction of labour.
BJOG 2015 Nov 5; DOI: 10.1111/1471-0528.13456. [Epub
ThFh ahead of print]
ThFh
ThFh
BJOG Donor oocyte conception and
ThFh pregnancy complications: a systematic
ThFh review and meta-analysis
Regarding systematic reviews,
1. the Newcastle-Ottawa scale is a tool used to
ThFh assess the quality of any study included in a
systematic review. ThFh
2. PRISMA is an international prospective
database for systematic reviews. ThFh
Regarding a meta-analysis,
3. large studies are more likely to dominate the
analysis in a random effects model, compared
with a fixed effect model. ThFh
4. a forest plot is primarily used as a visual aid
ThFh for detecting systematic heterogeneity. ThFh
5. a funnel plot is a scatter plot of treatment
effect versus a measure of study size. ThFh
ThFh
In this systematic review,
6. the risk of bias was assessed using an evidence-
based assessment tool. ThFh
ThFh 7. meta-regression suggested that the occurrence
of hypertensive disease was independent of age. ThFh
8. the impact of confounders would be lessened
by meta-analysis of individual
ThFh participant data. ThFh
9. studies with a comparison group, including
ThFh spontaneous conception, were included. ThFh

ª 2016 Royal College of Obstetricians and Gynaecologists 157

 CPD

This study demonstrates that donor oocyte pregnancies are Reference

associated with
10. a significantly higher risk of pregnancy-
induced hypertension than autologous
oocyte in vitro fertilisation pregnancies.
1. Jeve YB, Potdar N, Opoku A, Khare M. Donor oocyte
conception and pregnancy complications: a systematic review
and meta-analysis. BJOG 2016 Feb 8; DOI: 10.1111/1471-
0528.13910. [Epub ahead of print]
ThFh

158 ª 2016 Royal College of Obstetricians and Gynaecologists

 DOI: 10.1111/tog.12286
The Obstetrician & Gynaecologist
http://onlinetog.org
2016;18:160–161
APP REVIEW
TOG
Aim: A paperless
version of TOG
on the move!
Giving you quick
access to high-
impact educational review articles
in obstetrics and gynaecology,
complete with CPD questions for
each issue. Latest ‘early view’ articles
also available.
Operating system: iOS 6.0 or later.
Android 4.0 and up.
Usability: The app is very simple to
download. Its use is very intuitive,
allowing easy navigation through
issues and downloading of full text
articles for offline reading. The
toolbar offers access to diagrams,
citations, references and an email
link, which enables enhanced
productivity in collaborative
work. Other useful features
include enhanced search across all
downloaded content and keyword
alerts that ensure you stay ahead in
your field.
Recommend to colleagues/patients?
Overall a good app and we would
strongly recommend it to colleagues.
Cost: Free to download. Full access
to all content for RCOG Fellows,
Members, registered Trainees,
Associates, CPD Associates and
anyone with an online subscription
to the journal. Also free to view are
articles with infographics.
Reviewers: Barbara Quarshie MD
MRCOG, ST7 in Obstetrics and
Gynaecology and Moranda Elliott
MB BS MRCOG, ST6 in Obstetrics
and Gynaecology, Royal Victoria
Infirmary, Newcastle-upon-Tyne,
UK.
TOG rating:
160
TOG ratings ★★★★★
GUIDELINE SUMMARY
Scientific Impact Paper No. 7: Progress in Cervical
Screening in the UK
Cervical cancer prevention has been based on
cervical cytology screening for the last 50 years.
With rapid advances in our understanding of
the human papillomavirus (HPV) and its role
in carcinogenesis, and the clinical applications
of primary prevention by HPV immunisation
Written by: Abid Shah, Clinical Effectiveness Manager, RCOG, UK.
Download all RCOG guidance from: www.rcog.org.uk/guidelines
BOOK REVIEW
Fertility Counseling: Clinical Guide and
Case Studies
Editor: Sharon N Covington
ISBN 978-1107643116 / Paperback / 348 pages, £40.00 / Cambridge
University Press, 2015
This is the first edition of a fertility counselling
book with case studies for health professionals
working with couples who have difficulty
conceiving. The contributors are internationally
recognised experts in assisted reproduction
and psychological aspects of reproductive
health.
