Year : 2016 | Volume
: 11 | Issue : 6 | Page : 139--144
Neonatal lupus: An update
Department of Pediatrics, Christian Medical College, Vellore, Tamil Nadu, India
Department of Pediatrics, Christian Medical College, Vellore - 632 004, Tamil Nadu
Neonatal lupus erythematosus (NLE) is a syndrome that usually presents in the fetus or neonates that is caused by transplacental passage of autoantibodies from the mother. It is a clinical spectrum of cutaneous, cardiac, and systemic abnormalities observed in the newborn or infants whose mothers have autoantibodies against Ro/SSA and/or La/SSB. Congenital complete heart block is the most serious manifestation of NLE that can develop in utero or after birth. Multidisciplinary team involvement is indicated. This article will provide an overview the presentation of NLE and will review the evidence for current therapies.
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Kumar S. Neonatal lupus: An update.Indian J Rheumatol 2016;11:139-144
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Kumar S. Neonatal lupus: An update. Indian J Rheumatol [serial online] 2016 [cited 2020 Jul 7 ];11:139-144
Available from: http://www.indianjrheumatol.com/text.asp?2016/11/6/139/194548
Neonatal lupus erythematosus (NLE) is a syndrome characterized by skin, cardiac, and systemic abnormalities seen in newborn infants whose mothers have autoantibodies against Ro/SSA and/or La/SSB.  The condition was first described almost 60 years ago by McCuistion and Schoch, who noted the presence of characteristic skin lesions on a baby born to a mother who suffered from lupus.  By the late 1970s, NLE was found to be caused by maternal transplacental passage of the anti-SSA/Ro antibodies from mother to fetus.  The term NLE was initially selected because of the similarity of skin lesions with those that can occur in subacute cutaneous lupus. However, the disparities between the NLE and those living with systemic lupus, especially for cardiac involvement, highlight the inappropriateness of the term, and only minorities of mothers have defined systemic lupus erythematosus. Furthermore, many of the mothers have or go on to develop primary Sjogren's syndrome or undifferentiated autoimmune disease, and many of them are totally asymptomatic. This article will provide an overview of NLE including clinical presentations, pathogenesis, and treatment. Much of the current knowledge about this syndrome based on the study of the American Neonatal Lupus Registry , and a recent large French study. 
Neonatal Lupus Erythematosus
Clinical manifestations that present in the fetus, neonate, or infant due to the transfer of anti-SSA/Ro, and/or anti-SS-B/La and/or rarely anti-RNP antibodies are termed NLE.  These antibodies may be found in mothers who have been diagnosed with SLE, primary Sjogren's syndrome, antiphospholipid syndrome or other autoimmune disorders but only cause clinical disease in a minority of babies born to mothers with these autoantibodies.  The most common manifestations of NLE are permanent cardiac and transient cutaneous disease. Congenital complete heart block (CHB) due to congenital atrioventricular block (CAVB) in the absence of structural cardiac abnormalities is usually detected during the second trimester. CAVB is almost universally associated with maternal autoantibodies reactive with the 52-kD Ro, 60-kD Ro, or 48-kD La antigens.  The skin rash usually appears during the first 2 months after birth and appears preferably over the scalp and periorbital region.  Skin rash is also strongly linked to Ro/La maternal antibodies as well as to antibodies against U1 RNP. The skin rash seen in these babies often resemble the rash of subacute cutaneous lupus.  Despite its rarity, NLE has attracted great attention since it is a model of autoimmune disease acquired "passively" due to placental transfer of maternal antibodies to the fetus.
Epidemiology of Neonatal Lupus
In systemic lupus erythematosus, the generally accepted prevalence of anti-SSA/Ro is from 25% to 30% and anti-SSB/La antibodies from 5% to 15%.  The frequency of CAVB in women with anti-Ro antibodies is estimated between 1% and 2%.  When a woman has had a child with CAVB, the risk of recurrence of CAVB in a subsequent pregnancy is about 19% (data on 257 pregnancies resulting from US observatories, French and a European series). 
