Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis

Author:
Jill P Buyon, MD
. | This topic last updated: Oct 24, 2017.

INTRODUCTION — Neonatal lupus (NL) is an autoimmune disease in which passive transfer of

autoantibodies from the mother to the fetus results in fetal and neonatal disease. The major
manifestations are cardiac and cutaneous findings. The most serious complication of NL is complete
heart block (approximately 20 percent have an associated cardiomyopathy at the initial diagnosis or
develop it later. The cardiac manifestations of NL are referred to as cardiac-NL and can include any
degree of block (referred to as congenital heart block [CHB]) that may or may not be accompanied
by extranodal disease such as valvular abnormalities, endocardial fibroelastosis, and/or dilated
cardiomyopathy. Occasionally, those manifestations may occur in the absence of heart block.

EPIDEMIOLOGY — The cardiac manifestations of NL (cardiac-NL), which most commonly involve

injury to the conduction system (congenital heart block [CHB]), with complete atrioventricular (AV)
block being the most characteristic, occur in approximately 2 percent of offspring of women who
have antibodies to Ro/SSA (Sjögren syndrome type A antigen) and/or La/SSB (Sjögren syndrome
type B antigen) [3-8]. NL is responsible for 80 to 95 percent of all cases of congenital complete heart
block in the absence of structural defects diagnosed in utero or in the neonatal period [9,10]. NL is a
much less common cause of heart block presenting after the neonatal period (5 percent in one
study) [10]. The risk of developing cutaneous manifestations of NL is 7 to 16 percent in offspring of
anti-Ro- and anti-La-positive mothers [5,7] but is also sometimes associated with antibodies to
ribonucleoprotein (RNP) [11].

NL is associated with these specific autoantibodies (Ro/SSA, La/SSB) independent of maternal

disease. While some mothers may have systemic lupus erythematosus (SLE) and/or Sjögren
syndrome, in many other cases, the mother is totally asymptomatic [12]. Approximately one-half of
mothers with these autoantibodies who do not have other evidence of autoimmune disease at the
time of the baby's birth later develop autoimmune disease (more commonly Sjögren syndrome than
SLE) [12]. (See 'Pathogenesis' below.)

The prevalence of anti-Ro/SSA antibodies was initially reported as 0.2 to 0.72 percent in female
blood donors [13] and, more recently, as 0.86 percent in healthy females in the general population
(this may be an underestimation since a less reliable test for anti-Ro/SSAwas used for initial
screening) [14]. For patients with SLE, the estimated prevalence of this antibody is 40 percent [15]
and in those with SS between 60 to 100 percent [15]. The population prevalence of CHB in Finland
was reported as 1 in 17,000 live births [16], with the highest annual estimate at 1:6500. However,
this may be an underestimation since only children with pacemakers were included and fetal deaths
were not captured. If the true prevalence of anti-Ro/SSA approaches 0.9 percent [14] and CHB
occurs in 2 percent and recurs in 18 percent [4,17], this could yield approximately 600 to 700 cases
per year in the United States based upon the 2012 National Vital Statistics System data of 3,952,841
births. These results are consistent with a crude estimate based upon the 0.5 percent prevalence
of anti-Ro/SSA antibodies in asymptomatic pregnant women and the rate of CHB of 1 in 15,000 to 1
in 22,000 livebirths [18,19].

The risk of recurrence of CHB is approximately 18 percent [17], and the risk of recurrence of rash is
approximately 30 percent [20]. Crossover, with one pregnancy complicated by rash and a
subsequent one by heart block, occurs in approximately 13 to 18 percent [20].

PATHOGENESIS — NL is presumed to result from the transplacental passage of maternal anti-

Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren syndrome type B antigen)
antibodies that affect neonatal organs, particularly the skin and heart. The pathogenesis probably
requires more than the presence of these antibodies in the fetal circulation (eg, fetal genetic factors
and environmental stressors) since the disease is rare (1 in 50) in offspring of these mothers, even
when high titers of these antibodies are present [9,18]. In addition, discordance of disease in
monozygotic twins has been reported. Although the precise mechanism of injury is not fully
elucidated, it is proposed that heart block results from binding of anti-Ro/SSAand/or anti-
La/SSB antibodies to fetal cardiac cells that have undergone physiologic apoptosis during
remodeling, leading to autoimmune injury and secondary fibrosis of the atrioventricular (AV) node
and its surrounding tissue [21-24]. Autoantibodies may also act by inhibiting calcium currents
mediated by cardiac L and T type calcium channels [25-29]. L type channels are crucial to action
potential propagation and conduction in the AV and sinoatrial (SA) nodes, while the functional role of
the T type channel in the AV node is not completely understood.

Autoantibodies — Several studies have established the association between anti-Ro/SSA and anti-
La/SSB antibodies and NL by prospectively monitoring offspring of women with these reactivities [4-
7]. Although fetal disease is often referred to as a pathologic readout of passively acquired
autoimmune disease, many mothers with these antibodies are themselves clinically asymptomatic
and only identified to have serologic abnormalities when gestational surveillance reveals fetal
bradycardia or even after giving birth when the neonate is noted to have bradycardia. This important
point may be underappreciated since the term "neonatal lupus" has been applied to the cardiac and
skin disease in the offspring, yet the mother may or may not have systemic lupus erythematosus
(SLE) and the child does not have SLE. (See 'Epidemiology' above.)

The incidence of congenital heart block (CHB) is more common in offspring of women with high titers
of anti-Ro/SSA and anti-La/SSBcompared with mothers with low titers [30-35], although there is
considerable overlap in antibody titers between affected and unaffected cases and most women
have high titers that remain stable over time. Thus, a high titer alone is not sufficient to result in
CHB. The risk of CHB was slightly higher in one study if a mother had antibodies to
both Ro/SSA and La/SSB [32] but was independent of anti-La/SSB titers in another [33]. The risk of
cutaneous NL was higher in neonates of mothers with both anti-Ro/SSAand anti-
La/SSB autoantibodies in one study [5]. In another study, infants exposed to high titers of anti-
La/SSB were more likely to have noncardiac manifestations of NL [33]. In addition, one study
reported a lower risk of NL in offspring of women with anti-idiotype antibodies to La/SSB [36].
In addition to the traditional Ro antigen of 60 kD, another antigen of 52 kD has been identified.
Whether this second antigen is really "Ro" remains controversial since Ro52 does not contain an
RNA-binding domain. While several studies have attempted to identify specific epitopes within
the Ro/SSA and La/SSB antigens that associate with cardiac-NL, most of these studies report
epitopes common to the anti-Ro/SSA/La/SSB/ response regardless of fetal outcome. Moreover,
different antibody subsets are identified depending upon the immunoassay used for detection. For
example, the sensitivity of peptide or recombinant protein enzyme-linked immunosorbent assays
(ELISAs) for anti-Ro60 antibodies is low and may result in false negatives [32,34,37]. Newer assays
that use native antigen for SSA/Ro60 are more sensitive.