Psychosocial support for subfertile patients is
essential; they are a high-risk group for anxiety
and depression disorders. Early detection
and timely evaluation of psychosocial distress
improves patient quality of life and enhances
compliance with treatment.
Each chapter commences with a patient
history highlighting a spectrum of conditions
associated with assisted reproduction, e.g.
failed treatment often complicated by feelings
of worthlessness and fertility preservation
following cancer treatment. Navigating
through the book is straightforward with clear
signposting of chapter headings and content.
Reviewer: Kinza Younas MBBS MRCOG MD, Consultant in Reproductive Medicine, Fertility and
minimal access surgery, Singleton Hospital, Swansea, Wales.
TOG rating:
© 2016 Royal College of Obstetricians and Gynaecologists
and secondary prevention by high-risk HPV
testing, the approach to cervical cancer
prevention in the UK is undergoing significant
change. This paper evaluates the developments
in cervical screening in the UK and the
challenges it faces.
Topic boxes highlight salient features and each
patient story is explored in more detail.
This book is American so relates to practice
in the USA and under Food and Drug
Administration regulations, while
UK fertility services are governed by the
National Institute for Health and Care
Excellence and Human Fertilisation &
Embryology Authority. However, the basic
principles for supporting patients are the
same. The role of fertility counsellors is
recognised as an important aspect in each step
of a patient’s journey through this challenging
time.
It is an evidence-based source describing the
latest perspectives and pioneering insights
into fertility counselling. It is a useful guide
for medical and mental health professionals
to enhance their skills in managing the
psychological and diverse requirements of
fertility patients.
BOOK REVIEW
Compendium for the antenatal care of high-risk
pregnancies
Author: Harini Narayan
ISBN 978-0199673643 / Paperback / 592 pages, £49.99 / Oxford University
Press, 2015
This comprehensive guide to the care
of high-risk pregnant women has been
written for the practising obstetrician. It is
reasonably priced (under £50, paperback
edition) and truly comprehensive. Written
by a practising UK consultant (Harini
Narayan works in Swindon), it is an easy to
read, useful guide covering most conditions
you are likely to encounter (and a number
that you may not).
The layout of each condition is clear,
with a good description of the condition
itself, a discussion about pre-pregnancy,
antenatal, intrapartum and postnatal care,
Reviewer: Kate Harding MRCOG, Consultant Obstetrician, Guy’s and St Thomas’ NHS
Foundation Trust, London, UK.
TOG rating:
WEBSITE REVIEW
www.app-network.org
Postpartum psychosis affects thousands of
women each year in the UK. This severe
mental illness can happen to any woman
and symptoms are variable. This website,
produced by a network of women who
have experienced the condition, aims to
raise awareness and provide support and
information for patients, families and
friends. To these ends, it is successful. It
provides personal accounts from both
women and their partners. As well as
information on typical symptoms, it offers
Reviewer: Joanna B McKenna, MB BCh BAO, MRCOG, ST7 in Obstetrics and Gynaecology,
Belfast Trust, Belfast, UK.
TOG rating:
© 2016 Royal College of Obstetricians and Gynaecologists
and in many cases the drug treatment. The
references tend to be previously written
books, reviews and guidelines with few
original references from the last 5 years.
An added bonus is the section on patient
information, which could be used as a basis
for local leaflets.
The quality of the information is generally
good and will certainly help the generalist
when needing to source a quick reference.
It will be important for those using this
compendium to realise that the information
may not be up-to-date nor detailed enough
to manage a woman with complex needs.
advice on where to seek
help, including in an
acute situation, current
research into the condition and links to
other online sites of relevance. There is an
interactive online support forum, and one-
to-one peer support is available. The site
signposts to booklets and other literature
of interest. Overall this website has a well
designed layout, which is both engaging
and easy to navigate. It is a valuable
resource for patients and families.
TOG Ratings ★★★★★
APP REVIEW
BJOG
Aim: Allows users to keep
up-to-date with the latest
research in O&G through
mobile access to BJOG. In addition to full
PDF articles, the enhanced HTML format
provides quick links to figures and citations.
Personalised content can be synced across a
range of devices.
Operating system: iOS 6.0 or later.
Android 4.0 or later.
Usability: After login the user can choose
between the main journal or journal
news tab with a live Twitter feed. Issues
are presented in an easy-to-navigate
library; however, only those from the past
12 months are currently available. Each
issue can be read online or, alternatively, a
simple tap downloads it for future reading
without internet connection. Articles are
easy to read with a handy feature allowing
users to jump quickly between sections of
the article. Additional content, including
figures, can be viewed and shared easily.
