Arthritis & Rheumatism Official Journal of the American Rheumatism Association

NEONATAL LUPUS RISK TO NEWBORNS OF MOTHERS WITH

SYSTEMIC LUPUS ERYTHEMATOSUS

MICHAEL D. LOCKSHIN, ELOISA BONFA, KEITH ELKON, and MAURICE L. DRUZIN

We prospectively studied 91 infants born to women with systemic lupus erythematosus (SLE) or with SLE-like disease. Thirty-eight infants, including 3 sets of twins, were born to women who had anti-Ro, anti-La, or anti-RNP antibodies. Four infants had definite neonatal lupus, and 4 had possible neonatal I:ypus. No prospec- tively studied infant had congenital heart block. The presence of neonatal lupus did not correlate with the titer of anti-Ro antibodies. During the same time period, 2 additional babies with neonatal lupus and congenital heart block were born to mothers not previously known to have SLE. Taken together, these findings confirm the association of anti-Ro antibody with neonatal lupus, but indicate that life-threatening neonatal lupus is rare in children born to mothers who are known to have SLE, even when antibodies to Ro, La, or RNP are present. Prophylactic therapy is therefore not indicated for these women. An important proportion of mothers bearing children with neonatal lupus do not have recognized SLE and, currently, cannot be prospectively identified.

From the Hospital for Special Surgery and the New York Hospital-Cornell University Medical Center, New York, New York.

Supported in part by grants from the NIH (AM-32929 and AM-14627). the Jacobs Foundation, and the Discount Corporation.

Michael D. Lockshin, MD: Professor of Medicine; Eloisa Bonfa, MD: Instructor in Medicine; Keith Elkon, MD: Assistant Professor of Medicine; Maurice L. Druzin, MB: Associate Professor of Obstetrics and Gynecology.

Address reprint requests to Michael D. Lockshin, MD, Division of Rheumatic Diseases, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Submitted for publication September 28, 1987; accepted in revised form December 17, 1987.

Although the majority of infants with the neo- natal lupus syndrome are born to mothers with sys- temic lupus erythematosus (SLE) and autoantibodies to the Ro (SS-A), La (SS-B), or RNP (U1 RNP or nuclear RNP) antigens (1-3), the risk that unselected mothers with SLE and/or these autoantibodies will bear a child with neonatal lupus has not been defined in a prospective study. In one small study in which women were selected for having been delivered of a child with neonatal lupus, 3 of 12 subsequent children (25%) also had neonatal lupus (4). In a larger, retro- spective interview study, 6 (6%) of 96 infants of mothers with anti-Ro antibody had congenital heart block (5). The conclusions of the latter study were weakened by the exclusion of 43% of eligible patients and by the delay of antibody determination by as many as 10 years after the recorded birth. A third study, a case report, suggested that the risk of occurrence of fetal heart block in a second child is sufficiently high to warrant prophylactic therapy for pregnant women with anti-Ro or anti-La antibodies (6).

Prospective studies define risk more accurately than do retrospective studies. In retrospective studies, even such fundamental data as the number of pregnan- cies may be incorrect. For the last 4 years, we have prospectively studied consecutive patients with SLE or SLE-like illness who were pregnant and were receiving medical care at our medical center (7,8). In 91 of 109 pregnancies, the women were tested for antibody to the Ro, La, and RNP antigens. We present the results of these studies as a measure of the

Arthritis and Rheumatism, Vol. 31, No. 6 (June 1988)

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698 LOCKSHIN ET AL

likelihood that a pregnant woman with identified col- lagen disease will bear a child with neonatal lupus.

PATIENTS AND METHODS Patient selection. All women identified as being preg-

nant (high serum levels of beta human chorionic gonadotro- pin and subsequent sonographic identification of a fetus or birth of a fetus) and diagnosed, by either an obstetrician or rheumatologist, as having SLE or SLE-like disease were seen by one of us (MDL) and were classified by rheumato- logic diagnosis. Of 114 pregnant women (119 infants) who were initially screened, 99 infants were born to women who had SLE (according to the American Rheumatism Associa- tion diagnostic criteria) (9); 10 were born to women who had fewer than 4 diagnostic criteria (SLE-like), but either lupus anticoagulantlanticardiolipin antibody (7,8,10) or anti-Ro antibody (1 1). No woman had previously given birth to a child with neonatal lupus. Nine women (10 infants) were excluded for the following reasons: retrospective identifica- tion of maternal SLE because of fetal neonatal lupus (3 infants, including 1 normal twin), or maternal diagnosis other than SLE (7 infants). Sixty-eight of the infants studied were born at the New York Hospital.

