Version May 2024
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 [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 topic reviews the epidemiology, pathogenesis, clinical manifestations, and diagnosis of NL. The management and outcomes of NL are discussed in greater detail separately. Pregnancy in individuals with systemic lupus erythematosus (SLE) and diagnosis and management of fetal arrhythmias are also reviewed elsewhere. (See "Neonatal lupus: Management and outcomes" and "Pregnancy in women with systemic lupus erythematosus" and "Fetal arrhythmias".)
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 females who have antibodies to Ro/SSA (Sjögren's disease type A antigen) and/or La/SSB (Sjögren's disease type B antigen; albeit anti-La/SSB in isolation is very rare) [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 almost never the cause of heart block occurring after the neonatal period or even after 26 gestational weeks (1 in 20 mothers of children diagnosed after birth had anti-Ro antibodies) [10]. The risk of developing cutaneous manifestations of NL is 4 to 16 percent in offspring of anti-Ro/SSA- and anti-La/SSB-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's disease, in many other cases, the mother is totally asymptomatic and becomes aware of these antibody reactivities solely based upon the finding of a bradyarrhythmia in the fetus or a skin rash in the neonate [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 symptoms consistent with an autoimmune disease such as dry eyes or dry mouth, arthritis, Raynaud, rashes, or sufficient criteria to be classified with a known autoimmune disease (more commonly Sjögren's disease 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/SSA was used for initial screening) [14]. For patients with SLE, the estimated prevalence of this antibody is 40 percent [15] and, in those with Sjögren's disease, 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 individuals and the rate of CHB of 1 in 15,000 to 1 in 22,000 live births [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]. However, recurrence rates of CHB do vary since some studies include first-degree block and even isolated endocardial fibroelastosis. In addition, one study suggested that recurrence rates were even higher in pregnancies not exposed to hydroxychloroquine [21].
PATHOGENESIS — NL is presumed to result from the transplacental passage of maternal anti-Ro/SSA (Sjögren's disease type A antigen) and/or anti-La/SSB (Sjögren's disease type B antigen) antibodies that affect neonatal organs, particularly the heart and skin. The pathogenesis almost assuredly requires more than the presence of these antibodies in the fetal circulation (eg, fetal genetic factors and environmental stressors) [9,18] since even females with extremely high titers, which do increase risk, can have normal pregnancies [22,23]. In addition, discordance of disease in monozygotic twins has been reported. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)
Although the precise mechanism of injury is not fully elucidated, it is proposed that heart block results from binding of anti-Ro/SSA and/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 [24-27]. Autoantibodies may also act by inhibiting calcium currents mediated by cardiac L and T type calcium channels [28-32]. 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. Some studies have suggested a role for type I interferon (IFN) in the pathogenesis based upon transcriptomic evaluation of cells isolated from fetal hearts with CHB [33,34]. In addition, neonates exposed to maternal anti-Ro/La antibodies have higher frequencies of natural killer (NK) cells and increased type I and II IFN gene signatures compared with nonantibody-exposed neonates. These findings were observed in neonates without any cardiac abnormalities, suggesting that these changes, while potentially contributory to the risk of congenital heart block (CHB), are themselves insufficient to promote clinical injury [35]. Other data suggest that fibroblast heterogeneity (S100A4+ expressing and canonical myofibroblasts) induced by anti-Ro/SSA activated macrophage secretion of type I IFN contributes to tissue injury [36].
Autoantibodies — Several studies have established the association between anti-Ro/SSA and anti-La/SSB antibodies and NL by prospectively monitoring offspring of females with these reactivities [4-7]. Although fetal disease is often referred to as a pathologic readout of passively acquired autoimmune disease, many females 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.)