The CAVB is characterized by the presence of immune complex deposition, inflammation, and calcification of fibrosis at the fetal atrioventricular (AV) node.
However, to date, the molecular mechanisms that connect placental transfer of autoantibodies to abnormalities in fetal intracardiac conduction, and the process leading to myocarditis or fibrosis of the AV node are not completely understood. Recent literature suggests that factors such as maternal Vitamin D deficiency or hypothyroidism, immunological abnormalities in the fetus: Dysfunctions of toll-like receptors (TLRs), all in a context of increased physiological apoptosis including heart fetal cells are involved in pathophysiology of NLE. The normally intracellular antigens, Ro52 and Ro60, are expressed during apoptosis on the surface of fetal cells, and maternal anti-Ro and anti-La antibodies may well bind to these antigens and create inflammation and fibrosis, or target calcium channels on the surface of cardiomyocytes by cross-reaction or maternal chimerism, and cause fetal heart rhythm disorders. Inflammation and fibrosis, in turn, may be responsible for intracardiac conduction disorders, and for endomyocardial fibrosis and other disorders that occur occasionally. The team of Jill Buyon reported the existence of an excess of apoptosis and the presence of infiltration by macrophages in the hearts of fetuses died of CAVB.  They showed that apoptotic cardiomyocytes opsonized by maternal antibodies induce secretion by phagocytes of proinflammatory and profibrotic cytokines, responsible for the acquisition by cardiomyocytes of a fibrotic phenotype of.  In vitro, anti-Ro52 antibodies including those that recognize the p200 peptide can attach to the surface of cardiomyocytes and thus disturb the spontaneous movements of calcium, resulting in intracellular accumulation of calcium, loss of contractility, and finally a cell apoptosis. In animal models, the transfer of anti-Ro52 anti-p200 antibody specificity is associated with a greater frequency of CAVB presenting with sinus bradycardia in newborn than the other types of anti-Ro52 antibody but the importance of the anti-p200 specificity has not been confirmed in humans and testing for these specific antibodies is not routinely available.
The anti-Ro antibodies although important are neither necessary, nor sufficient to cause congenital heart block, as only 1%-2% of fetuses whose mothers' have anti-Ro antibodies are affected, anti-La antibodies alone are occasionally responsible and twins discordant for CAVB have been described. Other players in the pathogenesis of congenital heart block are not well understood but may include environment factors contributing to a seasonal pattern in some cases and an association with other autoimmune conditions including maternal hypothyroidism. ,
Microchimerism is a mechanism by which maternally derived cells crossed the placenta during pregnancy and remain in fetal tissues without being destroyed. They are thus able to survive in symbiosis. Jill Buyon raised the possibility that a maternal microchimerism phenomenon may contribute to the pathophysiology of CAVB. 
Innate immune mechanisms involving TLRs may be involved in neonatal lupus. Reaction between TLRs and nuclear material resulting from apoptosis could induce an inflammatory reaction in certain tissues causing the clinical symptoms observed particularly at cardiac level. In this case, the immune complexes formed of the fetal antigen Ro and the maternal autoantibodies to Ro may be internalized and react with endosomal TLR7. Activation of TLRs resulting in activation of autoreactive B-cells and macrophages and the generation of interferon α, could be responsible for the stimulation of macrophages capable of secreting the transforming growth factor β and endothelin 1, that play a role in inflammation and leading to cardiac fibrosis.  This hypothesis is supported by the observations that hydroxychloroquine (HCQ) can inhibit TLR7 signaling and HCQ can significantly reduce the risk of recurrence of CAVB in babies born to mothers with a previously affected baby. 
The contribution of genetic factors involved in the immune response is supported by some studies of patient populations and animal models have shown that the HLA-DRB1*04 and Cw*05 were associated with susceptibility to CAVB whereas the HLA DRB1*13 and Cw*06 appeared to be protective. More recently, Clancy et al. showed a strong association between certain HLA polymorphisms and the occurrence of CAVB, in a study of genomic SNP.  However, these studies do not currently have implications for prevention or treatment.