The antibody response against the p200 epitope, spanning Ro52 amino acids (aa) 200 to 239, is a
candidate biomarker of increased maternal risk for the development of cardiac-NL in an offspring
[38,39]. Although several groups have confirmed the high prevalence of the p200 response in
women giving birth to a child with cardiac-NL, there have been inconsistencies regarding its utility in
high-risk assessment relative to the pregnancy exposure [40]. In one study, maternal reactivity to
p200 did not confer an added risk of fetal conduction defects over full-length Ro52 or Ro60
autoantibodies [41]. Consensus has not been reached as to whether this antibody response is less
often encountered in anti-Ro/SSA-exposed healthy children when all other maternal antibody
reactivities to components of the Ro/SSA/La/SSB complex are equivalent.

Other factors — Other evidence suggests that the presence of maternal antibodies
to Ro/SSA and/or La/SSB, although a powerful risk factor for CHB, is not the only determinant of the
development of NL, as illustrated by the following observations:

●Maternal antibodies to other antigens may cause neonatal disease in some cases. As an
example, anti-U1 RNP (small nuclear ribonucleoprotein that associates with U1 spliceosomal
RNA) antibodies in the absence of anti-Ro/SSA or anti-La/SSB antibodies were found in a few
instances [11,42]. These patients had the classic rash of NL but not advanced CHB. There is
one report of transient first-degree block associated with anti-RNP absent anti-Ro/SSA-
La/SSB [43].
●The fact that heart block develops in only a minority of subsequent pregnancies, despite the
persistence of maternal anti-Ro/SSAand/or anti-La/SSB antibodies, strongly suggests that fetal
factors are important determinants of risk. There is evidence in Japanese and European
populations that fetal susceptibility to heart block may be influenced by specific human
leukocyte antigen (HLA) alleles [44,45]. HLA-DRB1*04 and HLA-Cw*05 were identified as fetal
HLA allele variants conferring susceptibility to CHB, and fetal DRB1*13 and Cw*06 emerged as
protective alleles in a Swedish study [46]. However, the discordance of heart block in identical
twins suggests that in utero factors in addition to genetic differences play a role [18]. The HLA
alleles DQB1*02, DRB1*03, and a polymorphism in the promoter region of the gene for tumor
necrosis factor (TNF)-alpha (-308A, associated with higher TNF-alpha production) are
associated with skin disease [47].
●Maternal-fetal microchimerism may contribute to CHB in NL. This was illustrated in an autopsy
study of hearts obtained from one fetus and three neonates who had heart block associated
 with maternal anti-Ro/SSA or anti-La/SSB antibodies [48]. Female, presumably maternal, cells
were found in the myocardium in all four of the males with heart block and in two of four
controls, with higher numbers of female cells found in the myocardium of those with heart
block.

CLINICAL MANIFESTATIONS — A fetus/newborn can have either cardiac or cutaneous findings or

both as the major manifestations of NL. Cardiac manifestations usually occur between 18 to 24
weeks of gestation, and the more advanced forms of heart block present as fetal bradycardia. The
rash can be present at birth but more often is observed within a few weeks after birth. It can appear
up to approximately four months of age. Other hepatobiliary and hematologic manifestations also
may be present.

Rash — The rash of NL usually comprises erythematous annular lesions or arcuate macules with
slight central atrophy and raised active margins that are located primarily on the scalp and periorbital
area (picture 1 and picture 2) [49]. The periocular, scaly rash often has a raccoon-eye appearance.
The atrophic lesions may be somewhat reticular and may remain even after the levels of transferred
maternal antibodies have fallen. The rash is sometimes seen on other parts of the body such as the
palms and soles or the diaper area [50,51], and it is often confused with a fungal skin infection or
seborrheic dermatitis. (See 'Differential diagnosis' below.)

The rash is noted at delivery in some cases but may not develop until after exposure to ultraviolet
(UV) light, which is thought to induce or exacerbate the rash [52]. In a cohort of 57 infants, the rash
was recognized at a mean of six weeks and lasted an average of 17 weeks [53]. The rash is usually
self-limiting and almost always resolves by six to eight months of age because the half-life of
immunoglobulin G (IgG) antibodies is approximately 21 to 25 days [54]. Telangiectasia on the face
or genitals occur in approximately 10 percent of patients beginning at 6 to 12 months of age [55].
These lesions may be the only manifestation of NL or may occur in areas previously affected by the
typical annular skin rash. Some studies have suggested that patients with cutaneous NL are at
increased risk of developing connective tissue disease throughout their lives [56,57]. (See "Neonatal
lupus: Management and outcomes", section on 'Autoimmune and/or rheumatic disease'.)

The histopathology of the erythematous-desquamative lesions more closely resembles that of

subacute cutaneous lupus erythematosus than discoid lupus [52]. Typical findings are vacuolar
alterations at the dermoepidermal interface and adnexal structures [58]. Some patients present with
urticaria-like lesions that have superficial and deep perivascular and periadnexal lymphocytic
infiltrates.

Heart block — Patients with NL may develop first-, second-, and third-degree heart block. This most
commonly occurs between 18 to 24 weeks of gestation. Advanced second-degree and third-degree
heart block present with fetal bradycardia. Bradycardia can also occur with milder forms of second-
degree block but does not occur with first-degree block. Third-degree (complete) heart block is the
most serious manifestation of NL. In complete heart block, there is complete dissociation of the atrial
and ventricular rates because there is no atrioventricular (AV) conduction. The atrial rate is usually
normal, and the ventricular rate is typically between 50 and 80 beats per minute (bpm) but can be
lower or higher. In some cases, the rate may slow as the pregnancy progresses. The clinical
manifestations of complete heart block in the neonate and child are discussed separately.
(See "Congenital third degree (complete) atrioventricular block", section on 'Clinical
manifestations' and "Bradycardia in children", section on 'AV heart block'.)

Fetal monitoring for development of heart block and the risk of progression from first- or second-
degree heart block, particularly to complete heart block, are discussed in greater detail separately.
(See 'Fetal surveillance for heart block' below and "Neonatal lupus: Management and outcomes",
section on 'First-degree heart block' and "Neonatal lupus: Management and outcomes", section on
'Second-degree heart block'.)

The sinoatrial (SA) node may rarely be involved in NL [18,59-62]. Sinus bradycardia (<100 bpm) was
present in 3 (3.8 percent) of 78 fetuses for whom atrial rates were recorded by echocardiogram in a
series of 187 with congenital heart block (CHB) [60]. The dysrhythmia is usually not permanent [60]
and, if sustained, carries a good prognosis if not associated with endocardial fibroelastosis (EFE),
ventricular dysfunction, and/or AV nodal block [61].