It has been stated that the incidence of CHB is more common in offspring of females with high titers of anti-Ro/SSA and anti-La/SSB compared with mothers with low titers [23,37-41], and very low titers probably confer no risk at all [42]. One study suggested increased risk in those with the highest titers of anti-Ro/SSA60 and supported that enhancing the assay measuring range allows improved specificity of identifying pregnancies at risk of cardiac-NL [23]. However, the difficulty in making such a statement relates to the definition of high titer. The immunoassay used by many commercial laboratories defines values as positive if >1 enzyme-linked immunosorbent assay (ELISA) unit, with a reported upper measurement limit of 8 ELISA units. Even titers >8 may not reach a threshold for the development of NL manifestations. Whether mothers with titers <8 should undergo less frequent surveillance is under debate.
Even if "high titers" are established, antibodies alone are 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 [39] but was independent of anti-La/SSB titers in another [40]. The risk of cutaneous NL was higher in neonates of mothers with both anti-Ro/SSA and 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 [40]. In addition, one study reported a lower risk of NL in offspring of females with anti-idiotype antibodies to La/SSB [43].
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 a ribonucleic acid (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 ELISAs for anti-Ro60 antibodies is low and may result in false negatives [39,44,45]. Newer assays that use native antigen for SSA/Ro60 are more sensitive. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)
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 [46,47]. Although several groups have confirmed the high prevalence of the p200 response in females giving birth to a child with cardiac-NL, there have been inconsistencies regarding its utility in high-risk assessment relative to the pregnancy exposure [48]. In one study, maternal reactivity to p200 did not confer an added risk of fetal conduction defects over full-length Ro52 or Ro60 autoantibodies [49]. 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. Most commercial assays do not evaluate antibody reactivity to p200.
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 [11,50]. 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 [51] and another of advanced block associated with anti-RNP only [52].
●The fact that heart block develops in only a minority of subsequent pregnancies, despite the persistence of maternal anti-Ro/SSA and/or anti-La/SSB antibodies and no substantive change in titers between affected and unaffected pregnancies 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 [53,54]. 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 [55]. 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 [56].
●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 [57]. 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 25 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) [58]. 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 [59,60], 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 [61]. In a cohort of 57 infants, the rash was recognized at a mean of six weeks and lasted an average of 17 weeks [62]. 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 [63]. Telangiectasia on the face or genitals occur in approximately 10 percent of patients beginning at 6 to 12 months of age [64]. 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 [65,66]. (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 [61]. Typical findings are vacuolar alterations at the dermoepidermal interface and adnexal structures [67]. Some patients present with urticaria-like lesions that have superficial and deep perivascular and periadnexal lymphocytic infiltrates.
Cutaneous involvement is one of the most common noncardiac manifestations of NL, affecting 4 to 16 percent of anti-Ro/SSA (Sjögren's disease type A antigen) and/or anti-La/SSB (Sjögren's disease type B antigen) antibody-exposed infants [5-7,68].
Heart block — Patients with NL may develop first-, second-, and third-degree heart block. This most commonly occurs between 18 to 25 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 identified by echocardiogram. However, second-degree block may be more readily identified with new modalities of identification such as fetal heart rate and rhythm monitoring by home Doppler [69]. 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 'Atrioventricular 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 [18,70-73]. 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) [71]. The dysrhythmia is usually not permanent [71] and, if sustained, carries a good prognosis if not associated with endocardial fibroelastosis (EFE), ventricular dysfunction, and/or AV nodal block [72].
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 [74]. 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 [75]. 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 and/or anti-La/SSB 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 [76-78]. 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) [74,76,79].
●EFE can occur in addition to conduction defects [10,80] 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 [81,82]. 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 [80]. 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 [77,83].
●Aortic dilation is associated with maternal anti-Ro/SSA antibodies. In a large series of over 200 children exposed to these antibodies, aortic dilation was present on echocardiogram in 13.5 percent of studies performed in the first year of life, 15 percent evaluated at >1 to 17 years of age, and in 9.4 percent tested at >17 years of age [84]. Some patients had new-onset aortic dilation after a previously normal echocardiogram. Thus, monitoring for late effects is recommended. The aortic dilation seen in cardiac NL is felt to be an epiphenomenon in the presence of chronic bradycardia and increased stroke volumes that result from poor contractility, with documented improvement after initiation of dual-chamber pacing [85,86]. There are no reports of aortic dilation in cardiac NL leading to aortic dissection or progressing to the point of requiring aortic surgery.