The mothers of 91 infants were tested for autoanti- bodies to the Ro, La, and RNP antigens. Eighteen women were not studied because our early studies of complement and anticardiolipin antibody had exhausted their serum samples (12 infants), or in later studies, fetal death occurred before the first serum sample during pregnancy was ob- tained. (All results presented are of sera taken from women during pregnancy. Since fetal outcome is known in the remaining cases, results on “unstudied” patients are pre- sented where appropriate.)

Definition and diagnosis of neonatal lupus. We con- sidered infants with rash and/or congenital heart block to have dejinite neonatal lupus, and those with thrombocyto- penia only or other cardiac disease without arrhythmia to have possible neonatal lupus. All infants born at the New York Hospital were examined by one of us (MDL). Those born to mothers with anti-Ro and/or anti-La antibodies had platelet count estimations and electrocardiograms before discharge from the hospital. Telephone followup confirmed the status of infants born at other hospitals. In most cases, babies were seen again by the authors within the first 6 months after birth.

Autoantibodies. All sera were tested for antibodies to the Ro, La, and RNP antigens by counterimmunoelectro- phoresis using saline-soluble extracts from dog spleen and rabbit thymus, as previously described (1 1). Screening tests were done on the first serum specimen obtained during pregnancy, which for most patients, was obtained before 12 weeks of gestation. The titers of anti-Ro were determined by serial dilution of the serum specimen obtained nearest the time of delivery.

RESULTS Frequencies of autoantibodies. Table 1 gives the

frequencies of the autoantibodies. Anti-Ro and anti- Ro/La were the most common antibodies found, with

Table 1. Frequencies of Ro, La, and RNP antibodies in pregnant women with systemic lupus erythematosus (SLE) and SLE-like disease*

SLE-like SLE disease Total

Antibody positive Ro, Ro/La Ro/RNP RNP only RNP/Sm La only

Antibody negative Not tested Total

36 19 3 9 1 4

46 17 99

2 38 2 0 0 0 0 I 53 1 18

10 109

* Women with SLE had 4 of the American Rheumatism Association diagnostic criteria (9); women with SLE-like disease had 0-3 criteria.

a frequency of 55% of all patients positive for anti- body, and 23% of all patients tested.

Frequency of neonatal lupus. Table 2 shows the frequency of neonatal lupus. Four liveborn children had definite neonatal lupus. Three liveborn children and 1 stillborn child had possible neonatal lupus. Six of these 8 infants were born to women with anti-Ro antibodies, 1 to a woman with anti-La antibody, and 1 to a woman with discoid lupus whose antibody status during pregnancy is not known. This latter patient had been incorrectly excluded initially because of the absence of systemic symptoms and negative antinu- clear and anti-DNA antibody test results. (On review,

Table 2. Frequencies of definite and possible neonatal lupus erythematosus (NLE) and of fetal death, according to Ro, La, or RNP antibody status of the mother*

Antibody Antibody Not positive negative tested Total (n = 38) (n = 51) (n = 18) (n = 109)

Liveborn Definite NLE 3 0 1 4 Possible NLE 3 0 0 3

Definite NLE 0 0 0 0 Possible NLE I 0 0 1 Other cause 5 16 I 28t

% with NLE 21$ 0 6 I % stillborn 17 31 39 27

* Six of the 7 liveborn children with definite or possible NLE were born to mothers with anti-Ro; the stillborn child was born to a mother with anti-La. t Twenty-four were associated with anticardiolipin antibody or toxemia. $ P < 0.005 versus antibody-negative group and antibody negative/ not tested group, by x2 with Yates’ correction.

Stillborn

NEONATAL LUPUS 699

no other patient was found to have been incorrectly classified.) None of the 10 patients with anti-RNP without simultaneous anti-Ro had an affected child. The associations between all the autoantibodies tested and neonatal lupus, and between the anti-Ro antibody and neonatal lupus were significant at P < 0.005 and P < 0.001 (by chi-square with Yates’ correction).

Of the 7 liveborn children with neonatal lupus, 3 had rash, 1 had rash plus thrombocytopenia, 2 had thromboc ytopenia only, and 1 had Coombs-negative hemolytic anemia; all these conditions remitted with- out treatment. No liveborn child had evidence of carditis. One stillborn child of a mother with anti-La antibody had equivocal carditis. Fetal echocardio- graphy documented pericardial effusion, but normal rhythm, shortly before the child’s death in utero. Autopsy demonstrated myocardial hypertrophy with- out inflammation, and antibody eluted from the heart was present in concentrations equal to that eluted from the skin and kidney (12). No infant of a mother with anti-Ro/La or anti-RNP had rash or carditis. No other infants with thrombocytopenia were identified, but healthy full-term children of antibody-negative moth- ers with normal platelet counts were not routinely tested.

