Neonatal Lupus Erythematosus

Etiology

NLE results from passive transplacental transfer of maternal anti–Ro/SSA and anti–La/SSB autoantibodies to the fetus. Anti-Ro/SSA antibodies recognize 2 proteins: Ro52, localized in the nucleus and cytoplasm, and Ro60, localized in the nucleus and nucleolus. Anti-La/SSB antibodies target a 47 kDa protein between the nucleus and cytoplasm. No specific epitope has been identified; however, animal models suggest a predominant role for anti-Ro52 in NLE pathogenesis.[1][3]

Epidemiology

NLE is a rare disorder, occurring in approximately 1 in 12,500-20,000 live births. The incidence rate is about 2% among infants born to mothers with anti-Ro/SSA or anti-La/SSB antibodies, with an 18% to 20% recurrence risk in subsequent pregnancies. These autoantibodies are present in 0.1% to 1.5% of healthy pregnant women. Still, they are common in autoimmune diseases—detected in up to 90% of patients with Sjögren syndrome, 20% to 30% with SLE, and 3% to 4% with rheumatoid arthritis. At delivery, about 25% of mothers of affected infants are asymptomatic, and another approximately 25% have only undifferentiated autoimmune features; however, about half of initially asymptomatic mothers develop systemic autoimmune disease, most often SLE or Sjögren disease, within 3 years postpartum.[8][9][10][11][12]

Cardiac involvement is the most serious complication of NLE, accounting for 80% to 95% of severe congenital atrioventricular (AV) block cases in the neonatal period, but only 5% of AV block cases thereafter. In mothers with a previously affected child, the recurrence risk in subsequent pregnancies is approximately 18%, representing a 6 to 10-fold increase.[4][13] Cutaneous manifestations occur in 7% to 16% of infants born to mothers who are anti-Ro/La positive, typically appearing only after birth. Less commonly, isolated cutaneous NLE without heart block is reported in infants of mothers with anti-U1 RNP antibodies.[14][15]

Pathophysiology

Fibrosis of the fetal cardiac conduction system, particularly the AV node, leads to congenital AV block in NLE. The predominant hypothesis is that maternal anti-Ro/SSA antibodies initiate an inflammatory cascade in fetal cardiac tissue. Injury typically occurs between 18 and 24 weeks' gestation, coinciding with the developmental expression of SSA/Ro antigens on the surface of fetal cardiomyocytes. Histopathology reveals replacement of the AV node and surrounding myocardium with fibrous tissue and calcifications, often accompanied by dense macrophage and T-cell infiltration.

An additional proposed mechanism is molecular mimicry between the Ro antigen and the L-type calcium channels in the heart. Maternal anti-Ro antibodies may bind these channels, disrupting calcium flux crucial for cardiac electrical propagation and conduction through the AV and sinoatrial node. This could explain conduction abnormalities preceding overt fibrosis. Higher maternal autoantibody titers increase the likelihood of AV block. Cardiac involvement in NLE may extend beyond the conduction system. Endocardial fibroelastosis—a thickening of the ventricular endocardium due to collagen and elastin deposition—can result in intrauterine myocarditis and has been reported in some NLE cases, often associated with complete heart block.[16][17][18][19]

Other NLE manifestations (such as the cutaneous rash, hepatobiliary involvement, and hematologic cytopenias) are typically transient, resolving spontaneously within months after birth as maternal autoantibodies are cleared from the infant's circulation. The pathogenesis of cutaneous NLE involves maternal antibody deposition at the dermal-epidermal junction. Skin biopsies from active lesions show a lupus-like pattern with IgG and C3 complement deposition along the basement membrane zone and interface dermatitis changes. Maternal anti-U1 RNP (small nuclear ribonucleoprotein associated with U1 spliceosomal ribonucleic acid) antibodies have been linked to some cutaneous manifestations. Hepatic involvement may present as mild lupus-like hepatitis with lymphocytic infiltrates. Hematologic involvement, including neutropenia and thrombocytopenia, likely results from passive transfer of anti-SSA/SSB antibodies binding fetal blood cell elements or forming immune complexes, leading to peripheral destruction.[2][3]

History and Physical

Clinical manifestations of NLE are diverse, affecting the skin, heart, liver, hematologic system, and occasionally the central nervous system. Maternal history should assess prior pregnancies affected by NLE, autoimmune disease, or known anti-Ro/SSA or anti-La/SSB antibody positivity. While most manifestations are transient, a significant proportion of infants develop irreversible cardiac arrhythmias, the most distinctive and serious complication.[20]

Cutaneous Manifestations

Characteristic skin lesions occur in up to 40% of affected infants, typically emerging within the first weeks of life. Eruptions are often misdiagnosed as birth trauma, infection, or eczema, especially if the mother is asymptomatic. Lesions are often absent or unclear at birth and appear after sun or ultraviolet exposure. They present as annular or elliptical erythematous plaques with raised margins and central clearing, most commonly on the face, especially in teh periorbital region, producing a "raccoon-eye" appearance, in 95% of cases, followed by the scalp (60%), trunk with or without groin (25%), extremities (25%), and rarely, generalized involvement (10%).[21][22][23] The classic rash resolves within 4 months in approximately 50% of cases, by 7 months in 80%, and within a year in all cases. Approximately 20% of affected neonates develop persistent cutaneous changes, including telangiectasia, hyperpigmentation, and atrophy.[24][25][26]

