Neonatal Lupus

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Neonatal Lupus

Description

  • Neonatal lupus is an uncommon disease associated with in utero exposure to maternal autoantibodies. Fetal and neonatal manifestations range in severity from congenital atrioventricular heart block and central nervous system abnormalities to usually mild and transient cutaneous lesions, cytopenias, and hepatobiliary disease.(1,2)

Also Called

  • Neonatal lupus erythematosus
  • Neonatal lupus syndrome
  • Congenital lupus erythematosus

Epidemiology

Incidence/Prevalence

  • Neonatal lupus is uncommon.(1,2)
  • Among the newborn population at an Italian hospital, 0.25% of infants were born to birthing parents who tested positive for anti-SSA/Ro antibodies (Autoimmun Rev 2017 Apr;16(4):427).
  • > 80% of severe atrioventricular blocks in newborns with structurally normal hearts are associated with neonatal lupus.(1)

Risk Factors

  • Maternal positivity for autoantibodies to Sjogren syndrome (anti-SSA/Ro or anti-SSB/La) is the primary risk factor for neonatal lupus.(1,2)
    • Among pregnant persons with anti-SSA/Ro or anti-SSB/La antibodies, the risk of giving birth to a child with neonatal lupus is reported to be:
      • 1%-2% for first pregnancies
      • 20% if there is a history of pregnancy affected by neonatal lupus
    • About half of affected pregnancies are in healthy pregnant patients whose positivity for autoantibodies is previously unknown.
  • The risk to subsequent pregnancies remains increased even if the neonatal lupus in an earlier pregnancy was mild. Neonatal lupus was reported in 36% of 39 infants born to a birthing parent with a history of prior pregnancy that resulted in cutaneous neonatal lupus in a prospective cohort study (Arthritis Rheum 2010 Apr;62(4):1153full-text).

Etiology and Pathogenesis

Causes

  • Neonatal lupus is caused by maternal autoantibodies that are transported across the placenta to fetal circulation in conjunction with other fetal factors that lead to tissue damage and disease.(1,2)
  • The first autoantibodies discovered in neonatal lupus were those directed against Sjogren syndrome autoantigens (SSA/Ro and SSB/La).(1,2)
  • Additional target antigens have since been identified.
    • Antibody reactivity to anti-ribonuclear protein (U1RNP) has been reported in neonatal lupus presenting with negative anti-SSA/Ro-SSB/La plus cutaneous manifestations only, transient first-degree atrioventricular (AV) block, or congenital heart block (Autoimmun Rev 2017 Sep;16(9):980).
    • Antibody reactivity to calcium channel proteins (extracellular epitope of gamma1G T-type) has been reported in neonatal lupus with negative anti-SSA/Ro-SSB/La and congenital heart block (PLoS One 2013;8(9):e72668full-text).
  • Other fetal factors likely play a role in the development of AV block, because most fetuses exposed to autoantibodies do not develop AV block.(1)

Pathogenesis

  • Antibody production in fetus and neonate:(1,2)
    • The fetus does not produce IgG and only small amounts of IgA and IgM.
    • The transport of maternal IgG across the placenta starts at about the third month of gestation.
    • Fetal IgG levels slowly increase and ultimately exceed maternal levels by about 10% at term.
  • There are 2 common autoantigens recognized by autoantibodies in Sjogren syndrome:(1)
    • Sjogren syndrome type A (SSA) antigens, also called Ro antigens (there are 2 – Ro52 and Ro60)
    • Sjogren syndrome type B (SSB) antigen, also called La antigen
  • 2 possible mechanisms have been proposed to explain atrioventricular (AV) heart block.(1)
    • During fetal cardiac development, 2 of the protein targets, Ro52 and Ro60, translocate to surface of the cardiomyocyte around 18-26 weeks gestation.
    • In the first model, autoantibodies bind these targets directly in the fetal cardiac conduction tissue, and the immune-directed response leads to AV node fibrosis.
    • In the second model, autoantibodies bind L-type calcium channels which disrupts calcium homeostasis.
  • Increased titers of autoantibodies directed to Sjogren autoantigens are associated with increased risk of offspring having AV block, but high titer alone is not sufficient to cause AV block.(1)
  • Factors other than autoantibodies that contribute to pathogenesis:
  • Noncardiac manifestations including the characteristic rash, cytopenias, and liver injury resolve as maternal antibodies are cleared. Most patients do not have longstanding complications from these noncardiac manifestations whereas central nervous system manifestations and AV block can be permanent (Autoimmun Rev 2017 Apr;16(4):427, Lupus 2013 Dec;22(14):1484).