NLE can be detected either in utero or during the postnatal period. In utero, the diagnosis is suspected in a fetus that exhibits any degree of CHB on a fetal echocardiogram. The presence of CHB in a fetus of a mother with a known autoimmune disorder is usually assumed to be due to the presence of maternal autoantibodies. CHB may develop in utero, once transplacental passage of immunoglobulins starts in the second trimester at about week 16. Postnatally, NLE is most often recognized based on the characteristic skin manifestations. If the baby manifests the characteristic skin rash, measurement of maternal serum autoantibodies is indicated to help confirm the diagnosis. Persistent neonatal bradycardia also suggests the presence of CHB. An echocardiogram and Doppler study of the heart is important to confirm CHB, to rule structural heart disease that can cause heart block, and to look for any other associated cardiac findings. A skin biopsy in the fetus may be necessary if one has doubt regarding the diagnosis of NLE or in the mother if the maternal diagnosis of subacute cutaneous lupus erythematosus needs confirming.
Cutaneous lesions appear most commonly between the 4 th and 6 th week of life or sometimes at birth and recover spontaneously without sequelae in more than three-fourth of the cases.  Lesions of NLE appears over sun-exposed areas, especially around the eyes, face, and scalp. , They are erythematous macules, or papules which are rounded, annular or elliptical in shape with erythema, and scaling sometimes covered with fine scales.  Lesions are superficial and resemble subacute cutaneous lupus erythematosus of the adult. Mucosa is not involved.  In some cases, the skin lesions can involve the almost the entire body. New lesions often appear over several weeks and they disappear by 6-8 months of age at the time when maternal autoantibodies clears from the baby's circulation.  Skin biopsy shows interface dermatitis and vacuolar alterations at the dermoepidermal interface and adnexal structures.  These findings on skin biopsy are seen on those infants who have the typical erythematous desquamative lesions. Another type of skin biopsy findings which correlate with cutaneous urticaria-like lesions are a superficial and deep perivascular and periadnexal lymphocytic infiltrates.  Immunofluorescence staining often shows deposits of IgG, IgM, IgA, or C3 at the dermo-hypodermic junction.
Cardiac Neonatal Lupus
Congenital atrioventricular block
Heart block can present in utero or rarely in the after birth.  Cardiac involvement can present as first, second, or third-degree heart block. The finding of persistent sinus bradycardia in a fetus may be the first clue that prompts investigation into CHB, especially in the absence of history of an autoimmune disease in the mother. The CAVB is usually found between 20 and 24 weeks of gestation during a routine ultrasound or when fetal bradycardia is observed on auscultation of the heart sounds but it can occur at any time from week 16 to term and may present occasionally after birth.  CAVB is mostly complete and irreversible, manifested as bradycardia below 100/min. Sometimes, evidence of a first- or second-degree heart block is found which does not cause clinical bradycardia. This may sometimes be spontaneously reversible but can progress to complete block before or after birth warranting systematic regular supervision. 
Other Heart Damage
During the last decade, the occurrence of dilated cardiomyopathy has been reported, which may occur later with a rated frequency between 5% and 28.6%.  Children with CAVB should be monitored not only in terms of heart rate but also in terms of overall heart function. Fetal hydrops is a devastating consequence of autoantibodies causing CAVB and affecting the myocardium resulting in dilated cardiomyopathy in some babies. The spectrum of neonatal lupus has also expanded with the description of cases of endomyocardial fibroélastoses. Recently, a histological study of 18 children hearts explants or fetus with CAVB showed abnormalities (including lesions fibroelastosis, endomyocardial) more extensive or more frequent than had been suggested by echocardiography.  Cimaz et al. have demonstrated QT prolongation in 21 children born to mothers with anti-SSA/Ro. 