Pulmonary hypertension — In a French registry, 4 of 73 anti-Ro-exposed neonates developed pulmonary hypertension. Diagnosis was suspected on transthoracic echocardiography at a median age of 42 days and confirmed by right heart catheterization. Lung computed tomography (CT) demonstrated ground glass anomalies in all. Management included immunosuppressive therapy in three and additional sildenafil in two. Pulmonary hypertension resolved in all at a median age of four weeks after treatment initiation and after one year for the one child who did not receive specific treatment [87].
Other manifestations — In addition to rash and cardiac abnormalities, there may be transient hepatic, hematologic, neurologic, or radiologic manifestations of NL [63]. Hydrops fetalis, a complication of NL due to cardiac injury, is seen in some fetuses with complete heart block [1,88]. 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 [61,89,90]. In one report, hepatobiliary disease occurred in 19 of 219 infants (9 percent) with NL, usually in conjunction with either cardiac or cutaneous involvement [91]. In another series of 54 infants with NL, 15 percent had transiently elevated transaminase levels [92]. Elevated liver enzymes can persist beyond six months [93].
●Hematologic manifestations also have been described, including anemia, neutropenia, thrombocytopenia, and, rarely, aplastic anemia [5,61,89,90,92,94-97]. The published literature suggests a range from 0 to 27 percent, with the more characteristic abnormality being low neutrophils. However, the true frequencies of hematologic manifestations is not known, since a complete blood count is not normally performed on otherwise healthy babies [96-98]. Neutropenia was present in 25 of 107 tested infants born to mothers with anti-Ro/SSA or anti-La/SSB antibodies in one prospective study, but no cases of neonatal sepsis occurred in these neutropenic children [5]. In a prospective study of 50 infants exposed to anti-Ro/SSA in utero, 1 (2 percent) had low platelets at birth, and 2 (4 percent) had low neutrophils. By three months of life, none had low platelets, but the number of infants with low neutrophils had risen to 12 (24 percent) [78]. However, an earlier prospective study of 51 anti-Ro/SSA-exposed infants found no cases of neutropenia, lymphopenia, or anemia; while two of the infants (3.9 percent) had thrombocytopenia, these cases may have been caused by other antiplatelet autoantibodies [79]. When limited only to anti-Ro/SSA and/or anti-La/SSB females with a diagnosed connective tissue disease, 219 prospectively evaluated pregnancies resulted in infants with 33 (15 percent) cases of cutaneous NL, 41 (18.7 percent) cases of neutropenia, and 3 (1.4 percent) cases of thrombocytopenia [98].
●Neurologic manifestations have been described [61], 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 [99]. 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 [100]. 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 [101].
●A unique radiographic finding of NL is stippling of the epiphyses (chondrodysplasia punctata) [61]. 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 or the affected child (if the mother is not tested for some reason, even though maternal testing is indicated) has anti-Ro/SSA (Sjögren's disease type A antigen) and/or anti-La/SSB (Sjögren's disease 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's disease type A antigen) and anti-La/SSB (Sjögren's disease 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 individuals at risk of having a pregnancy complicated by NL. Individuals who are more likely to have anti-Ro/SSA and anti-La/SSB antibodies include those with systemic lupus erythematosus (SLE), Sjögren's disease, rheumatoid arthritis, mixed connective tissue disease, an undifferentiated autoimmune disease, or NL with cutaneous and/or cardiac manifestations in a previous pregnancy. Individuals with these identifiable risk factors should be tested before conception or as early in pregnancy as possible. Although many of these individuals will have previously been tested and presence or absence of these antibodies is unlikely to change over time, the cautious approach is to recheck when pregnancy is confirmed. Routine screening of all pregnant persons for anti-Ro/SSA and anti-La/SSB antibodies is not performed, but this may change if preventive therapies are validated. (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 individual, since NL in a fetus can be the first sign that the mother has anti-Ro/SSA and/or anti-La/SSB antibodies. (See 'Autoantibodies' above.)