History and Physical

Clinical Presentation

  • The most serious complication of neonatal lupus is congenital atrioventricular (AV) heart block.(1,2)
    • Advanced second- and third-degree AV block typically presents in utero with fetal bradycardia (ventricular rate of 40-80 beats/minute).
    • A reported 2% of cases of AV heart block are diagnosed postnatally < 28 days after birth.
    • Most infants who develop postnatal heart block develop first-degree heart block.
    • Presentation of postnatal AV heart block:
      • Sinus bradycardia (< 100 beats/minute) is typical.
      • Rare signs may include peripheral edema, pallor, diaphoresis, crackles on lung auscultation, and prominent jugular veins.
  • Neonatal lupus and first-degree AV heart block diagnosed at age 3 months in otherwise healthy infant who initially presented with red facial plaques at 3 weeks post partum after uncomplicated pregnancy reported in case report (Lancet 2020 Oct 31;396(10260):1432).
  • Characteristic presenting features in neonates with neonatal lupus by approximate prevalence:(1,2)
    • Cutaneous rash, which occurs in 40% of cases, can have highly variable appearance.
    • Hematologic abnormalities occur in 35% of cases and may include anemia, thrombocytopenia, neutropenia, and rarely, aplastic anemia.
    • Hepatic dysfunction occurs in 35% of cases and may include hepatomegaly, asymptomatic elevated aminotransferases, or cholestasis. Severe liver injury occurs rarely.
    • Irreversible cardiac arrhythmias, including complete congenital atrioventricular block, occur in 25% of cases.
    • Reference – Autoimmun Rev 2017 Apr;16(4):427
  • Additionally, central nervous system (CNS) manifestations have been reported.
    • CNS involvement in neonatal lupus is most often detected on imaging in asymptomatic patients (Lupus 2013 Dec;22(14):1484).
    • Patients with symptomatic CNS involvement most often have a history of transient cutaneous rash and no maternal history of autoimmune disease (Lupus 2013 Dec;22(14):1484).
    • Neonatal lupus presenting as an acute ischemic stroke secondary to CNS vasculitis reported in 2-month-old infant without typical presenting features in case report (Eur J Paediatr Neurol 2014 May;18(3):444).
    • Neonatal lupus presenting with seizures preceded by pustular-like skin lesions of the face reported in neonate in case report (BMC Pediatr 2014 May 22;14:126full-text).
  • Other manifestations of cardiac disease may include:
    • Cardiomyopathy and heart failure(1)
    • Myocarditis(1)
    • Structural and valvular abnormalities(1)
    • QT prolongation on electrocardiography(1)
    • Coronary dilatation (J Pediatr 2021 Jan;228:305)
  • cutaneous, hematologic, and neurologic manifestations of neonatal lupus erythematosus generally mild and typically do not persist beyond age 9 months
    •  based on cohort study
    • 50 infants exposed to anti-SSA/Ro antibodies in utero who tested positive for anti-SSA/Ro antibodies on the first day of life were followed through age 9 months
    • 2 cases of congenital heart block were identified during pregnancy
    • other cardiac manifestations included
      • first-degree AV block in 1 newborn that persisted at 3, 6, and 9 months without progression
      • right bundle block in 1 newborn that persisted during follow-up with good clinical course
      • transient alterations in ventricular repolarization in 3 newborns that stopped at 3 months
    • none developed typical skin rash
    • hematologic abnormalities (none required medical intervention) in 8% at birth, 48% at 3 months, 20% at 6 months, and 2% at 9 months
    • mild elevation of liver test in 1 neonate at birth, 56% at 3 months, 40% at 6 months, and 6% at 9 months
    • normal neurologic exam at birth and during follow-up for all infants
    • echo-encephalographic abnormalities in 18% at birth that persisted in 2 infants at 3 months; no abnormalities detected in these patients at 6 and 9 months
    • Reference – Autoimmun Rev 2017 Apr;16(4):427
  • Clinical presentation reported in 123 cases of neonatal lupus in China.
    • Symptom onset occurred at birth in 12%, at age 0-2 weeks in 48%, and age > 2 weeks in 40%.
    • Cutaneous manifestations involving face and head occurred in 93%, involving an extremity occurred in 66%, and involving the trunk occurred in 53%.
    • Hematologic manifestations included anemia in 31%, thrombocytopenia in 14%, and both anemia and thrombocytopenia in 10%.
    • Cardiac manifestations occurred in 13%, including congenital heart block in 9%.
    • Reference – Int J Rheum Dis 2015 Sep;18(7):761

History

Family History (FH)