The liver injury can be isolated or secondary to heart failure in the context of CAVB. Hepatobiliary disease is rare and probably underestimated, its prevalence is estimated between 9% and 27%.  Hepatic involvement can manifest as hepatic failure presenting during gestation or in the neonatal period. It can also present with conjugated hyperbilirubinemia in the first few weeks of life with little or no elevations of aminotransferases. Or it could present with mild elevations of aminotransferases, which occurs approximately at 2-3 months of life. Prognosis depends on the severity of hepatic involvement.
Hematological Neonatal Lupus
Hematological abnormalities may involve any of the three cell lines and include Coombs' positive hemolytic anemia, neutropenia, and thrombocytopenia.  There is a recent report of an infant with neutropenia and mild abnormalities of liver functions who was born to a mother with anti/Ro-/La antibodies.  In this report, the neutropenia resolved over 2-3 months, and the baby did not have any infection during that time.
Other Rare Manifestations of Neonatal Lupus
In Boros et al.,  series of 47 NLE babies, five were reported to have hydrocephalus. Lung damage  or bone type chondrodysplasia punctate  have been exceptionally described in NLE.
Screening for congenital heart block
The most common time to develop CHB is 18-30 weeks in 82% of the cases, but it can occur up to 38 weeks (18% of the cases) and after birth.  Therefore, monitoring the fetal heart rate is currently recommended between 16 weeks and term, every week in babies whose mothers have anti-Ro and/or anti-La antibodies. Monitoring for the development of the first- or second-degree heart block and by fetal echocardiography is only available in a few specialist centers but may be done every 2-7 days if available and if the mother has had a previously affected baby with CAVB and poor outcomes. The logic of this screening is based on the possibility of treating patients at the earliest opportunity to prevent progression of incomplete heart block or intermittent block to permanent CHB. However, this seems unlikely since Friedman et al., who studied 95 patients with anti-SSA/Ro antibodies by measuring the PR interval, during weekly ultrasounds performed between the 16 th and 26 th weeks of gestation (PRIDE study) have found no abnormality in PR in the weeks before diagnosis of CAVB.  More recently, Ruffatti et al. have shown limited evidence that weekly plasmapheresis, fortnightly intravenous immunoglobulins (IVIG), and daily 4 mg betamethasone will be efficacious in stabilizing second-degree heart block and preventing progression to third-degree heart block. 
There is no evidence that established third-degree CAVB can be reversed by any of these treatments, but it has been hoped that early detection and treatment of CHB with fluorinated steroids might reduce the risk of complications that affect cardiac contractility, the risk of developing hydrops, and death of the fetus.
Preventive treatment of congenital atrioventricular block
The risk of CAVB is 1%-2% in the presence of anti-Ro antibodies, and no prophylactic treatment has been recommended in the past to women with no relevant medical history. The risk is however higher (16%-19%) in women with anti-Ro antibodies who already had a child with CAVB, , and various treatments have been tried for the secondary prevention in this situation. Prednisone, prednisolone, and methylprednisolone only cross the placenta in low concentrations and are not effective. The fluorinated steroids are no longer recommended as they are not effective at preventing progression of myocardial disease, cannot reverse third-degree heart block, and may be associated with obstetric complications or neuropsychiatric development abnormalities in the child.  Administration of fluorinated steroids may reverse first-and second-degree AV block, but this remains debatable and is not an option in centers that cannot monitor the fetus for incomplete block before bradycardia develops due to third-degree block. Friedman et al. found that steroids as a single agent failed to prevent the conversion of second-degree AV block to third-degree AV block. 
Jaeggi et al. found that cardiac complications of NLE were associated with moderate or high titers of maternal anti-Ro antibodies.  The event of CHB was 5% for fetuses with high Ro values compared to 0% for fetuses with low titers anti-Ro. Therefore, it is suggested that in future preventive therapies for cardiac NLE treatment should be aimed to develop agents that would decrease the levels of autoantibodies. In this context, HCQ is a promising agent. Maternal HCQ has been shown to decrease the risk of recurrence of CAVB in fetuses of mothers with anti-Ro antibodies and SLE and a previously affected child.  Izmirly et al. have also shown that infants born to women with anti-Ro/La antibodies (with or without lupus) and a previously affected child who are treated with HCQ have a significantly reduced rate of re-occurrence of CAVB. 