With regard to antibody testing, titer is highly relevant for reasons related to both underlying pathology and clinical management. Given the identification of fetal injury in the middle to late second trimester, it is pertinent that neonatal Fc receptor (FcRn) mediated placental transport of maternal IgG at this timepoint in gestation is only a fraction of the efficiency achieved at term [102]. This biology predicts that cardiac injury during the gestation period of fetal vulnerability should require very high titers of antibody.
●A US-based study examined the negative predictive value of antibody titers to identify pregnancies at low risk of fetal atrioventricular (AV) block that may not require surveillance [42]. Excluding females with previously affected children and leveraging samples obtained from anti-SSA/Ro-exposed pregnancies with and without congenital heart block (CHB), no case of block developed among subjects with anti-Ro52 and anti-Ro60 titers of <110 arbitrary units per milliliter using the multiplex bead assay of the Associated Regional and University Pathologists Laboratories (n = 141). Applying these 100 percent negative predictive value thresholds, approximately 50 percent of the anti-Ro/SSA antibody pregnancies that ultimately had no CHB could be excluded from surveillance.
●In a report from Canada of a prospectively followed cohort of 240 mothers, none of 14 negative for anti-Ro60 or 93 with levels considered positive but lower than the upper limit of the analytic measuring range of a commercial assay available in Toronto had a child with CHB [23]. In contrast, of 133 mothers with "high" positive anti-Ro60 antibodies exceeding the analytical measuring range, nine cases (7 percent) developed CHB. Extended evaluation of 122 mothers with further dilutions revealed that risk increased for those in the uppermost range for anti-Ro60, reaching 29 percent (6/21) and 56 percent (5/9) for the highest range obtained for both anti-Ro52 and Ro60, both rates higher than previously reported recurrence rates.
●A prospective study of over 400 anti-Ro positive pregnancies is underway (Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly; NCT04474223), and early unpublished data confirm that low anti-Ro/SSA titer does not pose risk and that high titer (top quartile of both the anti-Ro60 and 52 assays) confers an 8 percent risk if there is no history of a previously affected child [103].
Fetal surveillance for heart block — Recommendations regarding monitoring during pregnancies exposed to anti-Ro/SSA have varied, but most agree the driving rationale is that detection of heart block at earlier stages should improve outcomes [104-106]. Although persons with low titer antibodies are less likely to have offspring with cardiac-NL than those with high titers [37,40,41,49], in practical terms, this is difficult to implement in the clinical setting because commercial laboratories have different cutoff values. Nevertheless, values <8 enzyme-linked immunosorbent assay (ELISA) units in commercial laboratories that use the immunoassay discussed above (see 'Autoantibodies' above) may not warrant intense serial surveillance. The most vulnerable period for the fetus is during gestational weeks 18 to 25 [7]. Normal sinus rhythm (NSR) can progress to complete block in seven days during this high-risk period and even within 24 hours as detected by home Doppler [69]. New onset of heart block is less likely to develop during the 26th through the 30th week, and it rarely develops after 30 weeks of pregnancy.
Second-degree atrioventricular block (2° AVB) is potentially reversible based upon a meta-analysis [107] of five studies [1,88,108-110] in which overall regression to NSR was reported in 24 percent regardless of therapy. Another study of 21 cases of 2° AVB revealed three regressing to NSR [111]. Of these, one had received dexamethasone, and the other two regressed spontaneously (however, one mother was seronegative).
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 [112]. The American Heart Association suggests a few additional weeks of serial assessment, starting at 16 weeks and continuing through 28 weeks of gestation [104]. Echocardiography enables the diagnosis of first-degree heart block and second-degree block that does not manifest as fetal bradycardia, 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 [105,113,114]. However, fetal atrioventricular intervals were not predictive of progression of heart block in one small study [115].