  • Ask about maternal history of:(1,2)
    • Autoimmune disease
    • Previously affected pregnancy
  • Maternal positivity for autoantibodies may not be known. About half of cases occur in healthy pregnant persons whose positivity for autoantibodies was previously unknown.(1,2)

Physical

General Physical

  • Assess weight, height, and head circumference.
  • Macrocephaly with or without hydrocephalus has been reported in some infants with neonatal lupus.(1)

Skin

  • Infant may be jaundiced (Autoimmun Rev 2017 Apr;16(4):427).
  • Assess for cutaneous lesions.(1,2)
    • Rash can have highly variable presentation, including:
      • Confluent, scaly periorbital erythema with “eye mask” or “raccoon-like” appearance
      • Annular erythema without scaling
      • Erythematous patches
      • Erythematous plaques with central vesicles
      • Seborrheic-like lesions
      • Fungal-like lesions
      • Reference – J Dtsch Dermatol Ges 2012 Jun;10(6):407full-text
    • Typical rash affects upper eyelids, scalp and other areas exposed to light. Extremities and the trunk can also be affected.
    • Rash most commonly appears at age 2-3 months but can develop earlier or be present at birth.
    • Rash typically resolves after 6-12 weeks in most cases, but telangiectasias, atrophy, and hyperpigmented skin areas may persist.

Neck

  • Look for prominent jugular veins.(1)

Cardiac

  • Listen for:(1)
    • Intermittent murmurs and gallops
    • First heart sound of variable intensity
    • Intermittent cannon waves

Lungs

  • Listen for crackles.(1)

Abdomen

  • Palpate for hepatomegaly.(1,2)

Diagnosis

Making the Diagnosis

  • Prenatal diagnosis:(1)
    • Neonatal lupus is often first detected in utero with fetal monitoring.
    • Diagnosis is made if fetus develops atrioventricular block and pregnant person is positive for anti-SSA/Ro or anti-SSB/La antibodies.
  • Postnatal diagnosis:(1)
    • Suspect neonatal lupus in neonates and infants with characteristic findings including rash, cytopenias, and hepatobiliary manifestations without other explanation.
    • Diagnosis is made in these infants if birthing parent is positive for anti-SSA/Ro or anti-SSB/La antibodies.

Differential Diagnosis

  • Differential for cutaneous manifestations presenting in an infant of an asymptomatic birthing parent includes:(1)
    • Birth trauma
    • Fungal infection
    • Eczema

Testing Overview

  • Indications to test a pregnant person for anti-SSA/Ro or anti-SSB/La antibodies if not previously tested:(1)
    • Slow fetal heart rate detected during fetal monitoring
    • Suspicion of neonatal lupus based on clinical features of neonate or infant
  • Monitoring for congenital heart block and identifying at-risk fetuses:
    • Monitoring pregnant patients who test positive for anti-SSA or anti-SSB antibodies involves serial fetal echocardiograms.(1)
      • Serial screening typically performed starting from 16 weeks gestation.
      • Cardiac arrhythmias are usually diagnosed after 18 weeks gestation.
      • Screening frequency may be reduced after 26 weeks gestation if no atrioventricular (AV) heart block is detected.
    • Reported risk factors for adverse outcomes include early gestational age at diagnosis, endocardial fibroelastosis and dilated cardiomyopathy, low heart rate, and fetal hydrops (Fetal Diagn Ther 2021;48(1):1).
    • Fetal heart rate at any time after 20 weeks gestation below 50th percentile for gestational age as determined by longitudinal model is associated with increased rate of adverse perinatal outcomes; the unvalidated model was developed based on 44 cases of grade III congenital heart block identified in utero with positive maternal serum antibodies (Fetal Diagn Ther 2021;48(1):1).
  • Testing in neonates to support diagnosis and/or evaluate extent of organ involvement:(1,2)
    • Autoantibody testing of newborn
      • Anti-SSA/Ro and anti-SSB/La
      • Anti-ribonucleoprotein (anti-RNP)
    • Complete blood count with differential white cell count
    • Electrocardiography and echocardiography
    • Liver function testing
    • Cerebral ultrasonography
    • Reference – Autoimmun Rev 2017 Apr;16(4):427
  • Additional evaluations to consider depending on severity of initial findings:(1,2)
    • Liver biopsy in rare cases of severe liver injury
    • Additional brain imaging with computed tomography or magnetic resonance imaging if ultrasound abnormalities are detected (lenticulostriate vasculopathy or pseudocysts of the choroid plexus)
    • Skin biopsy not typically required; histologic findings include interface dermatitis with IgG deposits at dermo-epidermal junction
    • Reference – Autoimmun Rev 2017 Apr;16(4):427