Other cardiac abnormalities — Autoantibody-mediated heart block in NL is typically associated

with a structurally normal heart. However, structural abnormalities such as valvular lesions are
occasionally reported [63]. Additional cardiac abnormalities that may be associated with NL with
complete heart block include congestive heart failure due to cardiomyopathy that is often associated
with EFE or, on rare occasions, with myocarditis [64]. The following observations illustrate the range
of other cardiac manifestations reported in patients with NL:

●Structural heart disease in association with NL is occasionally reported. However, caution is

needed in interpreting such reports because some structural abnormalities may cause heart
block per se (eg, L transposition of the great vessels with a single ventricle, heterotaxia, and AV
septal defects). Thus, heart block in a fetus/infant with one of these structural abnormalities and
exposure to maternal anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-
La/SSB (Sjögren syndrome type B antigen) antibodies may be simply due to the structural
anomaly rather than NL. Of these anomalies, only ventricular septal defect (VSD) has been
reported in association with NL [65-67]. Other congenital structural cardiac anomalies observed
in association with NL include persistent patent ductus arteriosus, patent foramen ovale,
pulmonic stenosis, pulmonary valvular dysplasia, fusion of chordae tendineae of the tricuspid
valve, and ostium secundum type atrial septal defects (ASDs) [63,65,68].
●EFE can occur in addition to conduction defects [10,69] and has also been reported in the
absence of a conduction defect in infants exposed to maternal anti-Ro/SSA and anti-
La/SSB antibodies [70,71]. In a report of 13 affected children, 7 had EFE at presentation (4
fetal and 3 postnatal), and 6 developed EFE weeks to as long as five years after the diagnosis
of CHB [69]. Nine patients died, and two underwent cardiac transplantation because of the
EFE. (See "Definition and classification of the cardiomyopathies", section on 'Endocardial
fibroelastosis'.)
 ●There are a few reported cases of suspected myocarditis (with cardiomegaly and moderate
mitral and tricuspid valvular regurgitation in one patient and sudden death in another) in
association with NL and CHB [66,72].

Other manifestations — In addition to rash and cardiac abnormalities, there may be transient
hepatic, hematologic, neurologic, or radiologic manifestations of NL [54]. Hydrops fetalis is seen in
some fetuses with complete heart block [1,73]. It is a condition of excess fluid accumulation in the
fetus that can result in fetal demise and is a poor prognostic sign.

●Hepatic manifestations include asymptomatic elevated liver enzymes, mild

hepatosplenomegaly, cholestasis, and hepatitis [52,74,75]. In one report, hepatobiliary disease
occurred in 19 of 219 infants (9 percent) with NL, usually in conjunction with either cardiac or
cutaneous involvement [76]. In another series of 54 infants with NL, 15 percent had transiently
elevated transaminase levels [77].
●Hematologic manifestations also have been described, including anemia, neutropenia,
thrombocytopenia, and, rarely, aplastic anemia [52,74,75,77,78]. Neutropenia was present in
25 of 107 tested infants born to mothers with anti-Ro/SSA or anti-La/SSBantibodies in one
prospective study, but no cases of neonatal sepsis occurred in these neutropenic children [5].
Antibodies from mothers of children with CHB can bind neutrophils [79]. However, the
frequency of neutropenia among infants of anti-Ro/SSA-positive mothers is unknown because
healthy infants do not routinely undergo complete blood counts.
●Neurologic manifestations have been described [52], but whether there is an association
with anti-Ro/SSA antibodies is uncertain. In one study, 7 of 87 infants exposed to
maternal Ro/SSA were reported to have hydrocephalus, and 10 had macrocephaly [80]. These
findings have not been reported in other cohorts of anti-Ro/SSA-exposed children. In a study
from New York, there was a trend toward higher parental reporting of neuropsychiatric
dysfunction in children with NL compared with normal friend controls [81]. Based upon a
systematic literature review, most reported neonates considered to have NL with central
nervous system involvement were identified by neuroimaging and were asymptomatic. Only
seven cases (most associated with rash and none with CHB) were considered symptomatic by
virtue of having a physical disability or requiring neurosurgery [82].
●A unique radiographic finding of NL is stippling of the epiphyses (chondrodysplasia punctata)
[52]. It generally resolves without treatment within the first year of life.

DIAGNOSIS — The diagnosis of NL is made when the following are both present:

●The mother has anti-Ro/SSA (Sjögren syndrome type A antigen), anti-La/SSB (Sjögren
syndrome type B antigen), or possibly anti-ribonucleoprotein (RNP) antibodies.
●The fetus or newborn develops heart block, or the newborn develops the typical rash or
hepatic or hematologic manifestations in the absence of another explanation. (See 'Clinical
manifestations' above.)
SCREENING AND SURVEILLANCE — The following recommendations for pre- and postnatal
screening and surveillance are based upon the potential cardiac manifestations of NL and their
associated morbidity and mortality.

Prenatal — Prenatal evaluation includes maternal screening for anti-Ro/SSA (Sjögren syndrome
type A antigen) and anti-La/SSB(Sjögren syndrome type B antigen) antibodies and in utero
surveillance for heart block.

Maternal screening — Prenatal screening for anti-Ro/SSA and anti-La/SSB antibodies is warranted
for women at risk of having a pregnancy complicated by NL. Women who are more likely to
have anti-Ro/SSA and anti-La/SSB antibodies include those with systemic lupus erythematosus
(SLE), Sjögren syndrome, rheumatoid arthritis, mixed connective tissue disease, an undifferentiated
autoimmune disease, or NL with cutaneous and/or cardiac manifestations in a previous pregnancy.
Women with these identifiable risk factors should be tested before conception or as early in
pregnancy as possible. Although many of these women will have previously been tested and
presence or absence of these antibodies is unlikely to change over time, the cautious approach is to
recheck before the end of the first trimester. (See "Pregnancy in women with systemic lupus
erythematosus".)

Maternal testing for anti-Ro/SSA and anti-La/SSB antibodies is also indicated if there is detection of
a slow fetal heart rate and subsequent echocardiographic confirmation of heart block, even in an
asymptomatic woman, since NL in a fetus can be the first sign that the mother has anti-
Ro/SSA and anti-La/SSB antibodies. (See 'Autoantibodies' above.)

Fetal surveillance for heart block — More intensive monitoring during pregnancy, with frequent
fetal echocardiographic surveillance, is indicated for women who test positive
for Ro/SSA and La/SSB autoantibodies. Although women with low titer antibodies are less likely to
have offspring with cardiac-NL than women with high titers [30,33,41], in practical terms, this does
not really reduce the number of antibody-positive pregnant women who should have fetal
surveillance, because laboratories have different cutoff values and most women with these
antibodies have high titers. The most vulnerable period for the fetus is during the period from 18 to
24 weeks gestation [7]. Normal sinus rhythm (NSR) can progress to complete block in seven days
during this high-risk period. New onset of heart block is less likely during the 26th through the
30th week, and it rarely develops after 30 weeks of pregnancy.

