PEDIATRICS Vol. 121 No. 4 April 2008, pp. e803-e809 (doi:10.1542/peds.2007-1659)
ARTICLE |
Outcome and Growth of Infants Fetally Exposed to Heart Block-Associated Maternal Anti-Ro52/SSA Autoantibodies
a Rheumatology Unit, Department of Medicine
b Pediatric Cardiology Unit
c Obstetrics and Gynecology, Department of Women and Child Health, Karolinska Institutet, Stockholm, Sweden
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The purpose of this work was to analyze outcome with focus on growth in infants fetally exposed to heart block-associated maternal anti-Ro52/SSA autoantibodies and identify maternal factors other than the autoantibodies increasing the risk of fetal heart block.
PATIENTS AND METHODS. Thirty-two pregnancies in 30 anti-Ro52-positive mothers were included. Seven fetuses developed second-degree or third-degree atrioventricular block, 8 developed first-degree atrioventricular block, and 17 had normal atrioventricular conduction, as diagnosed by using Doppler echocardiography. Three of 6 surviving fetuses with second-degree or third-degree atrioventricular block received treatment with fluorinated steroids. Two fetuses with second-degree atrioventricular block converted to first-degree atrioventricular block without any signs of progression during the study period. Maternal and longitudinal infant data were collected from planned neonatal follow-up and childhood health records from birth to 12 months of age in 31 survivors.
RESULTS. Women giving birth to infants with prenatal second-degree or third-degree atrioventricular block were older and with higher parity than those with first-degree atrioventricular block or normal atrioventricular conduction. Second-degree or third-degree atrioventricular block pregnancies were <40 completed weeks, whereas pregnancies with first-degree atrioventricular block or normal atrioventricular conduction had a normal duration. Fetuses with second-degree or third-degree atrioventricular block were retarded by –0.98 ± 0.77 SD in weight at birth and did not show any catch-up during infancy. In contrast, fetuses with first-degree atrioventricular block or normal atrioventricular conduction had a weight reduction of –0.51 ± 1.01 SD with a catch-up during the first months after birth.
CONCLUSIONS. This report documents that newborns with autoantibody-mediated second-degree or third-degree atrioventricular block are retarded in growth, with no catch-up during infancy, whereas fetuses with first-degree atrioventricular block or normal atrioventricular conduction have a normal growth soon after birth. Increased maternal age and/or parity seem to carry an increased risk for fetal heart block.
Key Words: infant • weight • length • autoantibodies • Ro/SSA • congenital heart block
Abbreviations: SLE—systemic lupus erythematosus • SS—Sjögren's syndrome • AVB—atrioventricular block • ECG—electrocardiogram • NC—normal atrioventricular conduction • AVB II-III—second-degree or third-degree atrioventricular block • AVB I—first-degree atrioventricular block
Pregnant women with connective tissue diseases as a group have an increased risk for preeclampsia, perinatal death, and preterm delivery, as well as giving birth to a child small for gestational age.1,2 Preterm birth and intrauterine growth retardation are more frequently found in women with systemic lupus erythematosus (SLE),3,4 whereas mothers with Sjögren's syndrome (SS) give birth to infants who are not more premature or growth retarded than newborns of healthy women.3,5,6
In women with connective tissue disease there is also an increased risk of having a child with congenital heart block.7 Isolated congenital heart block is a passively acquired autoimmune condition that develops after placental transfer of maternal anti-Ro/SSA autoantibodies.7,8 A complete third-degree atrioventricular block (AVB) occurs in 1% to 2% of fetuses born to anti-Ro-positive women9–11 and is suggested to be somewhat more frequent in women in whom the anti-Ro activity is targeted to the 52-kd component of the Ro antigen.12–14 Although a complete AVB commonly is considered permanent, novel Doppler echocardiographic methods to estimate fetal atrioventricular conduction have allowed identification of a new group of fetuses where the cardiac involvement is less severe and transient in the majority of cases.15 Thus, in a prospective study of 24 anti-Ro52 antibody-positive pregnant women during their 18th to 24th week of gestation, we found indirect signs of first-degree AVB in one third of the pregnancies.15 Two of these 8 fetuses progressed to a higher degree of heart block, whereas the remaining 6 spontaneously normalized their atrioventricular conduction before or shortly after birth.