Management

Management Overview

  • If a pregnant person is known to be positive for anti-SSA and anti-SSB antibodies, the fetus should be closely monitored with serial fetal echocardiograms for the development of congenital heart block.
  • Prevention of congenital heart block in fetuses exposed to autoantibodies:
    • Hydroxychloroquine is recommended for pregnant patients with systemic lupus erythematosus (SLE, as well as those with SLE considering pregnancy) to prevent and manage disease flares. It may also reduce risk of congenital heart block in fetuses exposed to anti-SSA/Ro antibodies.
    • Fluorinated steroids are not recommended for the prevention of congenital heart block due to uncertain benefit and known maternal and fetal side effects.
  • Once congenital heart block is detected, evidence to guide management is limited, and optimal management is not known.
  • Postnatal management depends on the presence and degree of congenital heart block and other noncardiac manifestations.

Prevention and Management of Congenital Heart Block During Pregnancy

  • Preventing the development of congenital heart block in fetuses exposed to anti-SSA and anti-SSB antibodies:
    • Hydroxychloroquine, which is recommended for pregnant patients with systemic lupus erythematosus (SLE, as well as those with SLE considering pregnancy) to prevent and manage disease flares, may also reduce risk of congenital heart block in fetuses exposed to anti-SSA/Ro antibodies.
      • European League Against Rheumatism (EULAR) recommends routine hydroxychloroquine during pregnancy and preconceptually in persons with systemic lupus erythematosus (EULAR Level 1, Grade B) (Ann Rheum Dis 2017 Mar;76(3):476full-text).
      • The benefits of maternal hydroxychloroquine during pregnancy may include reduced risk of congenital heart block.
        • hydroxychloroquine during pregnancy reported to reduce recurrence of congenital heart block in pregnant persons positive for anti-SSA/Ro (level 3 [lacking direct] evidence)
          •  based on uncontrolled trial
          • 54 pregnant persons with anti-SSA/Ro positivity and history of pregnancy complicated by congenital heart block had hydroxychloroquine 400 mg/day throughout pregnancy starting before 10 weeks gestation
          • 9 patients had fluorinated steroids and/or IV immunoglobulin (IVIG) during period after enrollment but before primary outcome
          • 9 additional patients were recruited who had hydroxychloroquine and no fluorinated steroids or IVIG during the trial period
          • secondary or tertiary congenital heart block occurred in
            • 4 of 54 pregnancies (7.4%) in intention-to-treat analysis
            • 4 of 54 pregnancies (7.4%) not exposed to fluorinated steroids or IVIG in per-protocol analysis
          • historic recurrence rate of congenital heart block reported to be 18%
          • Reference – PATCH trial (J Am Coll Cardiol 2020 Jul 21;76(3):292full-text), editorial can be found in J Am Coll Cardiol 2020 Jul 21;76(3):303
        • hydroxychloroquine during pregnancy associated with reduced recurrence of cardiac manifestations of neonatal lupus in pregnant persons with anti-SSA/Ro antibodies (level 2 [mid-level] evidence)
          •  based on cohort study
          • 257 pregnancies in patients with anti-SSA/Ro antibodies and history of previous birth affected by cardiac neonatal lupus including 16% exposed to hydroxychloroquine were evaluated
          • hydroxychloroquine exposure was defined as initiation of drug before 10 weeks gestation with continued use throughout pregnancy
          • cardiac neonatal lupus was defined as second- or third-degree heart block or as isolated cardiomyopathy including endocardial fibroelastosis occurring in utero or at birth
          • comparing outcomes with hydroxychloroquine exposure vs. no exposure
            • recurrence of cardiac neonatal lupus 7.5% vs. 21.2% (p = 0.05)
            • mortality 0% vs. 22% (no p value reported)
          • in multivariable analysis, hydroxychloroquine use during pregnancy associated with decreased risk of cardiac neonatal lupus (adjusted odds ratio 0.23, 95% CI 0.06-0.92)
          • Reference – Circulation 2012 Jul 3;126(1):76full-text
    • Fluorinated steroids:
      • EULAR does not recommend fluorinated steroids for the prevention of congenital heart block in fetuses exposed to anti-SSA/Ro antibodies due to uncertain benefit and known maternal and fetal side effects (Ann Rheum Dis 2017 Mar;76(3):476full-text).
        • The efficacy of maternal fluorinated steroids for prevention of complete heart block in fetuses exposed to anti-SSA/Ro antibodies is limited to small reports. Adverse effects in the fetus/neonate have been reported including adrenal insufficiency, both mild and severe.
          • in pregnant persons with anti-SSA/Ro antibodies plus history of pregnancy affected by congenital heart block, maternal dexamethasone reported to prevent congenital heart block but also to result in adrenal insufficiency in 2 live births and marked adrenal hypoplasia in 1 stillbirth (level 3 [lacking direct] evidence)
            •  based on case series
            • 13 fetuses born to 7 patients with anti-SSA/Ro antibodies and history of fetus with congenital heart block were evaluated including
              • 6 fetuses treated with maternal dexamethasone 4-5 mg/day
              • 4 fetuses treated with maternal prednisone 10 mg/day
              • 3 fetuses not treated with steroids
            • no congenital heart block reported
            • outcomes for 6 fetuses treated with maternal dexamethasone included 4 spontaneous abortions or stillbirths and 2 live births with adrenal insufficiency
            • outcomes for 4 fetuses treated with prednisone resulted in 4 live births
            • outcomes of 3 fetuses not treated with steroids included 2 spontaneous abortions and 1 live birth
            • Reference – Ann Rheum Dis 2003 Oct;62(10):1010full-text
          • prednisolone or betamethasone early in pregnancy might reduce risk of congenital heart block in fetuses exposed to anti-SSA/Ro antibodies in utero (level 2 [mid-level] evidence)
            •  based on cohort study