Many experts in the field advise performing weekly pulsed-Doppler fetal echocardiography
(measures the mechanical PR interval from the onset of atrial contraction [initiation of mitral valve
movement] to ventricular contraction [aortic pulsation]) from the 18th through the 26th week of
pregnancy [83]. The American Heart Association suggests a few additional weeks of serial
assessment, starting at 16 weeks and continuing through 28 weeks of gestation [84].
Echocardiography enables the diagnosis of first-degree heart block, as well as endocardial
fibroelastosis or more serious valvular disease, that would not be picked up on examination with the
standard handheld continuous Doppler ultrasound device that measures the fetal heart rate but does
not supply an image [85,86]. Complete heart block (and usually second-degree block) results in fetal
bradycardia that can be detected by routine fetal auscultation. Thus, if weekly echocardiography is
not available, the alternative is to perform weekly monitor for fetal bradycardia with Doppler
ultrasound and confirm any findings by echocardiography. (See "Overview of the general approach
to diagnosis and treatment of fetal arrhythmias", section on 'Pulsed wave Doppler' and 'Heart
block' above.)

Postnatal testing — Testing for maternal anti-Ro/SSA antibodies should be performed in the
mother of any neonate with heart block and no identified causal structural abnormalities because
these antibodies account for 80 to 95 percent of reported cases of congenital heart block (CHB) in
the fetus and neonate [9,10]. Infants up to eight months of age with an annular or polycyclic
rash and/or any degree of heart block (although de novo development of CHB after birth is
extraordinarily rare and may indeed represent evolved first- or second-degree block missed in utero)
should also be tested for maternally derived anti-Ro/SSA and anti-La/SSB antibodies. A positive test
in the child or mother fulfills the diagnostic criteria for NL.

DIFFERENTIAL DIAGNOSIS

Rash without heart block — The differential diagnosis for NL rash includes various rashes seen in
the newborn period. These other rashes are not associated with congenital heart block (CHB) or with
maternal anti-Ro/SSA (Sjögren syndrome type A antigen), anti-La/SSB (Sjögren syndrome type B
antigen), or anti-ribonucleoprotein (RNP) antibodies.

The differential diagnosis of isolated polycyclic skin lesions in a newborn or neonate includes the
following diseases [87]:

●Urticaria – Urticarial lesions are intensely itchy, circumscribed, raised, erythematous plaques,
often with central pallor (picture 3). Unlike NL rash, the center of an urticarial lesion is usually
raised rather than atrophied. In addition, individual urticaria lesions are transient, disappearing
within 24 hours. (See "New-onset urticaria".)
Urticaria multiforme (acute annular urticaria) is a self-limited urticarial hypersensitivity eruption
that primarily occurs in infants and very young children. Lesions appear on the face, trunk, and
extremities as annular erythematous plaques with central clearing or dusky-blue centers. Unlike
NL, the duration of individual lesions does not exceed 24 hours, and pruritus is typically
present. (See "Approach to the patient with annular skin lesions", section on 'Migratory
lesions'.)
●Tinea corporis – Tinea corporis often begins as a pruritic, circular or oval, erythematous,
scaling patch or plaque that spreads centrifugally (picture 4). Central clearing follows, while an
active, advancing, raised border remains. Unlike tinea corporis, scale is absent in NL rash, and
no fungal hyphae are seen on a potassium hydroxide (KOH) preparation of skin scrapings.
(See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)
●Seborrheic dermatitis – While the most common manifestation of seborrheic dermatitis in
newborns and infants is "cradle cap," an asymptomatic and noninflammatory accumulation of
 yellowish, greasy scales on the scalp, sometimes the eruption starts on the face, with
erythematous, scaly, salmon-colored plaques (picture 5). The NL rash is more purpuric in color,
and the scaling is less prominent. (See "Cradle cap and seborrheic dermatitis in infants".)
●Annular erythemas of childhood – These are rare, poorly defined diseases with similar
names, including erythema annulare centrifugum (picture 6 and picture 7), familial annular
erythema [88], erythema multiforme (picture 8 and picture 9 and picture 10), and annular
erythema of infancy [89]. They can be distinguished from NL by their migrating course,
presence of peripheral lesions, a scaly border with erythema, lack of atrophy, disappearance of
individual lesions after days to weeks with subsequent appearance of new lesions elsewhere,
and a long-lasting course (usually beyond six months). (See "Dermatophyte (tinea) infections",
section on 'Diagnosis' and "Pathogenesis, clinical features, and diagnosis of erythema
multiforme", section on 'Clinical manifestations'.)
●Cutis marmorata telangiectasia congenita (CMTC) – These lesions can be confused with
the reticular, atrophic lesions of NL [90]. However, CMTC lesions most commonly affect the
limbs, particularly the lower extremities, and are usual unilateral. The affect limb can become
discrepant in size and shape. Lesions resolve more slowly than in NL, usually within two years.
(See "Vascular lesions in the newborn", section on 'Cutis marmorata telangiectatica congenita'.)
●Langerhans cell histiocytosis (LCH) – Infants with LCH may present with brown to purplish
papules with a purpuric hue similar to that of NL rash. Alternatively, patients with LCH may
present with an eczematous rash resembling a candidal infection and seborrheic involvement
of the scalp. Other skin lesions may be pustular, purpuric, petechial, vesicular, or
papulonodular. Over half of patients who present with rashes are determined to have
multisystem disease (including liver, spleen, lung, bone, bone marrow, lymph nodes, and
central nervous system) upon further evaluation. LCH can be distinguished histologically and
immunophenotypically from NL based upon skin biopsy evaluation. (See "Clinical
manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)
●Autoinflammatory syndromes – Some autoinflammatory diseases that closely resemble
lupus erythematosus can begin during the neonatal period. These include stimulator of
interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), chronic
atypical neutrophilic dermatitis with lipodystrophy and elevated temperature syndrome
(CANDLE syndrome), autoinflammation and PLCG2-associated antibody deficiency and
immune dysregulation (APLAID), and C1q deficiency. Most of these patients present with
fever and/or have multisystem involvement unlike NL. (See "Periodic fever syndromes and
other autoinflammatory diseases: An overview", section on 'Other autoinflammatory
disorders' and "Inherited disorders of the complement system", section on 'C1 deficiency'.)