Users can view/download articles in PDF
format as an alternative to the default
enhanced HTML format. Notifications
of new publications as they happen are
optional. Overall the app is well designed
and intuitive to use on any platform.
Recommend to colleagues/patients?
This app is recommended for trainees
and senior clinicians, offering benefits
over the online version, including the
user-friendly layout, and the ability to
sync online content across devices or
download content to a single device for
access offline.
Cost: Free to download app. Full access is
available to RCOG fellows and Members,
and users with online personal/institutional
subscription. Guest users can access all of
BJOG’s free content.
Reviewer: Dr Brian Gordon, ST6 in
Obstetrics and Gynaecology, Royal Victoria
Infirmary, Newcastle upon Tyne, UK.
TOG rating:
161
 DOI: 10.1111/tog.12293 2016;18:162
The Obstetrician & Gynaecologist
http://onlinetog.org
Please note that letters and emails to
the editor should be no more than
500 words with a maximum of five
references.
Re: The Obstetrician & Gynaecologist Volume 17, Issue 4
Dear Sir
I must congratulate you on an excellent journal – Volume 17,
Issue 4 is a good combination of ‘down to earth’ obstetric care on the
one hand and gynaecological cancer research on the other.
The article on The molecular and genetic basis of inherited cancer risk
in gynaecology1 required a third careful reading for me to fully grasp all
the implications. However, as a recent retiree I found the update
worthwhile. It has become very easy to “give an oxytocic” but the
review of The use and abuse of oxytocin2 serves as a warning not to
become casual about stimulating the uterus in labour.
Alas, the article on management of malposition of the fetal
head in the second stage of labour3 is long overdue. The problem
is of such a nature that the practical tutorship of instrument
delivery requires a senior, trained, obstetrician to assess the
patient and guide the trainee through the process of delivery.
Accurate assessment is the crux of the problem and solution.
During 50 years (10 years in the UK) in obstetric practice, I’ve
seen young consultants clueless (and terrified) when faced with a
forceps delivery; to the extent of ordering all forceps to be locked
away and then not venturing near the scene. Instruction to the
registrar: do a caesarean section! The authors aptly sketch the
possible and all too frequent consequences. In a nutshell – do we
(in the western world) have anyone left capable of doing
the instruction?
Finally, I must take Professor Drife MD FRCOG FRCPEd
FRCSEd FCOGSA FFSRH back to the meeting with Christiaan
Barnard in 1967.4 I well remember the “questions from us
students that were hostile” (I was a registrar in Nottingham at the
time) – they were mainly of a political nature – cheap shots by
people who, themselves, wanted part of the media attention. The
paragraph which refers to Professor Barnard is untrue, unfair, and
insulting. I note the FCOGSA – did James Drife know Christiaan
Barnard? I doubt it.
References
1 Beirne JP, Irwin GW, McIntosh SA, Harley IJG, Harkin DP. The molecular and
genetic basis of inherited cancer risk in gynaecology. The Obstetrician &
Gynaecologist 2015;17:233–241.
2 Olah KSJ, Steer PJ. The use and abuse of oxytocin. The Obstetrician &
Gynaecologist 2015;17:265–271.
3 Tempest N, Navaratnam K, Hapagama DK. Management of delivery when
malposition of the fetal head complicates the second stage of labour. The
Obstetrician & Gynaecologist 2015;17:273–279.
162
Letters and emails
4 Drife J. Pioneers versus mockers. The Obstetrician & Gynaecologist
2015;17:298.