            •  87 neonates exposed to anti-SSA/Ro antibodies in utero including 26 neonates treated with maternal prednisolone or betamethasone before 16 weeks gestation were evaluated
            • comparing maternal prednisolone or betamethasone before 16 weeks gestation vs. no steroids or steroids started after 16 weeks gestation (no p values reported)
              •  congenital heart block in 0% vs. 25%
              •  skin lesions of neonatal lupus erythematosus in 15% vs. 26%
            •  complete congenital heart block did not respond to corticosteroid treatment in utero
            •  Reference – Obstet Gynecol 1999 Jun;93(6):952
  • Evidence to guide management of congenital heart block once detected is limited, and optimal management is not known.
    • The benefit of maternal fluorinated steroids for the treatment of complete heart block in fetuses exposed to anti-SSA/Ro or anti-SSB/La antibodies has been reported in small, anecdotal series, but has not been demonstrated in larger cohort studies.
      • maternal fluorinated steroids may not reduce disease progression, mortality, or need for pacemaker in fetuses exposed to anti-SSA/Ro antibodies with isolated advanced heart block (level 2 [mid-level] evidence)
        •  based on retrospective cohort study
        • 156 fetuses exposed to anti-SSA/Ro antibodies with isolated advanced heart block including 71 fetuses (46%) treated with fluorinated steroids were included
        • included fetuses had no evidence of extranodal disease (endocardial fibroelastosis, dilated cardiomyopathy, and/or hydrops) when advanced heart block was detected
        • all fetuses treated with fluorinated steroids started treatment within 1 week of detecting heart block
        • hydroxychloroquine use was higher in fluorinated steroids group compared to no fluorinated steroids group (12% vs. 1.2%, p < 0.006)
        • comparing fluorinated steroids vs. no treatment
          • development of extranodal disease 19.7% vs. 20% (not significant)
          • mortality 9.9% vs. 8.8% (not significant)
          • need for pacemaker 66% vs. 75% (not significant)
        • Reference – Ann Rheum Dis 2016 Jun;75(6):1161full-text
      • maternal dexamethasone does not appear to be effective for reversal of fetal third-degree heart block in fetuses exposed to anti-SSA/Ro antibodies (level 2 [mid-level] evidence)
        •  based on cohort study
        • 30 pregnancies with fetal cardiac dysfunction treated with dexamethasone and compared with 10 untreated pregnancies
          •  among treated pregnancies – third-degree block in 22, second-degree block in 6, and first-degree block in 2
          •  among untreated pregnancies – third-degree block in 9 and first-degree block in 1
        •  6 deaths occurred in dexamethasone group
        •  no reversal of third-degree block with therapy or spontaneously in either group
        • among pregnancies treated with dexamethasone
          •  progression from second-degree block to third-degree block in 1 fetus
          •  3 remained in second-degree block (postnatally 1 paced and 2 progressed to third degree)
          •  2 in second-degree block reverted to normal sinus rhythm (NSR)
          •  reversal of first-degree block to NSR within 7 days in 2 fetuses, no regression after discontinuation
        •  1 untreated fetus with first-degree block detected at 38 weeks had NSR at birth
        •  Reference – Am J Cardiol 2009 Apr 15;103(8):1102full-text
      • dexamethasone reported to reverse first-degree heart block in 6 fetuses exposed to anti-SSA/Ro or anti-SSB/La antibodies (level 3 [lacking direct] evidence)
        •  based on case series
        •  70 fetuses (56 pregnancies) exposed to anti-SSA/Ro and/or anti-SSB/La antibodies were observed
        • initial fetal kinetocardiogram at 13-18 weeks gestation, weekly follow-up to 24 weeks gestation, and then
          •  weekly if atrioventricular (AV) block diagnosed
          •  monthly if no evidence of AV block
        • 6 cases of first-degree AV block diagnosed between 21 and 34 weeks gestation
          •  maternal dexamethasone 4 mg/day started at diagnosis and continued until delivery
          •  prolonged AV conduction reversed toward normal conduction 4-14 days after initiation of steroid treatment in all cases
          •  postnatal exam, electrocardiogram, and echocardiography normal in all cases
        •  Reference – Circulation 2009 Apr 14;119(14):1867full-text, commentary can be found in Circulation 2009 Nov 24;120(21):e167
    • Evidence is limited to support the use of maternal beta-agonists to prevent heart failure in fetuses with complete AV block.
      • Commonly used beta-agonists include oral salbutamol and terbutaline. Reported maternal side effects include palpitations, tremors, and sweating (Int J Womens Health 2020;12:633full-text).
      • maternal beta-agonists reported to increase ventricular rate in fetuses with second- or third-degree atrioventricular heart block, but increase may not be clinically significant (level 3 [lacking direct] evidence)
        •  based on case series
        • 175 fetuses with second- or third-degree atrioventricular heart block (80% associated with maternal anti-Ro/SSA antibodies) were included
          • 23% were treated with beta-agonists, most often salbutamol
          • 38% were treated with fluorinated corticosteroids for a median of 10 weeks
        • among 15 fetuses treated with beta-agonists with available data, mean ventricular rate increased from 50.1 beats per minute (bpm) to 55.1 bpm after treatment with beta-agonist (p = 0.001)
        • no significant differences in survival comparing fetuses treated with or without beta-agonist or comparing fetuses treated with or without fluorinated corticosteroids
        • 159 newborns survived at birth and 138 neonates survived to 1 month
        • risk factors associated with increased risk of death included gestational age < 20 weeks at diagnosis, ventricular rate ≤ 50 bpm, fetal hydrops, and impaired ventricular function at diagnosis
        • 69% of 107 children with available follow-up had pacemaker by 1 year of age, and 8 children were diagnosed with cardiomyopathy
        • Reference – Circulation 2011 Nov 1;124(18):1919