Cardiac Manifestations

Newborns with NLE typically have a structurally normal heart. Cardiac involvement, present in approximately 25% of cases, is the most distinctive manifestation and most often presents as congenital heart block, which may be first-, second, or, most commonly, third-degree AV block. Congenital heart block is usually detected in utero between 18 and 24 weeks' gestation, presenting as fetal bradycardia (ventricular rates 40–80 bpm). Other cardiac manifestations include sinus bradycardia, QT-interval prolongation, cardiomyopathy, congestive heart failure, myocarditis, and structural or valvular defects such as ventricular septal defects, ostium secundum type atrial septal defects, patent foramen ovale, patent ductus arteriosus, pulmonary stenosis, pulmonary valve dysplasia, and fusion of the chordae tendineae of the tricuspid valve.[7][27][28]

Affected neonates may have persistent bradycardia or present with signs of congestive heart failure (poor feeding, diaphoresis, pallor, edema, lethargy, tachypnea, hepatomegaly, prominent jugular veins, and crackles on auscultation of the lungs). Cardiac auscultation may reveal a slow, regular heart rate, variable S1 intensity, or fixed split S2. Five percent to 10% of infants present with a severe AV block that precipitates myocardial dysfunction due to endocardial fibroelastosis and myocardial fibrosis, associated with right ventricular pacing and subsequent ventricular asynchrony and dysfunction.[1][27][29]

Hematological and Hepatobiliary Involvement

Hematologic findings in NLE include anemia, neutropenia, and thrombocytopenia, which are generally mild and transient. Aplastic anemia has been reported in approximately 20% of cases. Hepatic involvement occurs in 15% to 25% of cases and may present as asymptomatic elevation of aminotransferases, cholestasis, hepatomegaly, or splenomegaly, typically resolving within months.[30][31][32]

Neurological Involvement

Central nervous system involvement in NLE is rare. The classical manifestation is benign, transient hydrocephalus resulting in macrocephaly.[30]

Evaluation

When NLE is suspected or identified, a thorough evaluation should be performed to assess for associated systemic involvement. This includes targeted assessment of cardiac, cutaneous, hepatic, hematologic, and, when indicated, neurologic manifestations. 

Laboratory Testing

Diagnosis of NLE requires detecting maternal autoantibodies, ideally in the other if her serologic status is unknown, or in the infant's serum, where transplacental antibodies persist for 6 to 8 months. Testing should include anti-Ro/SSA and anti-La/SSB antibodies. If these are negative but clinical suspicion remains high, particularly in cases of isolated cutaneous involvement, anti-U1 ribonucleoprotein testing may be warranted. Additional evaluations may include complete blood count (to detect cytopenias), liver function tests, and inflammatory markers, although these are often normal or nonspecific.

Electrocardiogram

All infants with suspected NLE should undergo an electrocardiogram (ECG) to evaluate for AV block (prolonged PR interval), bundle branch block, or other rhythm disturbances. A normal ECG at birth is generally reassuring; however, if there was a known in utero first- or second-degree block that resolved, serial ECGs are recommended during the neonatal period, as late progression can occur. The risk of AV block is higher in infants born to mothers with a history of NLE-associated cardiac manifestations.

Echocardiography

Echocardiography is essential for both fetal screening and postnatal evaluation. In at-risk pregnancies (maternal anti-Ro/SSA or anti-La/SSA positivity), serial fetal echocardiograms are recommended beginning at age 16 weeks' gestation. Fewer than 20% of cases are detected after 26 weeks; thus, screening frequency may be reduced beyond that point if no abnormalities are identified. Fetal echocardiography can assess conduction delays via Doppler measurement of the mechanical PR interval and detect early signs of heart block or myocarditis, such as fetal bradycardia, atrial echogenic nodules (calcifications), or valvular regurgitation. 

A mechanical PR interval greater than 150 ms or evidence of second-degree block warrants closer surveillance or potential intervention. Postnatally, echocardiography is indicated in any infant with prenatal cardiac abnormalities or an abnormal ECG. Some experts recommend a screening echocardiogram to detect subclinical structural or functional cardiac changes even in asymptomatic infants with normal ECGs. In confirmed heart block, echocardiography is used to evaluate ventricular function, chamber dimensions, valvular competence, and signs of cardiomyopathy.[1][20][33][34]

Surveillance 

Approximately 2% of AV block cases are detected postnatally during the neonatal period, highlighting the importance of monitoring at-risk newborns for the first month of life. Beyond 28 days, routine cardiac monitoring screening is not recommended unless a heart abnormality has been diagnosed. A pediatric cardiologist must closely monitor first- and second-degree AV block identified after birth. In infants with a history of transient first-degree AV block in utero, ECG and echocardiography are recommended at 1 year of age; for those with transient second-degree block that resolved by birth, evaluation should be performed within the first 3 months of life.[1][35][36]