Diagnosis of the cause of fetal death. Twenty- four of the 28 fetal deaths (86%) occurred in mothers with either high-titered anticardiolipin antibody (8,lO) or preeclampsia (7,13), or both, as probable causes of fetal death. The other 4 fetal deaths occurred before 10 weeks gestational age. In pregnancies lasting more than 20 weeks, normal fetal cardiac rates were identi- fied by fetal monitoring and/or sonography antemor- tem. Autopsy or fetal tissue examination was per- formed in 15 instances; no additional cases of neonatal lupus were identified by such examinations. However, in many cases, incomplete or autolysed fetal tissue precluded definitive pathologic diagnosis. The fre- quency of fetal death among mothers with anti-Ro, anti-La, or anti-RNP antibodies was lower than, but not significantly different from, that among mothers without these antibodies (Table 2). It is thus unlikely that increased mortality due to unrecognized neonatal lupus (14) explains the low frequency of neonatal lupus we found. Of the 4 other mothers in whom fetal death occurred early, 2 were not tested during pregnancy, and 2 had antibody to Ro.

Antibody titers. The serum sample obtained nearest to the time of delivery for all mothers with anti-Ro was examined for the highest dilution that would demonstrate a positive result on counterimmu-

Table 3. Relationship between the titer of maternal anti-Ro antibody nearest to the time of delivery and the appearance of definite or possible neonatal lupus (NLE)

Serum dilution

s1:4 1:s-154 ?1:128 Total

Liveborn Normal 4 6* 3 13 Definite NLE 0 1 1 2 Possible NLE 0 0 2 2

Definite NLE 0 1* 0 1 Possible NLE 0 0 0 0 Other cause 1 1 3 5

Total 5 9 9 23

Stillborn

* Includes a retrospectively identified discordant twin pair

noelectrophoresis (Table 3). Peripartum serum sam- ples were not available for all mothers. A mother retrospectively identified as having SLE was included because of heart block in one of her twins. Two children with definite neonatal lupus were born to mothers with low titers of anti-Ro, at 1:16 and 1:64. Including children with possible neonatal lupus, 3 of the 4 live infants with neonatal lupus were born of mothers with high titers of anti-Ro, 21:128, but of a total of 6 mothers with this antibody titer who had liveborn infants, 3 of the liveborn infants were normal.

Outcome of second and twin pregnancies. Seven women had 2 pregnancies and 1 had 3 pregnancies during the study period. One of these women had anti-La antibodies and, after one intrauterine death (with fetal pericardial effusion), was delivered of a healthy infant. A second woman with anti-Ro antibody first bore a normal child, but a second child had transient Coombs-negative hemolytic anemia. The outcomes of 4 twin pregnancies, including 1 pregnancy studied retrospectively, in mothers with autoantibod- ies are shown in Table 4. Two of the 3 dizygotic twin pairs were discordant for neonatal lupus, and the monozygotic twin pair was concordant.

Table 4. Outcome of twin pregnancies in 4 women with anti-Ro antibodies

Infant’s symptoms

Mother Twin A Twin B Zygosity

A Low platelet count* Low platelet count* Mono B Rash? Normal Di C Normal Normal Di D Heart blockt Normal Di

* Possible neonatal lupus; mother also had low platelet count. t Definite neonatal lupus; mother was identified retrospectively.

700 LOCKSHIN ET AL

Table 5. Proportion of infants with definite or possible neonatal lupus, according to the selection criteria met by the prospectively studied mothers*

% with % with possible definite or definite

Selection criteria n NLE NLE

All with SLE and 1 09 3 I SLE-like disease

SLE-like disease

antibodies

All tested with SLE and 91 3 8

All with Ro, La, or RNP 38 8 21

All with Ro antibodies 24 13 25 All with Ro antibodies 19 16 32

and live births

* SLE = systemic lupus erythematosus; NLE = neonatal lupus erythematosus.

Retrospective diagnosis. During the study pe- riod, congenital heart block resulting from neonatal lupus occurred in 2 of 3 children delivered of 2 pregnancies. In both cases, the mother first came to our attention because of in utero heart block, and her Ro antibody status was confirmed anteparturn. One of these women had a vague history of arthralgia; the other had had thrombocytopenic purpura 5 years earlier. Since neither woman would have been identi- fied had the fetal abnormality not occurred, both are considered to have retrospective diagnoses and are not included in the risk calculations.