Fetal bradycardia/heart block — The most common causes of fetal bradycardia, in the absence of
labor, are complete heart block, sinus bradycardia, and blocked atrial bigeminy. NL is the most
common cause of CHB in the fetus/newborn, but CHB can also result from congenital heart defects.
In addition, there is an idiopathic familial form of CHB. The etiology and differential diagnosis of
complete CHB and the causes of fetal bradycardia are discussed in detail separately.
(See "Congenital third degree (complete) atrioventricular block", section on
'Etiology' and "Congenital third degree (complete) atrioventricular block", section on 'Differential
diagnosis' and "Overview of the general approach to diagnosis and treatment of fetal arrhythmias",
section on 'Bradyarrhythmias'.)

SUMMARY AND RECOMMENDATIONS

●Neonatal lupus (NL) is a passively acquired autoimmune disease that occurs in offspring of
mothers with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren
syndrome type B antigen) antibodies. (See 'Introduction' above and 'Pathogenesis' above.)
●The risk of having a child with complete heart block in these mothers is approximately 2
percent for first pregnancies or if previous babies were healthy. The risk increases
approximately 10- and 5-fold, respectively, if a previous child had complete heart block or
cutaneous NL. (See 'Epidemiology' above.)
●The primary clinical features are heart block and a rash that is usually found on the scalp and
periorbital areas. Patients may also present after birth with hepatic or hematologic
abnormalities. The large majority of cases of congenital complete heart block without major
structural abnormalities that are diagnosed in utero or in the neonatal period are associated
with maternal anti-Ro/SSA antibodies. Cardiomyopathy can occur in isolation or more
commonly with heart block and is associated with an increased risk of fetal/neonatal demise.
(See 'Clinical manifestations' above and "Congenital third degree (complete) atrioventricular
block".)
●The diagnosis of NL is made when the following are both present (see 'Diagnosis' above):
•The mother has anti-Ro/SSA, anti-La/SSB, or possibly anti-ribonucleoprotein (RNP)
antibodies.
•Thefetus or newborn develops heart block, or the newborn develops the typical rash or
hepatic or hematologic manifestations in the absence of another explanation.
●Weekly pulsed-Doppler fetal echocardiography from the 18th through the 26th week of
pregnancy is often advised in mothers with autoimmune disease who screen positive for anti-
Ro/SSA and/or anti-La/SSB antibodies. Previous recommendations for weekly
echocardiographic surveillance included every other week testing after 26 weeks to 32 weeks.
However, the rarity of de novo heart block after 26 weeks has raised questions as to the
necessity of such rigorous monitoring. (See 'Fetal surveillance for heart block'above.)
●The detection of a slow fetal heart rate and subsequent echocardiographic confirmation of
heart block or postnatal diagnosis of heart block and no identified causal structural
abnormalities, even in an asymptomatic woman, warrants immediate maternal testing for anti-
Ro/SSA and La/SSB antibodies if not previously performed. (See 'Maternal screening' above
and 'Postnatal testing'above.)

REFERENCES

1. Izmirly PM, Saxena A, Kim MY, et al. Maternal and fetal factors associated with mortality and
morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.
Circulation 2011; 124:1927.
 2. Izmirly PM, Saxena A, Sahl SK, et al. Assessment of fluorinated steroids to avert progression
and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system.
Ann Rheum Dis 2016; 75:1161.
3. Brucato A, Cimaz R, Caporali R, et al. Pregnancy outcomes in patients with autoimmune
diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol 2011; 40:27.

Neonatal lupus: Management and outcomes

Author:
Jill P Buyon, MD
Section Editors:
John K Triedman, MD
Joseph A Garcia-Prats, MD
Deputy Editor:
Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Oct 25, 2017.

INTRODUCTION — Neonatal lupus (NL) is an autoimmune disease that is passively transferred

from the mother to the fetus. The major manifestations are cardiac and cutaneous findings. The
most serious complication of NL is complete heart block (approximately 20 percent have an
associated cardiomyopathy at the initial diagnosis or develop it later [1,2]). In this topic review, the
cardiac manifestations of NL are referred to as cardiac-NL and can include any degree of block
(referred to as congenital heart block [CHB]) that may or may not be accompanied by extranodal
disease such as valvular abnormalities, endocardial fibroelastosis, and/or dilated cardiomyopathy.
Occasionally, those manifestations may occur in the absence of heart block.

This discussion emphasizes issues related to the treatment and potential prevention of NL. Testing
for candidate antibodies is important prior to initiating therapy for a presumed case of cardiac-NL
because there are cases of heart block not associated with anti-Ro/SSA (Sjögren syndrome type A
antigen) or La/SSB (Sjögren syndrome type B antigen), and, thus, the management may be
different. This testing is discussed separately. The specific indications for cardiac pacing in infants
with congenital complete heart block are also discussed separately. (See "Neonatal lupus:
Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Screening and
surveillance' and "Congenital third degree (complete) atrioventricular block".)

The epidemiology, pathogenesis, clinical manifestations, diagnosis, screening, and surveillance of

NL are discussed in greater detail separately. Pregnancy in women with systemic lupus
erythematosus (SLE) and diagnosis and management of fetal arrhythmias are also reviewed
elsewhere. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and
diagnosis" and "Pregnancy in women with systemic lupus erythematosus" and "Overview of the
general approach to diagnosis and treatment of fetal arrhythmias".)
IN UTERO MANAGEMENT — Complete heart block, once identified, is irreversible despite all
therapies attempted to date, including glucocorticoids, apheresis, intravenous immune
globulin (IVIG), and hydroxychloroquine [2-5]. Second-degree heart block may be reversible, but it
also may progress to complete heart block despite therapy [4-7]. The clinical relevance of first-
degree heart block is unclear since progression from first-degree block (defined as a PR interval
longer than 150 msec) to more advanced heart block in untreated fetuses has not been well
documented but can occur.

Efficacy and side effects of fluorinated glucocorticoids — Published data are limited and
discordant regarding the efficacy of fluorinated glucocorticoids in reducing mortality in cardiac-
NL. Dexamethasone and betamethasone, which are not inactivated by placental 11-beta
dehydrogenase, may ameliorate pleuropericardial effusions or hydrops, and there are reports of
improved outcomes [4,8-10]. However, there are risks of glucocorticoid therapy to both the mother
(eg, infection, hypertension, avascular necrosis, insulin resistance, and gestational diabetes) and the
infant (eg, oligohydramnios, growth restriction, and the still undetermined potential effect upon
neurocognitive development) [11,12]. The use of fluorinated glucocorticoids for each degree of heart
block is discussed in the sections below. (See "Safety of antiinflammatory and immunosuppressive
drugs in rheumatic diseases during pregnancy and lactation", section on 'Glucocorticoids' and 'First-
degree heart block' below and 'Second-degree heart block' below and 'Third-degree heart
block' below.)