Theoretically IVIG could decrease transplacental passage of anti-Ro and anti-La antibodies from mother to fetus. However, in one study, IVIG failed to prevent the development of CHB in the fetus when given at 3 rd weekly intervals to anti-Ro and/or anti-La pregnant women who had a previous pregnancy in which CHB developed. 
Outcomes and Recurrences
The majority of women with high anti-Ro levels and no other significant disease manifestations ultimately have normal pregnancy outcomes, and the babies have a good prognosis. Apart from CAVB which is permanent the skin, liver, and hematologic manifestations of NLE resolve within 6 months because this is the lifespan of the maternal IgG antibody in the infant.  Skin and heart findings can manifest after discharge from the hospital. Persistent telangiectatic lesions and hyperpigmented macules can be treated with laser therapy. , The cutaneous lesions are photosensitive and can get exacerbated by ultraviolet light exposure; hence, strict photoprotection is recommended. ,
Children with third-degree block usually require pacing if they are symptomatic. , On long-term follow-up, babies with cardiac NLE have a risk of developing cardiomyopathy (18%).  Cardiomyopathy can develop despite early institution of permanent pacemaker.  In the French study after 7 years of follow-up, 79% had a pacemaker, 18% had cardiomyopathy, and 11% had died.  These babies may also develop an autoimmune disorder later in childhood.  The risk factors for poor outcomes (neonatal deaths) are hydrops, prematurity, and low birth weight. Having a pacemaker, prenatal and postnatal cardiomyopathy are risk factors for death during childhood. 
Diagnosis of NLE in a baby does not predict that the mother will progress to systemic autoimmune disease. Mother continues to possess these antibodies and may develop clinical features over the next 10 years even if asymptomatic at the time of the baby's birth. 
NLE is a rare disease the clinical manifestation classically involves congenital CHB in the fetus and/or typical skin rash recognizable at birth. More recently, other manifestations of the syndrome including neutropenia, thrombocytopenia, or elevated liver enzymes have been described. While the rash is transient, CHB is irreversible and majority of affected infants will require pacemaker. There is evidence that HCQ administration to anti-Ro positive mothers with or without SLE can prevent development CHB in the infant. Further work is required to establish effective treatment regimen to prevent or reverse third-degree heart block of NLE.
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|1||Buyon JP, Rupel A, Clancy RM. Neonatal lupus syndromes. Lupus 2004;13:705-12.|
|2||Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res 2009;301:107-10.|
|3||Silverman E, Jaeggi E. Non-cardiac manifestations of neonatal lupus erythematosus. Scand J Immunol 2010;72:223-5.|
|4||Izmirly PM, Saxena A, Kim MY, Wang D, Sahl SK, Llanos C, et al. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation 2011;124:1927-35.|
|5||Lee LA, Sokol RJ, Buyon JP. Hepatobiliary disease in neonatal lupus: Prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics 2002;109:E11.|
|6||Levesque K, Morel N, Maltret A, Baron G, Masseau A, Orquevaux P, et al. Description of 214 cases of autoimmune congenital heart block: Results of the French neonatal lupus syndrome. Autoimmun Rev 2015;14:1154-60.|
|7||Guinovart RM, Vicente A, Rovira C, Suñol M, González-Enseñat MA. Facial telangiectasia: An unusual manifestation of neonatal lupus erythematosus. Lupus 2012;21:552-5.|
|8||Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Huong DL, Denjoy I, Vauthier D, et al. Outcome of pregnancies in patients with anti-SSA/Ro antibodies: A study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum 2004;50:3187-94.|
|9||Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012;126:76-82.|
|10||Clancy RM, Kapur RP, Molad Y, Askanase AD, Buyon JP. Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block. Arthritis Rheum 2004;50:173-82.|