Postnatal Management

  • Monitor all infants exposed to anti-SSA/Ro and anti-SSB/La antibodies in utero for manifestations of neonatal lupus (Autoimmun Rev 2017 Apr;16(4):427).
  • A reported 2% of cases of atrioventricular (AV) block are diagnosed postnatally up to age 1 month.(1)
  • Newborns and infants with complete AV block require cardiac pacing. See Management in Atrioventricular (AV) Conduction Disorders for guidance on permanent cardiac pacing.
  • Restoration of normal sinus rhythm reported in 5 infants with neonatal lupus and prolonged PR interval treated with IV immunoglobulin 1 g/kg for 2 days in case series (Asian Pac J Allergy Immunol 2016 Jun;34(2):174).
  • Noncardiac manifestations are often managed with observation alone, and symptoms typically resolve spontaneously.(1)
  • Management of cutaneous manifestations:(1)
    • Mainstay of treatment is avoiding sun exposure and using protective clothing and sunscreen.
    • Topical steroids or calcineurin inhibitors are used by some practitioners in select cases.
    • Laser therapy is sometimes used in cases of residual telangiectasia.
  • Blood or platelet transfusion is used to treat symptomatic anemia and thrombocytopenia.(2)
  • Breastfeeding is independent of the development of neonatal lupus. Encourage breastfeeding both in cases of established neonatal lupus, as well as in asymptomatic neonates exposed to autoantibodies in utero.(1)
  • Counsel families about the risk for future pregnancies.(1)

