Neonatal lupus erythematosus is a disease of the newborn characterized by congenital heart block and cutaneous lupus lesions.1–3 Rarely, it is also associated with hepatic and hematologic abnormalities.4,5 Placentally transmitted maternal antibodies to Ro/SSA or La/SSB antigens or both are recognized as an almost universal finding in this condition.6–8 The main cause of morbidity and mortality in neonatal lupus erythematosus is congenital heart block. There is a tendency toward similar disease expression, in terms of congenital heart block or cutaneous lupus, in successive siblings.9 With respect to preventing neonatal lupus erythematosus or treatment of congenital heart block, available clinical data are limited because of the rarity of this disease. We studied neonatal outcomes in relation to prenatal corticosteroid treatment in 87 offspring of 40 anti-Ro/SSA-positive mothers.
Materials and Methods
Since 1979, we screened sera from patients with symptoms of connective tissue diseases for precipitating autoantibodies against extractable nuclear antigens. Forty mothers who were positive for anti-Ro/SSA antibodies were included in this study. Twenty-eight women had been followed at our hospitals, and seven were referred for care after fetal bradycardia was diagnosed. In the other five cases (two infants with congenital heart block and three infants with cutaneous lupus lesions), serum samples were obtained after birth of an infant with neonatal lupus erythematosus. Clinical finding were reported previously for a mother of two infants with cutaneous lupus lesions.7 Twenty-six mothers were analyzed for human leukocyte antigen class II distributions in relation to neonatal outcomes.9
The mean age of the mothers at their first delivery was 28.3 years old, and the mean parity was 2.15. Fourteen mothers had systemic lupus erythematosus, four had primary Sjögren's syndrome, two had both systemic lupus erythematosus and Sjögren's syndrome, three had idiopathic thrombocytopenic purpura, and three had undifferentiated connective tissue disease. One mother (case 23) with Raynaud's phenomenon10 developed autoimmune hemolytic anemia 5 years after her first delivery. The other 13 mothers were asymptomatic.
Diagnosis of systemic lupus erythematosus was based on criteria proposed by the American College of Rheumatology.11 Sjögren's syndrome was diagnosed according to criteria proposed by the Japanese Research Committee for Sjögren's syndrome.12
Precipitating antibodies to Ro/SSA, La/SSB, U1RNP, and Sm were screened by Ouchterlony double immunodiffusion against rabbit thymus (Pel-Freez Biologicals, Rogers, AR) or human spleen (from an autopsy source) extracts. Antibody specificity was defined by the presence of lines of identity with reference sera. Protocols for enzyme-linked immunosorbent assay using full-length recombinant human 52-kd Ro/SSA and 48-kd La/SSB proteins expressed in Escherichia coli were described previously.13
As shown in Table 1, oral corticosteroid therapy was given to 26 women (33 pregnancies, including a twin pregnancy, second and third offspring of case 28). Prednisolone or betamethasone was started before 16 weeks' gestation in 25 pregnancies (26 offspring) and after 16 weeks' gestation in eight pregnancies.
In 14 pregnancies, corticosteroid therapy was required for underlying disease (in ten cases for maintenance therapy, and in four cases for exacerbation of the disease). In four pregnancies, maternal therapy with prednisolone or betamethasone was begun after fetal bradycardia was diagnosed.
In 1985, we began giving corticosteroid treatment to women who were at high risk of having offspring with congenital heart block, ie, with high titer anti/Ro/SSA precipitating antibodies, with a history of a congenital heart block, or both. Recently, we administered corticosteroid therapy prophylactically to anti-52-kd Ro/SSA-positive women who were more susceptible to having offspring with neonatal lupus erythematosus.14
In 12 pregnancies (including the case of twin pregnancy), 15–20 mg of prednisolone per day was initiated before 16 weeks' gestation and tapered to 10 mg/day or less during the pregnancy. In the other three pregnancies (second offspring of cases 20, 26, and 39), betamethasone, which passes the placenta more effectively than prednisolone, was substituted for prednisolone at 9 or 12 weeks' gestation.