Controversy regarding fetal surveillance has escalated with the publication of a consensus statement by the Society for Maternal-Fetal Medicine (SMFM) recommending that serial fetal echocardiograms for assessment of the PR interval not be routinely performed in patients with anti-SSA/SSB antibodies outside of a clinical trial setting, since the scientific rigor of the data remain insufficient and treatment is not convincingly effective [116]. This statement was criticized in a rebuttal letter from many pediatric cardiologists and rheumatologists [117] pointing out that this statement differed from that of the American College of Rheumatology (ACR) Reproductive Health Guideline, which conditionally recommends fetal echocardiograms, recognizing that this area is controversial, and that risks and benefits should be discussed with the patient in a shared decision-making process [118].
Complete heart block (and usually second-degree block) results in fetal bradycardia that can be detected by routine fetal auscultation. An emerging approach that is inexpensive and that empowers the mother to take part in their own pregnancy surveillance is home fetal heart rate and rhythm monitoring (FHRM), which can be used in combination with surveillance echocardiography weekly or every two weeks [69]. While reported studies have only evaluated twice-daily home monitoring, thrice-daily monitoring is also an option and is under study (NCT04474223). Early detection of a transition from NSR to incomplete block may represent the most optimal time for intervention to make a difference. No false-negative results with the home Doppler were reported, supporting that the Doppler did not miss a clinically meaningful abnormality that was later identified by echocardiogram. Moreover, the false-positive rates were likewise low. Further studies are ongoing in this emerging area of surveillance. (See 'Heart block' above and "Fetal arrhythmias", section on 'Modalities for diagnostic evaluation'.)
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 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's disease type A antigen), anti-La/SSB (Sjögren's disease 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 [119]:
●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 or transient 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 [120], erythema multiforme (picture 8 and picture 9 and picture 10), and annular erythema of infancy [121]. 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 "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations' and "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)
●Cutis marmorata telangiectasia congenita (CMTC) – These lesions can be confused with the reticular, atrophic lesions of NL [122]. However, CMTC lesions most commonly affect the limbs, particularly the lower extremities, and are usual unilateral. The affected 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 "The autoinflammatory diseases: An overview" 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 "Fetal arrhythmias", section on 'Bradyarrhythmias'.)
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Neonatal lupus (NL) is a passively acquired autoimmune disease that occurs in offspring of mothers with anti-Ro/SSA (Sjögren's disease type A antigen) and/or anti-La/SSB (Sjögren's disease type B antigen) antibodies. (See 'Introduction' above and 'Pathogenesis' above.)
●Risk of NL with congenital heart block – The risk of having a child with congenital heart block (CHB) 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. While prospective confirmation awaits, individuals with titers of anti-Ro/SSA antibodies that are considered "low" may not be at risk for CHB, and risk seems to increase as titer increases. (See 'Epidemiology' above.)
●Clinical manifestations – The primary clinical features are heart block and a rash that is usually found on the scalp and periorbital areas (picture 1 and picture 2). Patients may also present after birth with hepatic or hematologic abnormalities. The large majority of cases of congenital 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".)
●Diagnosis – 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 (in the case of cutaneous disease).
•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.
●Fetal surveillance for heart block – While there is not uniform consensus in the recommendations provided by societies representing maternal fetal medicine, pediatric cardiology, and rheumatology, biweekly or weekly fetal echocardiography from the 18th through the 26th week of pregnancy is often advised in females with anti-Ro/SSA and/or anti-La/SSB antibodies (albeit anti-La/SSB antibodies are extremely rare in isolation without anti-Ro/SSA), regardless of health status. 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. For females with "low" titers of antibodies (definition of which varies with different laboratories), surveillance may not be needed at all. Frequent Doppler monitoring by the pregnant female may identify earlier (incomplete block), potentially reversible disease. (See 'Fetal surveillance for heart block' above.)
●Maternal screening for anti-Ro/SSA and La/SSB antibodies – 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 female, warrants immediate maternal testing for anti-Ro/SSA and La/SSB antibodies if not previously performed. In addition, a periorbital rash in an infant less than six months warrants antibody testing in the mother. (See 'Maternal screening' above and 'Postnatal testing' above.)
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