Complications

  • Cardiac disease develops in about 20% of patients, including:(2)
    • Cardiomyopathy
    • Valvular dysfunction
    • Endocardial fibroelastosis
  • Late development of heart block is usually first degree. There are rare reports of third-degree block developing in adulthood.(2)
  • Complications in patients with congenital heart block requiring pacing at birth include:(2)
    • Neurodevelopmental sequelae
    • Aortic root dilation
    • Conduction abnormalities
  • in neonates born to birthing parents with anti-SSA/Ro antibodies, 7% had congenital heart block, and 4% had perinatal demise
    •  based on systematic review of observational studies
    • systematic review of 18 observational studies with data to assess incidence of adverse pregnancy outcomes in 1,675 patients (1,920 pregnancies) with anti-SSA/Ro antibodies
    • proportion of patients with systemic lupus erythematosus (SLE) not reported
    • pooled perinatal outcomes
      • congenital heart block in 7% of patients (95% CI 3%-13%) in analysis of 13 studies with 1,435 patients
      • perinatal death in 4% of patients (95% CI 2%-6%) in analysis of 7 studies with 1,280 patients
      • cutaneous neonatal lupus erythematosus in 19% of patients (95% CI 14%-25%) in analysis of 3 studies with 239 patients
      • hematologic manifestations in 16% of patients (95% CI 8%-32%) in analysis of 3 studies with 401 patients
      • hepatobiliary disease in 12% of patients (95% CI 5%-30%) in analysis of 3 studies with 401 patients
      • endocardial fibroelastosis in 6% of patients (95% CI 2%-17%) in analysis of 3 studies with 568 patients
      • dilated cardiomyopathy in 6% of patients (95% CI 5%-8%) in analysis of 3 studies with 317 patients
      • intrauterine growth retardation in 3% of patients (95% CI 0%-6%) in analysis of 4 studies with 373 patients
    • Reference – Pediatr Rheumatol Online J 2023 Mar 4;21(1):22full-text
  • children born to birthing parent with systemic lupus erythematosus may have increased risks of congenital heart disease, Kawasaki disease, atrioventricular block, and death
    •  based on population-based cohort study
    • 3,505,737 children born between 2007 and 2017 from national health database in South Korea were assessed until 2020
    • 0.7% had birthing parent with SLE
    • propensity score for likelihood of having birthing parent with SLE was calculated for each child based on clinical and demographic factors
    • 23,330 children with birthing parent with SLE were propensity matched to 93,320 children with birthing parent who did not have SLE
    • comparing children with birthing parent with SLE vs. without SLE
      • congenital heart disease in 5.5% vs. 4.6% (odds ratio [OR] 1.21, 95% CI 1.14-1.29)
        • atrial septal defect in 3.2% vs. 2.7% (OR 1.18, 95% CI 1.09-1.28)
        • patent ductus arteriosus in 1.6% vs. 0.4% (OR 1.15, 95% CI 1.03-1.3)
      • Kawasaki disease (mucocutaneous lymph node syndrome) 2.1% vs. 1.7% (OR 1.27, 95% CI 1.15-1.43)
      • atrioventricular block in 0.6% vs. 0.006% (OR 10, 95% CI 3.88-25.79)
      • neonatal lupus in 0.5% vs. < 0.1% (OR 12.16, 95% CI 8.34-17.73)
      • death in 0.4% vs. 0.3% (OR 1.32, 95% CI 1.04-1.66)
      • cardiac arrest in 0.1% vs. 0.1% (OR 1.64, 95% CI 1.07-2.52)
      • cardiomyopathy in 0.1% vs. < 0.1% (OR 1.4, 95% CI 1.17-1.68)
    • Reference – Front Pediatr 2023;11:1294823full-text