Albert Zinn MB ChB FRCOG
Retired Consultant Obstetrician/Gynaecologist, Witbank and Middleburg
Hospitals, South Africa
Author’s reply
Dear Sir
The closest I got to Professor Barnard was when I was a
member of the 500-strong audience at the lecture he gave in
Edinburgh in 1968 after he had performed the world’s first heart
transplant on 3rd December 1967 – and after the recipient had
died of pneumonia 18 days later. The question which
disconcerted the professor came from a student friend of
mine. Far from being a “cheap shot”, it reflected widespread
concern that the science of immunosuppression was not yet
ready to cope with heart transplantation.1,2 Indeed, the first
operations were followed by a ten-year moratorium until science
caught up with surgery.3 The controversy and media frenzy in
the early years of heart transplantation have been vividly
described by those involved3 and Professor Barnard’s charisma
and enjoyment of fame are well documented.4 Being reluctant to
trust my memory of events so long ago, I checked these
contemporary sources – and more – before writing the
paragraph to which Dr Zinn refers. Finally, the Honorary
FCOGSA (of which I’m intensely proud) was awarded after I
helped to set up the South African Confidential Enquiry into
Maternal Deaths in the 1990s. I was admitted to the Fellowship
in 2002 at a moving ceremony in Johannesburg.5 Professor
Barnard died in Cyprus in 2001.
References
1 Dempster WJ, Melrose DG, Bentall HH. Scientific, technical, and ethical
considerations in cardiac transplantation. BMJ 1968;1:177.
2 Anonymous. Too many too soon. Lancet 1968;1:1413–4.
3 Tansey EM, Reynolds LA, editors. Early Heart Transplant Surgery in the UK:
Volume 3. Wellcome Witnesses to Twentieth Century Medicine. London:
Wellcome Trust; 1999.
4 Treasure T. Christiaan Neethling Barnard. BMJ 2001;323:696.
5 Drife JO. Feel free to ululate. BMJ 2002;325:1369.
James Drife MD FRCOG FRCPEd FRCSEd FCOGSA FFSRH
Emeritus Professor of Obstetrics and Gynaecology, Leeds, UK
ª 2016 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12283
The Obstetrician & Gynaecologist
http://onlinetog.org
UKOSS update
The epidemiology and outcomes of women
with postpartum haemorrhage requiring
massive transfusion with eight or more
units of red cells
 Postpartum haemorrhage (PPH) remains a common cause
of maternal morbidity and mortality worldwide; however,
little is known about the incidence, management and
outcomes of women with severe PPH undergoing
massive transfusion.
 The aims of this study were to ascertain the incidence of
massive transfusion in obstetrics in the UK, and describe
the current management practices and clinical outcomes
for these women.
 The study identified 181 women who had undergone
massive transfusion, giving an estimated incidence of 23
per 100 000 maternities (95% CI 19–26).
 The median estimated blood loss was 6 l (interquartile
range 4.5–8.0 l) and the principal causes of haemorrhage
were uterine atony (40%), placental abnormalities (33%)
and trauma, including uterine rupture (19%).
 At presentation, the median platelet count was lowest for
placenta accreta, compared with other causes, while the
median prothrombin time and fibrinogen were <1
5x mean
normal and <3 g/l, respectively for all aetiologies.
 The median platelet count and fibrinogen fell to <75x109/l
and <2 g/l, respectively for all causes of bleeding, except
for trauma.
 In total, 45% of women underwent hysterectomy; women
with placenta accreta had the highest hysterectomy
rate. Two women died, 82% were admitted to
intensive care/high-dependency units, and 28% developed
major morbidities.
 This study showed that massive transfusion because of
PPH is associated with high rates of morbidity and
ª 2016 Royal College of Obstetricians and Gynaecologists
2016;18:163
UKOSS update
hysterectomy. The coagulopathy in women with PPH
undergoing massive transfusion differs significantly
depending on its cause, suggesting that more targeted
transfusion strategies are required.
Marian Knight MA DPhil FFPH FRCP Edin
Professor of Maternal and Child Population Health
National Perinatal Epidemiology Unit, Nuffield Department of Population
Health, University of Oxford, Old Rd Campus, Oxford, OX3 7LF, UK
Email: marian.knight@npeu.ox.ac.uk
References
1 Green L, Knight M, Seeney FM, Hopkinson C, Collins PW, Collis RE, et al. The
epidemiology and outcomes of women with postpartum haemorrhage
requiring massive transfusion with eight or more units of red cells: a national
cross-sectional study. BJOG 2015; DOI: 10.1111/1471-0528.13831. [Epub
ahead of print]
2 Green L, Knight M, Seeney F, Hopkinson C, Collins PW, Collis RE, et al. The
haematological features and transfusion management of women who
required massive transfusion for major obstetric haemorrhage in the UK: a
population based study. Br J Haematol 2016;172:616–41.
Acknowledgement
Thank you to all members who contributed information to
this study.