Likelihood of having a child with neonatal lupus. Risk, defined as the percentage of infants affected per the total number in the category, was calculated for the prospectively studied pregnancies, according to the following criteria: type of maternal antibody, cer- tainty of diagnosis of neonatal lupus, and live or stillborn status of child (Table 5). Depending on the selection criteria used, the minimum risk that a preg- nant woman who is identijied in advance as having lupus or a lupus-like syndrome will bear a child with definite neonatal lupus is 3%. The maximum risk for possible or definite neonatal lupus is 32% if the woman has anti-Ro antibody and her child is liveborn. The risk for clinically evident carditis in the child of a woman with anti-Ro is much lower than 3%, and is not calculable from the current data because the only children with heart block were delivered of mothers with SLE-like disease who were identified retrospec- tively.

DISCUSSION There is no standard definition of neonatal lupus.

Life-threatening (carditis) and non-life-threatening,

self-limited symptoms (rash, cytopenias) may be pre- sent. Several retrospective studies have reported an association between anti-Ro and neonatal lupus, and possibly between anti-La and anti-RNP and neonatal lupus (1,2,4,5). Some physicians have recommended aggressive prophylactic therapy for pregnant women who have the Ro antibody (6). Prophylactic therapy is appropriate when the likelihood of an adverse event (neonatal lupus) is high, when the risk of therapy is less than that of the complication, when the therapy is known to be effective, and when a cause-and-effect relationship between the marker and the event is established. None of these conditions is yet true for neonatal lupus. The current study was therefore designed to identify a max- imal likelihood that any manifestation of clinically iden- tifiable neonatal lupus will occur. We recognize that the inclusion of hemolysis and thrombocytopenia, which may have causes other than neonatal lupus, will cause an overestimation of the true frequency of this complica- tion. Secondarily, the study was designed to provide a measure of the likelihood of the occurrence of life- threatening complications that would justify prophylac- tic treatment of pregnant women.

The findings of this study confirm the associa- tion of anti-Ro antibody and neonatal Lupus and dem- onstrate that clinically important manifestations of this illness occur infrequently. Given the rarity of congen- ital heart block in unselected populations and the high frequency of anti-Ro, anti-La, and anti-RNP in SLE patients, we anticipated that congenital heart block must occur rarely in infants of patients with these antibodies.

Two infants with congenital heart block were born to mothers who were not known to have SLE until neonatal lupus occurred in the child. Thus, an important number of children with neonatal lupus are born of mothers who are not prospectively identifiable as having SLE. Studies which include such retrospec- tive cases (43) overestimate the risk that should be quoted to the mother who is known to have SLE. Conversely, if neonatal lupus developed after the infants left the hospital, then the risk may have been underestimated. We doubt that this occurred because: (a) 12 of the 32 liveborn infants of mothers with autoantibodies were premature and were repeatedly reexamined during their several-week hospital stays, (b) we remain in contact with all but 3 of the mothers, and (c) all mothers were asked to report any rash or other abnormalities in their infants. We may also have underestimated risk if neonatal lupus caused in utero

NEONATAL LUPUS 70 1

death or if corticosteroid therapy in the mother ame- liorated the disease in the infant. However, no mother received betamethasone or dexamethasone, both of which cross the placenta, except in the 48 hours immediately preceding birth. In the present series, 86% of the fetal deaths occurred in mothers who were known to have either high titers of anticardiolipin antibody or preeclampsia, both of which are sufficient explanations for the fetal deaths (7,8,10). Moreover, the fetal death rate in women with anti-Ro, anti-La, or anti-RNP antibodies was less than in women who did not have these antibodies. It is thus unlikely that fetal deaths due to undiagnosed neonatal lupus biased our conclusions.

This study does not provide data that predict which child of a mother with anti-Ro antibody will develop neonatal lupus. In contrast to findings from another study (5) , we did not find that high titers of anti-Ro antibody predict congenital heart block. Since twin pregnancies in this study and in others (15,16) were often discordant, it is clear that passive transfer of maternal autoantibody is not sufficient to explain neonatal lupus. The presence of DR3 in the mother (17) has been cited as an additional risk factor, but this was not tested in the present study.

For gravid women with SLE and anti-Ro anti- bodies, life-threatening neonatal lupus occurs in fewer than 1 in 38 pregnancies. This study does not disprove that the routine use of prophylactic therapy prevents neonatal lupus or that therapy for identified in utero carditis is useful. However, because proposed therapies carry some risk for the mother, until better prognostic markers for neonatal lupus are identified, prophylactic therapy for anti-Ro antibody during pregnancy is not justified.

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