Prognosis

  • Neonatal cardiac disease in neonatal lupus is associated with a 20% mortality rate.(2)
  • Patients who develop cardiomyopathy, valvular dysfunction, or endocardial fibroelastosis have a poorer prognosis.(2)
  • Other manifestations usually spontaneously resolve, including facial rash, cytopenias, and liver injury.(1,2)
  • Although the rash is transient, subcutaneous fat atrophy secondary to the rash may result in scarring or pitting.
  • history of pregnancy resulting in cutaneous neonatal lupus does not preclude more severe cardiac manifestations in future pregnancies
    •  based on cohort study
    • 77 infants born to 58 mothers with history of infant with cutaneous neonatal lupus
    • 49% of infants were healthy
    • 51% had neonatal lupus; manifestations included
      • cutaneous in 30%
      • second- or third-degree congenital heart block in 18%
      • hematologic or hepatic in 1%
    • overall recurrence of neonatal lupus was 36% in subset of 39 children born prospectively after enrollment of initial child with cutaneous neonatal lupus
    • development of neonatal lupus type (cutaneous vs. cardiac) was not associated with particular maternal age, race/ethnicity, or SSB/La status, breastfeeding, or use of nonfluorinated steroids
    • Reference – Arthritis Rheum 2010 Apr;62(4):1153full-text
  • autoimmune disease diagnosed in childhood in 12% of 49 children with history of neonatal lupus
    •  based on cohort study
    • 55 mothers with anti-SSA/Ro and/or anti-SSB/La antibodies filled out 94 questionnaires for their children ≥ 8 years old including 49 children who had neonatal lupus and 45 unaffected siblings
    • manifestations of neonatal lupus in affected group included
      • isolated congenital heart block in 55%
      • isolated cutaneous manifestations in 39%
      • cardiac plus cutaneous involvement in 6%
    • autoimmune disease diagnosed at follow-up in 6 children who had neonatal lupus (all mothers of these children had symptomatic autoimmune disease), including
      • polyarticular juvenile idiopathic arthritis in 1 child at age 2 years
      • oligoarticular juvenile idiopathic arthritis in 1 child at age 5 years
      • Hashimoto thyroiditis in 1 child at age 7 years
      • psoriasis and iritis in 1 child at age 13 years
      • type I diabetes in 1 child at age 7 years and later psoriasis at age 8 years
      • congenital hypothyroidism at age 5 weeks and later nephrotic syndrome at age 3 years
    • none of unaffected siblings diagnosed with autoimmune disease at follow-up
    • among 55 blood samples from children submitted by mothers, antinuclear antibodies identified in 2 of 33 children with history of neonatal lupus and 2 of 22 unaffected siblings
    • Reference – Arthritis Rheum 2002 Sep;46(9):2377full-text
    • Increased risk of autoimmune disease after diagnosis of neonatal lupus is likely due to transfer of genetic risk of autoimmunity from parent and is not caused by passive transfer of antibodies from birthing parent.

Prevention and Screening

Prevention

Screening

  • Screening strategies focus on serial fetal echocardiography in pregnant persons with known positivity for anti-SSA or anti-SSB antibodies. See Testing Overview for information on monitoring for congenital heart block and identifying at-risk fetuses.
  • These screening protocols miss at-risk fetuses in pregnant persons with previously unknown positivity for autoantibodies, which account for about a half of cases ((1), Lancet Rheumatol 2019 Nov;1(3):e187).
  • Although not supported by professional organizations, universal preconceptual screening for anti-SSA or anti-SSB antibodies is considered by some an important method to screen for possible neonatal lupus.

Guidelines and Resources

Guidelines

  • European League Against Rheumatism (EULAR) recommendation on women’s health and management of family planning, assisted reproduction, pregnancy, and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome can be found in Ann Rheum Dis 2017 Mar;76(3):476full-text.

Review Articles

Patient Information

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

  1. Vanoni F, Lava SAG, Fossali EF, et al. Neonatal Systemic Lupus Erythematosus Syndrome: a Comprehensive Review. Clin Rev Allergy Immunol. 2017 Dec;53(3):469-476.
  2. Klein-Gitelman MS. Neonatal Lupus: What We Have Learned and Current Approaches to Care. Curr Rheumatol Rep. 2016 Sep;18(9):60.

Recommendation Grading Systems Used

  • European League Against Rheumatism (EULAR) grading system for recommendations:
    • Grade of recommendation:
      • Grade A – based on Level 1 evidence without concerns for validity of evidence
      • Grade B – based on Level 1 evidence but with concerns about validity of evidence; or, extrapolated recommendations from Level 1 evidence; or, based on Level 2 evidence without concerns for validity of evidence
      • Grade C – based on Level 1 or 2 evidence but with concerns about validity of evidence; or, extrapolated recommendations from Level 2 evidence; or, based on Level 3 evidence without concerns for validity of evidence
      • Grade D – expert opinion; or, evidence from non-systemic lupus erythematosus (SLE)/antiphospholipid antibody syndrome (APS) literature; or, based on Level 3 evidence but with concerns about validity of evidence
    • Level of evidence:
      • Level 1 – available evidence is strong and includes consistent results from well-designed, well-conducted studies; ≥ 1 randomized controlled trial (RCT) or meta-analysis of RCTs
      • Level 2 – available evidence is sufficient to determine effects, but confidence in estimate is constrained by such factors as: the number, size, or quality of individual studies, inconsistency of findings across individual studies, limited generalizability of findings; controlled (nonrandomized) studies
      • Level 3 – available evidence is limited or insufficient due to limited number or size of studies, important flaws in study design or methods, inconsistency of findings across individual studies, gaps in chain of evidence, lack of information on important outcomes; descriptive studies, such as comparative studies, correlation studies, or case-control studies
    • Reference – EULAR recommendations on women’s health and management of family planning, assisted reproduction, pregnancy and menopause in patients with SLE and/or APS (Ann Rheum Dis 2017 Mar;76(3):476full-text)

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