First-degree heart block — Treatment of isolated first-degree block (defined in some series as a
PR interval >150 msec) with glucocorticoids in utero is controversial because of the risks of therapy,
the evidence that first-degree block can revert to normal sinus rhythm (NSR) without therapy, and
the inconsistent evidence that untreated first-degree block in the fetus can progress to more
advanced block [13]. The absence of substantial evidence is due in part to the fact that treatment is
often provided to mothers with fetuses with first-degree block, and there is variability in both the
technique of detection and cutoff values to define first-degree heart block among the different
studies. In addition, if the block does revert to NSR with glucocorticoid treatment, it is unclear
whether this supports continuing therapy for the remainder of the pregnancy.

Some centers prefer the watch-and-wait approach, while others treat all mothers whose fetuses
have first-degree block [14-16]. The author's approach is to first confirm within 24 hours that the PR
interval is indeed prolonged. If verified, the mother is started on oral fluorinated glucocorticoid
(dexamethasone 4 mg per day or betamethasone 3 mg per day), and fetal monitoring by
echocardiography is performed weekly. If there is progression to complete block and no evidence of
extranodal disease, then dexamethasone is discontinued. If the block remains at first degree or
reverts to NSR, then dexamethasone may be continued to 26 weeks gestation and then
discontinued since vulnerability decreases after that time period and further inflammatory insult is
less likely. However, other experts would not treat fetal first-degree block. (See "Neonatal lupus:
Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance
for heart block'.)
Small, uncontrolled cases reports and series have shown that progression is rare, with the majority
not progressing in the absence of treatment or resolving with treatment. In a Canadian study of 165
fetuses of 142 anti-Ro/La antibody-positive women referred for serial echocardiography, fetal
atrioventricular (AV) prolongation or type 1 second-degree block (occurring in 15) were not treated,
and none progressed [14]. Other small studies and case reports showed normalization of AV
conduction in one to two weeks in fetuses with first-degree heart block whose mothers were treated
with dexamethasone [5,13,15,16]. Spontaneous resolution was seen in other case series [17,18].
Progression from first- to third-degree heart block was reported in only two cases [17,19].

Second-degree heart block — Most second-degree block detected in utero progresses to complete
heart block [6,20,21]. In addition, it is hypothesized that incomplete block represents a reversible
inflammatory state (more advanced than first-degree block and thus more clinically concerning) in
which the AV node has not already been damaged and fibrosed. Thus, the goal of glucocorticoids in
the case of second-degree block is twofold, decrease inflammation and prevent third-degree block,
which is not reversible. However, second-degree block can revert to NSR without treatment, and not
all cases respond to treatment. As such, prenatal treatment with fluorinated glucocorticoids (eg,
oral dexamethasone 4 mg per day or betamethasone 3 mg per day) is suggested for mothers of
fetuses with second-degree heart block, beginning as soon after detection as is feasible, as is
monitoring with weekly echocardiography.

The challenge is the decision of when to stop such therapy. If the fetus improves, continuing therapy
through the end of pregnancy is reasonable. However, discontinuation with vigilant observation (ie,
weekly monitoring by echocardiography) is also an option since the vulnerability of the fetal heart
decreases after 26 weeks gestation. If the fetus progresses to third-degree block or does not
respond, discontinuation of therapy is reasonable if there is no other indication (eg, cardiomyopathy,
myocarditis, hydrops) for treatment with glucocorticoids. However, this approach is not uniformly
agreed upon, as many clinicians still worry about progression.

Small, uncontrolled case series document that both treated and untreated patients with second-
degree block can progress, stabilize, or revert to NSR. In one report, four fetuses with second-
degree heart block treated with dexamethasone or betamethasone reverted to first-degree block by
birth [4]. In contrast, two patients with second-degree heart block in utero who were not treated with
fluorinated glucocorticoids progressed to complete heart block. Another study found that, of six
fetuses with second-degree block treated with dexamethasone, three remained in second-degree
block, two reverted to NSR, and one progressed to third-degree block [5]. However, in a study from
France, the use of glucocorticoids was not associated with regression of second-degree block in
eight patients [22], and, in a Canadian study, 15 patients with type 1 second-degree block who were
not treated did not progress [14].

Third-degree heart block — Complete heart block once documented does not revert and is
associated with fetal demise in 5 to 20 percent [1,8,20,23]. Treatment of third-degree heart block
with glucocorticoids in utero is somewhat controversial. It is generally notadvised, unless there are
other factors that indicate glucocorticoid treatment (eg, cardiomyopathy, endocardial fibroelastosis
[EFE]), since reversal of third-degree block has not been documented [5] and most studies have not
shown improved survival or prevention of the development of extranodal disease (eg,
cardiomyopathy, EFE) [2,9,22]. Thus, management of the fetus with complete AV block is primarily
expectant. Fetal echocardiography is usually performed weekly to look for extranodal disease.
Postnatal management, including indications for pacemaker implantation, and mortality risk factors
are discussed in detail separately. (See "Congenital third degree (complete) atrioventricular block",
section on 'Post-natal treatment' and "Congenital third degree (complete) atrioventricular block",
section on 'Prognosis' and 'Cardiomyopathy/endocardial fibroelastosis' below.)

Fluorinated glucocorticoids have not been shown to reverse third-degree block, as was
demonstrated in a multicenter, open-label, nonrandomized study in which there was no reversal in
31 fetuses with third-degree heart block regardless of whether they were treated with glucocorticoids
(n = 22) or not (n = 9) [5]. In addition, most studies have not supported the use of fluorinated
glucocorticoids to prevent disease progression or death. In a study of 202 cases of third-degree
block reported from France, the use of fluorinated glucocorticoids was not associated with improved
survival [22]. In another retrospective study that included 71 fetuses with isolated advanced heart
block in utero exposed to fluorinated glucocorticoids within one week of detection and 85 that were
not treated, fluorinated glucocorticoids did not significantly prevent development of disease beyond
the AV node, reduce mortality, or forestall/prevent pacemaker implantation [2].

Maternal beta-agonist therapy — Fetuses generally tolerate the arrhythmia well when ventricular
rates are >55 beats per minute (bpm) in the absence of anomalies [24,25]. Administration of
maternal beta-agonist therapy when the fetal heart rate is <50 to 55 bpm was shown to increase the
heart rate and stroke volume in small case series [9,26]. Most centers use this approach routinely if
the fetal heart rate is <50 bpm, although it has not been evaluated by comparative studies.

Indications for early delivery — Early delivery should be avoided unless there is evidence of poor
overall health, intrauterine growth restriction, hydrops, or other indications since early delivery in the
absence of these factors does not improve outcomes [2]. At the time of labor, it is possible to monitor
fetal wellbeing using the atrial rate as detected by Doppler devices normally used in fetal monitoring.
A normal atrial rate with normal heart rate variability is reassuring. It is also possible to perform serial
biophysical profile assessments or fetal pH measurements, if these resources are available.
(See "Intrapartum fetal heart rate assessment" and "Management of intrapartum category I, II, and III
fetal heart rate tracings" and "The fetal biophysical profile".)