Further information
Details of this and other UKOSS study results can be
obtained from the UKOSS website http://www.npeu.ox.ac.
uk/ukoss/completed-surveillance. If you would like a reprint
of any UKOSS publications please contact ukoss@npeu.ox.
ac.uk.
163
 DOI: 10.1111/tog.12282
The Obstetrician & Gynaecologist
2016;18:164
http://onlinetog.org
Do it yourself
James Drife MD FRCOG FRCPEd FRCSEd FCOGSA FFSRH
Emeritus Professor of Obstetrics and Gynaecology, Leeds, UK
Do consultants still have secretaries? I suspect the answer is:
“Some do, some don’t, and most share”. At least, that’s the
impression I got recently after trying to phone colleagues who
were no longer responding to emails. To be honest, I was
surprised to find that secretaries still exist in the NHS. Several
years ago, just before I retired, our hospital was proposing to
replace them with a trust-wide electronic dictation system. This
was met with united resistance from consultants and secretaries,
who pointed out that theirs was the core relationship that kept
the service going. I’m told the plan was eventually shelved
because of problems with the voice recognition system. Pity.
Judging by the subtitles on television news programmes, the
resulting letters would have been hilarious.
But of course secretaries do much more than type. Mine
taught me a lot, including the system I still use for organising
appointments. An experienced secretary has a network of
contacts who know how the hospital really works. She (in my
day it was always ‘she’, never ‘he’) would protect you from
time-wasters – and from yourself. Irate letters dictated in the
heat of the moment went to the bottom of the pile until you
cooled down. Indeed, she could sometimes stop you in
mid-paragraph by just raising an eyebrow. I hope this skill is
still classed as ‘essential’ in a shared secretary’s job specification.
Just shred it, professor
In retirement I have to do it all myself. Electronic gadgetry is
no help. Even with a spam filter there’s a load of incoming
messages to delete: billets-doux from every hotel and theatre
I’ve ever booked online; ungrammatical invitations from
open-access journals with unlikely American addresses;
circulars from the university and the hospital, telling me that
the sandwich found in the photocopier has now been claimed
and that the issues with the web-based outpatient booking
system are being urgently addressed; and all of those pharmacy
updates – reading them would be a full-time job. No wonder
the juniors are exhausted.
What I can’t do alone, though, is chuck things out. The boxes
of papers I brought home when I cleared my office are still in a
bulging cupboard, waiting for some ruthless secretary to dispose
of them. How can I decide what to recycle and what to preserve?
Opening those files is like looking into a lost world – page after
page of perfectly punctuated correspondence written by people
who could spell. An agenda without bullet points – gosh, how
164
And finally. . .
long ago was that? This is history, but not quite old enough to
be digitised.
Personal organiser
Never mind. I’ve discovered a task I can manage unaided –
conference organising. Normally, this is a secretary’s big
chance to shine and be appreciated. At the end of a conference
dinner the official host will stand up, thank the person who
has done all of the hard work and present her with a bouquet.
The delegates’ applause will be heartfelt and prolonged. They
know that, without her input, the speakers would have ended
up on the wrong campus, the buses would have been late and
the meals would have had no vegetarian option.
My introduction to this stressful world came early in my
career. At medical school I was part of a small committee that
inherited the task of running a summer school in medical
research techniques for overseas students. Shepherding our
visitors to the electron microscopes was the easy part.
Organising their late-night parties was more challenging, and
counselling them about personal problems was, frankly, a
nightmare. In those days, when someone asked you how to
apply for political asylum, you couldn’t simply google
the answer.
Never say never again. A mere 30 years later I was stepping
up to the plate once more with the Leeds bid to host the
RCOG British Congress. My wife and I scouted locations for
the Accompanying Persons Programme and selected photos
for the submission document (a wow factor is essential for
impressing the judges). At the meeting itself the professional
organiser took charge. My job was to walk around looking
calm and wearing a large rosette.
Rediscovering Leeds
So when our travelling club visited Leeds last year, I felt I
already had all of the basic skills; I just needed a crash course
on the city’s one-way system, an update on sports bars and
some expert advice about beauty spas. I even walked into a
shopping mall unaccompanied. Had I still had a secretary,
these exhilarating learning experiences would have passed me
by. Doing it myself was fun. It gave my emails that all-
important personal touch, and of course we saved money on
the bouquet.
ª 2016 Royal College of Obstetricians and Gynaecologists