Key Diagnostic Criteria

NLE is diagnosed when a neonate presents with 1 or more characteristic clinical features, such as congenital heart block, typical rash, cytopenias, or hepatic involvement, and either the mother or infant tests positive for anti-Ro/SSA or anti-La/SSB antibodies. Because maternal antibodies can persist in the infant for up to 6 months, serologic testing of the neonate reflects maternal antibody status. Importantly, congenital heart block in an antibody-negative infant is not considered NLE and should prompt evaluation for alternative causes.[37]

Treatment / Management

Reversible noncardiac features such as rash, cytopenias, and liver dysfunction typically resolve spontaneously and are managed with observation. Photoprotection is central to the management of cutaneous involvement. Topical corticosteroids may be beneficial in select cases; however, systemic therapies like hydroxychloroquine are not routinely indicated. Persistent telangiectasias may later be treated with laser therapy. Symptomatic anemia or thrombocytopenia can be managed with blood or platelet transfusions, glucocorticoids, or intravenous immunoglobulin, all of which have demonstrated efficacy in certain cases.[4][22]

Cardiac involvement, especially AV heart block, is associated with significant morbidity and mortality and requires coordinated care by an interprofessional team. Management includes maternal serologic screening, serial fetal echocardiography, and parental counseling. Fluorinated corticosteroids (eg, betamethasone or dexamethasone) have been used to prevent progression of fetal AV heart block based on early reports; however, subsequent studies have failed to confirm consistent benefit, and their use carries risks such as fetal growth restriction and oligohydramnios. Intravenous immunoglobulin has also been investigated for prevention and treatment, but results remain inconclusive.

Hydroxychloroquine (400 mg daily), initiated between 6 and 10 weeks' gestation, has been associated with a reduced risk of neonatal cardiac lupus, especially in women with a prior affected child. Beta-receptor agonists may improve fetal heart rate and stroke volume, but do not reduce the risk of AV block development. A ventricular rate of less than 55 per minute, hydrops fetalis, cardiomegaly, atrioventricular valve regurgitation, or low aortic flow velocity indicates poor fetal prognosis and outcome. Temporary pacing may be used while awaiting definitive therapy. Infants with a first-degree or stable second-degree block may be observed, as conduction may improve with the clearance of maternal antibodies. Long-term cardiology follow-up is essential. Despite intervention, up to 15% may develop late-onset cardiomyopathy.

In uterol treatment options for AV block are limited. The primary approach involves close monitoring and coordinated follow-up. If fetal distress occurs, early delivery with immediate access to emergency pacing is indicated. Permanent pacemaker implantation is the definitive therapy postnatally, and the severity of conduction abnormality and clinical status should guide optimal timing.[2][4][38][39](B2)

Differential Diagnosis

The differential diagnosis of cutaneous NLE includes neonatal rashes unassociated with congenital heart block or maternal autoantibodies (anti-Ro/SSA, anti-La/SSB, or anti-U1 RNP). These rashes include acute annular urticaria, tinea corporis, seborrheic dermatitis, annular erythema of childhood, cutis marmorata telangiectasia congenita, Langerhans cell histiocytosis, and some autoinflammatory syndromes such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome; autoinflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation syndrome; stimulator of interferon genes–associated vasculopathy with onset in infancy syndrome; and C1q deficiency.

Other causes of fetal bradycardia or heart block include congenital heart block defects such as L-transposition of the great arteries, endocardial cushion defects, Holt-Oram syndrome, and idiopathic familial congenital heart block. Differentiating these structural or genetic causes from autoimmune-mediated block is essential, as management strategies and prognoses differ significantly. Neonatal sepsis may present with rash and signs of heart failure, but the timing and characteristics of the rash typically differ. For example, TORCH infections (toxoplasmosis, other [including syphilis], rubella, cytomegalovirus, and herpes simplex virus) can cause a "blueberry muffin" rash associated with thrombocytopenia. A thorough maternal history and targeted diagnostic testing are essential to distinguish these conditions from neonatal lupus.[1][2]

Prognosis

The prognosis in NLE is generally favorable in the absence of cardiac involvement. Cutaneous, hepatic, and hematologic abnormalities typically resolve within the first year of life without lasting consequences. In contrast, congenital heart block is associated with a higher morbidity and mortality, with a fetal or neonatal death rate of approximately 15% to 30%, particularly in cases complicated by hydrops fetalis or cardiomyopathy. Prompt pacemaker implantation yields a long-term survival rate exceeding 90%. Most affected children achieve normal neurodevelopment and quality of life with appropriate cardiac follow-up and management.[4][40][41]

Complications

NLE can cause the following complications: 

• Permanent congenital heart block and lifelong pacemaker dependency
• Endocardial fibroelastosis and myocardial fibrosis
• Progressive cardiomyopathy
• Residual cutaneous scarring or telangiectasia
• Rare neurodevelopmental delay secondary to chronic hypoperfusion