Cardiomyopathy/endocardial fibroelastosis — Fluorinated glucocorticoids

(eg, dexamethasone, betamethasone) and/or IVIG are often used if there is extranodal disease (eg,
a more global cardiomyopathy). However, the effectiveness of these agents in the treatment of EFE
is unclear [8]. In an interinstitutional study from Toronto, a retrospective review of the use of
glucocorticoids and IVIG, both in utero and after birth, suggested a potential survival benefit in cases
with advanced heart block associated with cardiomyopathy/EFE (rate of demise at a median follow-
up of three years was 20 percent compared with a rate of demise or need for cardiac transplant of
85 percent in historical controls) [27]. A study from France reported five cases of anti-Ro-associated
EFE without conduction abnormalities [28]. Two mothers were treated with betamethasone, one
chose to have a therapeutic abortion, and two chose no treatment. None of the electrocardiograms
at birth (n = 4) showed heart block.

POSTNATAL MANAGEMENT — Post-natal management primarily depends upon what degree of

heart block, if any, was noted in utero and what the findings are on initial neonatal electrocardiogram
(ECG).

Infants and children at risk for complete heart block — An ECG should be performed on all
neonates born to mothers with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-
La/SSB (Sjögren syndrome type B antigen) antibodies, even in the absence of any cardiac
abnormalities detected with in utero monitoring. In addition, consultation with a pediatric cardiologist
should be obtained if fetal monitoring has detected any degree of heart block in utero (including PR
intervals >3 standard deviations [SD] or 150 msec, or second-degree block that reversed) and/or if
the neonatal ECG is abnormal.

●First- or second-degree block identified after birth – Infants with first- or second-degree
heart block identified after birth are at risk of postnatal progression to a higher-degree block,
including complete heart block [6,20,21]. Thus, careful observation of these infants is
necessary in the postnatal period under the oversight of a pediatric cardiologist.
●Transient in utero second-degree block – Infants with second-degree block in utero that
reverted to normal sinus rhythm (NSR) and that have NSR at birth should be evaluated within
the first three months of life by a pediatric cardiologist with performance of an ECG and
echocardiogram as they are still at risk of developing third-degree heart block [6]. The need for
further monitoring can be assessed at that time.
●Transient first-degree block – Obtaining an echocardiogram and ECG at one year is a
conservative approach for those with transient first-degree block, defined as PR prolongation
>3 SD, in utero and a normal ECG at birth. In a study of 57 anti-Ro-exposed children, 6 (38
percent) of 16 with first-degree block in utero (using 2 SD, not 3 SD) who had NSR on birth
ECG were found to again have first-degree block during preschool years [29]. Conclusions
based upon these data are limited in part by the less stringent cutoff of first-degree block to a
95 percent reference range.
●Noncardiac manifestations of NL after birth – Patients who are diagnosed with NL manifest
as noncardiac involvement (rash or hematologic/liver abnormalities) after birth and have no
evidence of heart block of any degree at birth (by exam and ECG) are unlikely to develop
cardiac disease. For those who do, referral to cardiology is indicated.
The rash of NL generally does not cause scarring and disappears within six to eight months.
Appearance of NL skin lesions postnatally is independent of breastfeeding [30,31]. Thus,
breastfeeding is not contraindicated in mothers with anti-Ro/SSA and/oranti-La/SSB antibodies.
●No in utero or neonatal evidence of NL – Late de novo development of complete heart
block is rare in children of women who test positive for Ro/SSA and La/SSB autoantibodies with
no in utero conduction abnormalities and a normal ECG at birth. Thus, further cardiac
surveillance is probably not justified in these children.
 In a study of 57 anti-Ro-exposed children, none of the children with completely normal prenatal
echocardiograms developed any conduction abnormality [29]. However, several cases of
postnatal de novo complete heart block were identified in a retrospective study [32], and rare
cases of isolated cardiomyopathy (one fatal) have been reported in the Research Registry for
Neonatal Lupus. Although a normal pre- and/or perinatal heart rhythm was confirmed in the
patients in the retrospective series, the shortcoming of this observation is the absence of
frequent serial in utero echocardiographic surveillance, which may have revealed a transient or
incomplete block that went clinically undetected.

Complete heart block — Some infants with complete heart block require insertion of a cardiac
pacemaker, especially if the heart rate at delivery is less than 55 beats per minute (bpm). Infants and
young children with complete heart block who are asymptomatic usually end up requiring a
pacemaker later in childhood, adolescence, or adulthood. However, exercise limitation and even
death are possible in the absence of pacing. The prognosis following pacemaker implantation is
excellent for most children, although development of heart failure may occur. The postnatal
management and prognosis of complete heart block are discussed in greater detail separately.
(See "Congenital third degree (complete) atrioventricular block", section on 'Post-natal
treatment' and "Congenital third degree (complete) atrioventricular block", section on 'Prognosis'.)

NL rash — The rash associated with NL typically resolves by six to eight months of age without
sequelae. Thus, treatment is not required. However, treatment with topic corticosteroids may hasten
the resolution of lesions [33,34]. Sun protection is also advised, including avoidance of direct
sunlight and fluorescent light. (See "Overview of cutaneous photosensitivity: Photobiology, patient
evaluation, and photoprotection".)

Adrenal insufficiency — Prolonged in utero exposure to fluorinated glucocorticoids

(eg, betamethasone or dexamethasone) can lead to adrenal hypoplasia and result in neonatal
adrenal insufficiency [35]. This is a rare complication that can be anticipated and for which neonates
can be tested. Neonatal hypotension that potentially results from adrenal insufficiency should be
treated empirically with hydrocortisone in addition to standard supportive care. The diagnosis and
treatment of adrenal insufficiency are discussed in greater detail separately. (See "Diagnosis of
adrenal insufficiency in children" and "Treatment of adrenal insufficiency in children".)