Comparisons between groups were calculated using Fisher exact test. P values less than .05 were considered significant.
Results of clinical and serologic studies as well as neonatal outcomes in anti-Ro/SSA-positive mothers are given in Table 1. Fourteen mothers were positive for both anti-Ro/SSA and La/SSB antibodies, and 26 mothers had only anti-Ro/SSA antibodies. As reported previously,13,15 there was no specific antibody profile unique to mothers of children with neonatal lupus erythematosus compared with anti-Ro/SSA-positive mothers with asymptomatic children. However, mothers with only a low titer of anti-Ro/SSA antibodies that did not recognize recombinant 52-kd Ro/SSA peptide were likely to be at low risk of having affected infants (cases 35, 36, 38, and 40). During follow-up, the anti-Ro/SSA and anti-La/SSB antibody profiles did not change significantly over time, although antibody titers gradually diminished by corticosteroid maintenance therapy in some mothers.
As summarized in Table 2, the current study included 87 offspring (86 pregnancies) of 40 mothers whose sera contained precipitating antibodies against Ro/SSA with or without La/SSB. Fifteen fetuses had congenital heart block (with three perinatal deaths), and 16 infants had cutaneous involvement of neonatal lupus erythematosus. Five fetal deaths were from causes other than congenital heart block (first offspring of case 16, placental infarction; first offspring of case 28, complicated heart defects; first offspring of case 32, true knot of the umbilical cord; second offspring of cases 23 and 28, unknown cause).
None of 26 infants whose mothers were treated with steroids before 16 weeks' gestation had congenital heart block, whereas 15 of 61 infants whose mothers received no medication or were treated after 16 weeks' gestation had congenital heart block. Occurrence of congenital heart block was significantly different between the two groups of primiparas (zero of five compared with nine of 35, P < .05). However, four infants whose mothers had corticosteroid therapy had skin lesions of lupus erythematosus.
Neonatal outcomes were analyzed according to the purpose and timing of corticosteroid treatment. In 14 pregnancies in which mothers were treated with corticosteroid for underlying disease, skin lesions developed in two successive siblings of a mother with systemic lupus erythematosus (second and third offspring of case 3). The remaining 12 infants were asymptomatic.
Prophylactic corticosteroid treatment was given in 15 pregnancies (16 neonates). Thirteen infants were asymptomatic, and skin lesions developed in two infants within 2 weeks after birth (fourth offspring of case 13 and second offspring of case 39). One infant (second offspring of case 28, one of the twins) died antenatally of unknown cause but did not have congenital heart block.
We diagnosed four cases of fetal heart block at 20 or 21 weeks' gestation and treated these mothers with oral betamethasone or prednisolone for the remainder of the pregnancy. In one fetus (third offspring of case 15), associated pleural effusion was treated successfully with intramuscular injections of betamethasone to the mother. All four children were born with complete congenital heart block requiring permanent pacemakers, one of whom (third offspring of case 15) died of heart failure at age 3 years.
Of the 53 untreated pregnancies, 11 fetuses had complete congenital heart block; three died perinatally, five infants required permanent pacemakers, and three others did not require treatment. Twelve infants had the transient skin lesions of neonatal lupus erythematosus. Four fetuses died perinatally from causes other than congenital heart block (one of the infants had complicated cardiac defects, as reported previously).10 The remaining 26 infants were asymptomatic.
Neonatal lupus erythematosus was originally described in children born to mothers with systemic lupus erythematosus and Sjögren's syndrome, but recent studies have shown that in many mothers, the symptoms of connective tissue disease are absent or mild at the time of delivery of the affected infants.4,15,16 Permanent cardiac and transient cutaneous disease are two major manifestations of neonatal lupus erythematosus.17,18 According to previous findings5,17 as well as those of the present study, congenital heart block is most often identified during the mid to late second trimester; it causes a high mortality rate in the neonatal period; and more than 60% of the surviving children require pacemakers. In mothers with anti-Ro/SSA and/or La/SSB antibodies who have not previously had a child with congenital heart block, the incidence of a second child with congenital heart block is higher than the incidence of a first child with congenital heart block.