|11||Reed JH, Sim S, Wolin SL, Clancy RM, Buyon JP. Ro60 requires Y3 RNA for cell surface exposure and inflammation associated with cardiac manifestations of neonatal lupus. J Immunol 2013;191:110-6.|
|12||Ambrosi A, Dzikaite V, Park J, Strandberg L, Kuchroo VK, Herlenius E, et al. Anti-Ro52 monoclonal antibodies specific for amino acid 200-239, but not other Ro52 epitopes, induce congenital heart block in a rat model. Ann Rheum Dis 2012;71:448-54.|
|13||Spence D, Hornberger L, Hamilton R, Silverman ED. Increased risk of complete congenital heart block in infants born to women with hypothyroidism and anti-Ro and/or anti-La antibodies. J Rheumatol 2006;33:167-70.|
|14||Stevens AM, Hermes HM, Rutledge JC, Buyon JP, Nelson JL. Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 2003;362:1617-23.|
|15||Alvarez D, Briassouli P, Clancy RM, Zavadil J, Reed JH, Abellar RG, et al. A novel role of endothelin-1 in linking toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block. J Biol Chem 2011;286:30444-54.|
|16||Clancy RM, Marion MC, Kaufman KM, Ramos PS, Adler A; International Consortium on Systemic Lupus Erythematosus Genetics, Harley JB, et al. Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus. Arthritis Rheum 2010;62:3415-24.|
|17||Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: Characteristics of mothers and children enrolled in a national registry. J Pediatr 2000;137:674-80.|
|18||Inzinger M, Salmhofer W, Binder B. Neonatal lupus erythematosus and its clinical variability. J Dtsch Dermatol Ges 2012;10:407-11.|
|19||Peñate Y, Guillermo N, Rodríguez J, Hernández-Machín B, Montenegro T, Afonso JL, et al. Histopathologic characteristics of neonatal cutaneous lupus erythematosus: Description of five cases and literature review. J Cutan Pathol 2009;36:660-7.|
|20||Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, et al. Autoimmune-associated congenital heart block: Demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31:1658-66.|
|21||Moak JP, Barron KS, Hougen TJ, Wiles HB, Balaji S, Sreeram N, et al. Congenital heart block: Development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 2001;37:238-42.|
|22||Llanos C, Friedman DM, Saxena A, Izmirly PM, Tseng CE, Dische R, et al. Anatomical and pathological findings in hearts from fetuses and infants with cardiac manifestations of neonatal lupus. Rheumatology (Oxford) 2012;51:1086-92.|
|23||Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43:1049-53.|
|24||Kanagasegar S, Cimaz R, Kurien BT, Brucato A, Scofield RH. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. J Rheumatol 2002;29:187-91.|
|25||Boros CA, Spence D, Blaser S, Silverman ED. Hydrocephalus and macrocephaly: New manifestations of neonatal lupus erythematosus. Arthritis Rheum 2007;57:261-6.|
|26||Morton RL, Moore C, Coventry S, Langston C, Schikler K, Eid NS. Pulmonary capillaritis and hemorrhage in neonatal lupus erythematosus (NLE). J Clin Rheumatol 2004;10:130-3.|
|27||Friedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon JP. Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR interval and dexamethasone evaluation (PRIDE) study. Am J Cardiol 2009;103:1102-6.|
|28||Ruffatti A, Cerutti A, Favaro M, Del Ross T, Calligaro A, Hoxha A, et al. Plasmapheresis, intravenous immunoglobulins and bethametasone - A combined protocol to treat autoimmune congenital heart block: A prospective cohort study. Clin Exp Rheumatol 2016;34:706-13.|
|29||Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al. Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis 2016;75:1161-5.|
|30||Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed fetuses and infants. J Am Coll Cardiol 2010;55:2778-84.|
|31||Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 2010;69:1827-30.|
|32||Pisoni CN, Brucato A, Ruffatti A, Espinosa G, Cervera R, Belmonte-Serrano M, et al. Failure of intravenous immunoglobulin to prevent congenital heart block: Findings of a multicenter, prospective, observational study. Arthritis Rheum 2010;62:1147-52.|