Autoimmune and/or rheumatic disease — Children who have had NL may be at increased risk of
developing an autoimmune and/orrheumatic disease, albeit this is rare. In a cohort of 49 children
followed to at least the age of eight years, six patients (12 percent) developed a well-defined
systemic rheumatic and/or autoimmune disease [36]. The disorders noted in these children included
oligoarticular and polyarticular juvenile idiopathic arthritis, psoriasis, thyroid disease, iritis, type 1
diabetes mellitus, and nephrotic syndrome. None of the children with neonatal disease, nor any of
their unaffected siblings, developed systemic lupus erythematosus (SLE) during at least eight years
of follow-up.
PREVENTION OF NL IN SUBSEQUENT PREGNANCIES — Hydroxychloroquine is an antimalarial
drug that inhibits ligation of endosomal Toll-like receptors (TLRs). It is one of the drugs used to treat
systemic lupus erythematosus (SLE) and is often continued during pregnancy because it is
associated with minimal risk to the fetus and mother. Data suggest it may also decrease the risk of
the fetus developing cardiac-NL when there is a prior history of cardiac-NL in a sibling. The efficacy
in the setting of prior cutaneous-NL is not known. Thus, we suggest pre-emptive treatment with
hydroxychloroquine (400 mg orally once a day) in pregnant women with anti-Ro/SSA (Sjögren
syndrome type A antigen) and/or anti-La/SSB (Sjögren syndrome type B antigen) antibodies who
have previously given birth to a child with cardiac-NL, regardless of maternal health status.
Hydroxychloroquine is initiated between 6 and 10 weeks gestation in women who are not already on
the medication to optimize effective exposure by 16 weeks of gestation. Pre-emptive treatment is not
used if there is only a history of noncardiac-NL. (See "Safety of antiinflammatory and
immunosuppressive drugs in rheumatic diseases during pregnancy and lactation" and "Pregnancy in
women with systemic lupus erythematosus", section on 'Selective use allowed during pregnancy'.)

Several retrospective studies have suggested that hydroxychloroquine decreases the overall risk of
cardiac-NL [37-39]. One retrospective study based upon data from NL registries in the United States,
France, and the United Kingdom included pregnancies of women who had previously given birth to a
child with cardiac-NL and had anti-Ro/SSA antibodies, regardless of maternal health status (ie, the
mother could have been asymptomatic at the time of pregnancy or have had an associated
autoimmune disease) [38]. Two-hundred fifty-seven pregnancies (40 exposed and 217 unexposed to
hydroxychloroquine) were identified. Cardiac-NL developed in 3 of 40 (7.5 percent) of exposed
fetuses and 46 of 217 (21.2 percent) of unexposed fetuses, with 10 fatalities in the unexposed
group. Another retrospective, single-center study examined 268 pregnancies, 73 of which had
exposure to hydroxychloroquine throughout the pregnancy [39]. Ninety-nine offspring developed
cardiac NL, with a nonsignificant trend toward a protective effect of hydroxychloroquine on cardiac
NL. A prospective, open-label study (not randomized because of the rarity of the disease) to confirm
these observations is ongoing (clinicaltrials.gov).

Preventive treatment with glucocorticoids is not recommended, even in mothers with a previously
affected fetus, because the risks of these medications in the majority of expectant mothers and their
fetuses who would be unnecessarily exposed outweigh the uncertain potential benefits.

Intravenous immune globulin (IVIG) is also not recommended. In two multicenter, prospective,
observational studies, IVIG at replacement doses (400 mg/kg) given every three weeks from weeks
12 to 24 was not effective in preventing congenital heart block (CHB) [40,41]. It is unknown whether
higher anti-inflammatory (1 to 2 g/kg) doses would be efficacious.

SUMMARY AND RECOMMENDATIONS

●Neonatal lupus (NL) is a passively acquired autoimmune disease that occurs in offspring of
mothers with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren
syndrome type B antigen) antibodies. The most serious complication of NL is complete heart
block. (See 'Introduction' above.)
●Prenatal treatment of first-degree block is perhaps the most controversial because of the risks
of therapy and absence of consistent evidence regarding benefit. We would first confirm within
24 hours that the PR interval is indeed prolonged (>150 msec). If verified, we suggest starting
the mother on a fluorinated glucocorticoid (oral dexamethasone 4 mg per day
or betamethasone 3 mg per day) (Grade 2C). The glucocorticoid is discontinued if there is
progression to complete block and no evidence of extranodal disease. If the block remains at
first degree or reverts to normal sinus rhythm (NSR), then the glucocorticoid is continued to 26
weeks gestation and then stopped since vulnerability decreases after that time period and
further inflammatory insult is less likely. Observation rather than treatment is a reasonable
alternative. (See 'First-degree heart block'above.)
●We suggest prenatal treatment with fluorinated glucocorticoids (oral dexamethasone 4 mg per
day or betamethasone 3 mg per day) for mothers of fetuses with second-degree heart block,
beginning as soon after detection as is feasible (Grade 2C). Therapy is usually continued
through the end of pregnancy if the heart block reverts, although discontinuation after 26 weeks
(less vulnerable period) is also reasonable. Glucocorticoids are typically discontinued if the
fetus progresses to third-degree heart block or does not improve if there is no other indication
for treatment with glucocorticoids (eg, cardiomyopathy, myocarditis), although continuing
therapy through the end of pregnancy is also reasonable. (See 'Second-degree heart
block' above.)
●Reversal of prenatal third-degree block with glucocorticoid therapy has not been documented,
and most studies suggest treatment with glucocorticoids does not improve survival or prevent
the development of extranodal disease. Thus, we suggest against treating in utero third-degree
block without any signs of myocarditis or cardiomyopathy with glucocorticoids (Grade 2C). Most
of these patients will require cardiac pacing after birth. (See 'Third-degree heart block' above
and "Congenital third degree (complete) atrioventricular block".)
●An electrocardiogram (ECG) should be performed on all neonates born to mothers with anti-
Ro/SSA and/or anti-La/SSBantibodies, even in the absence of any cardiac abnormalities
detected with in utero monitoring. In addition, a pediatric cardiologist should be consulted for
further evaluation including echocardiograms and additional ECGs if fetal monitoring has
detected any degree of heart block in utero (including PR intervals >3 standard deviations [SD]
or 150 msec, or second-degree block that reversed) and/or if the neonatal ECG is abnormal.
(See 'Infants and children at risk for complete heart block' above.)
●There appears to be no risk of later cardiac involvement in patients who have no evidence of
heart block of any degree in utero or at birth. Second-degree block detected in utero or at birth
can progress to complete heart block. Infants and young children with complete heart block
usually require a pacemaker at some point in life. The prognosis following pacemaker
implantation is excellent for most children, although development of heart failure may occur
despite the complete clearance of maternal autoantibodies from the child's circulation. The rash
of NL generally does not cause scarring and disappears within six to eight months.
(See 'Postnatal management' above and "Congenital third degree (complete) atrioventricular
block", section on 'Prognosis'.)
 ●We suggest pre-emptive treatment with hydroxychloroquine (400 mg orally once a day) in
pregnant women who have previously given birth to a child with cardiac manifestations of NL
(cardiac-NL) and who have anti-Ro/SSA and/or anti-La/SSB antibodies, regardless of maternal
health status (Grade 2B). Hydroxychloroquine should be initiated between 6 and 10 weeks
gestation in women who are not already on the medication. (See 'Prevention of NL in
subsequent pregnancies' above.)

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