We studied neonatal outcomes and medication status in 87 offspring of 40 anti-Ro/SSA-positive mothers. None of 26 neonates whose mothers received corticosteroid maintenance therapy initiated before 16 weeks' gestation had congenital heart block. Complete congenital heart block, once developed, did not respond to corticosteroid treatment in utero. There were four cases of cutaneous lupus erythematosus in the infants whose mothers received corticosteroid maintenance therapy before 16 weeks' gestation.
Several authors also described the persistence of heart block despite prenatal treatment with corticosteroids beginning at 22–24 weeks' gestation.19–23 However, Buyon et al24 reported that in 19 pregnancies treated with fluorinated steroids (dexamethasone or betamethasone), one fetus had second-degree heart block that reverted to sinus rhythm, and in two fetuses with third-degree block the degree of block improved. A study of maternal prednisolone therapy for Sweet's disease25 strongly supported the potential reversibility of congenital heart block. In addition, many reports support corticosteroid treatment of fetal pleural effusion, hydrops, and cardiac inflammation including myocarditis.20,21,24,26,27 In one of our cases (third offspring of case 15), fetal pleural effusion resolved after maternal betamethasone pulse therapy.
A few reports on the prophylactic treatment of women positive for anti-Ro/SSA, La/SSB, or both, have been published. Barclay et al28 treated a woman by using a combination of prednisone and plasmaphoresis beginning at 14 weeks' gestation. A normal infant was delivered at 34 weeks, although four previous pregnancies had been unsuccessful, the last two involving congenital heart block and fetal bradycardia. Buyon et al29 treated a woman with Sjögren's syndrome whose previous child had congenital heart block. At week 19, plasmaphoresis was begun; prednisone 60 mg per day was added at week 23, dexamethasone was substituted at week 35, and a living child was delivered by cesarean. Whether these cases represented successful treatment or were normal pregnancies without neonatal lupus cannot be determined. According to report by Buyon et al,24 however, the administration of prednisone (in low and moderate doses) early in pregnancy does not prevent the development of congenital heart block in the fetus. Because prednisone is cleared from the circulation faster than other synthetic corticosteroids, including dexamethasone and betamethasone,30,31 it is less effective.
Currently, it is presumed that the inflammatory process in the fetus is secondary to placentally transferred maternal antibodies. Autopsy studies of infants who died in utero or during the first week of life support the hypothesis that congenital heart block is a complication of a more widespread inflammatory response in the heart.19 The human heart attains most of its adult characteristics by the sixth to eighth week of gestation.32 The sinus node can be recognized in the first trimester, and the conduction system reaches functional maturity by the 16th week of gestation, when maternal antibodies begin to affect the fetal heart.33 According to previous reports,19,24,33 bradycardia has been noted after an initially normal fetal heart rate, with problems developing after 16 weeks' gestation. However, relatively few mothers with anti-Ro/SSA or anti-La/SSB antibodies have offspring with congenital heart block. Mothers of affected infants can also give birth to disease-free infants, as shown in previous reports34,35 and in some of our patients. Thus, if autoantibodies are involved, the mechanism is complex and requires more than the existence of autoantibodies to cause disease. Recent reports suggest the importance of genetic factors in determining neonatal outcomes.9,36
In the present of study of anti-Ro/SSA-positive women, 15 (17%) of 87 offspring had congenital heart block, which is significantly higher than the 1% to 2% risk in the general anti-Ro/SSA-positive population.16 This high frequency of congenital heart block presumably reflects referral bias. Seven women were referred to our hospitals after fetal bradycardia was diagnosed elsewhere. In addition, our study included the high-risk group of women16 with both anti-Ro/SSA and anti-La/SSB antibodies (14 women, 35%), or with precipitating anti-Ro/SSA antibodies alone but possessing anti-52-kd Ro/SSA activity (18 women, 45%). Moreover, two women (cases 11 and 15) each had two offspring with congenital heart block.
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