Many investigators have clearly demonstrated that a complete AVB is associated with a substantial perinatal mortality and postnatal morbidity.16–21 Some of these studies also report on the weight of the infant at birth, but to our knowledge, no study has been performed to investigate whether the occurrence of fetal heart block has any additional effect on the intrauterine growth restriction observed in pregnant women with connective tissue disease. In a recent neurodevelopmental follow-up of children with complete fetal heart block, 
50% were reported to have a low birth weight for gestational age.22 However, the majority had also been prenatally exposed to dexamethasone, a treatment that has been associated with diminished birth weight23 and intrauterine growth retardation.24
The presence of anti-Ro antibodies in pregnant women with SLE has been suggested to increase the incidence of intrauterine growth retardation.25 This finding has, however, not been confirmed in later studies in which no significant differences in gestational age, birth weight, or fetal growth retardation between infants of anti-Ro-positive and anti-Ro-negative women with connective tissue disease were found.11,26 Having systematically followed a cohort of anti-Ro52-positive women during midtrimester pregnancy and characterized the cardiac involvement in their fetuses, the primary objective of the present study was to investigate how these infants grew and developed both in relation to their degree of fetal atrioventricular conduction disturbance, as well as the diagnosis of their mothers. As a second goal, we also wanted to characterize the role of maternal age and parity in the development of fetal heart block.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
During a 5-year period, 1999–2004, 25 anti-Ro52-positive pregnant women were referred from the maternity clinic at the Karolinska University Hospital to the pediatric cardiology unit at Astrid Lindgren Children's Hospital (Stockholm, Sweden) for fetal surveillance with Doppler echocardiography. Two women were studied during 2 consecutive pregnancies. Weekly examinations between 18 and 24 weeks of gestation showed that 10 of 27 fetuses had indirect signs of first-degree AVB, defined as
2 examinations where the Doppler atrioventricular time intervals exceeded our 95% reference range.27 As reported previously, 1 of these fetuses developed a complete heart block not responding with betamethasone treatment, and another reverted from a second-degree to first-degree AVB during transplacental treatment with betamethasone.15,28 All of these 27 fetuses had a structurally normal heart. During the same time period, fetal bradycardia was the presenting symptom of isolated fetal heart block in 5 additional pregnant women subsequently confirmed to be anti-Ro52 positive. One fetus had a second-degree AVB responding to transplacental treatment with fluorinated steroids; in another, complete heart block could not be established at the first examination, and betamethasone was given for less than a week. Otherwise, no fluorinated steroids were given during these pregnancies. In all of the pregnancies, gestational age had been determined by ultrasound biometry before 18 weeks of gestation. This study includes the 32 offspring (16 girls and 16 boys) of these 30 mothers. Sixteen mothers were diagnosed with SLE,29 12 with SS,30 and 1 with rheumatoid arthritis,31 and 3 had no or undifferentiated connective tissue disease.
One fetus with complete heart block died an intrauterine death at 36 weeks of gestation, most likely because of the combined effect of low ventricular heart rate and poor myocardial performance. The remaining 31 newborn infants were followed up with at least a clinical cardiac examination and an electrocardiogram (ECG) after birth. All 17 of the fetuses with normal Doppler atrioventricular time intervals had a normal ECG at birth. Of the 8 of 10 with prolonged time intervals without progression to a higher degree of heart block, 3 had a first-degree AVB, and the remaining 5 had a normal atrioventricular conduction (NC) time on ECG. Before 1 month of age, all 8 had normalized their ECGs. Both fetuses with second-degree block responding to treatment with fluorinated steroids had a first-degree block on ECG at birth without any signs of progress during infancy. Three of the fetuses with a complete heart block who were born alive had a heart rate of 55 to 60 bpm and received permanent pacemakers as neonates, whereas the fourth had a better ventricular rate and a pacemaker implanted at 1.5 years of age. The numbers of fetuses, newborns, and infants with their degree of atrioventricular conduction are summarized in Table 1. The human ethics committee at the Karolinska University Hospital approved the study, and informed consent was obtained from all of the parents.
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Collection and Calculation of Clinical Data
During infant and preschool years,
100% of Swedish children are weighed, measured, and have their psychomotor skills systematically followed and documented by nurses at local childhood health centers. These records and our own perinatal reports were reviewed to obtain information on the maternal age and parity, as well as the gestational age and gender of the infant. They were also used to extract longitudinal data, from birth to 1 year of age, on infant weight, length, and head circumference. Using national Swedish standard growth charts,32 these original body measurements were manually corrected for gestation and converted to a standardized score (z score) by plotting, as follows: (z score = [x – reference population mean]/reference population SD). BMI was calculated by the formula weight/(length)2. In addition, we used the health care records to collect data on the infants' improvements in motor performance, communication, and cognitive development according to standard developmental milestones.
Statistical Analysis
Statistical analysis was performed by using Statistica 7.0 (Statsoft, Tulsa, OK). Shapiro-Wilk's W test was used to test for normality. For variables shown not to fit a normal distribution (parity and body length at birth), we used the Mann-Whitney U test. The t test for single means was used to statistically investigate the standardized z scores. Otherwise, analysis of variance with contrast analysis and F test were used. The level of significance was set at a P value of <.05.
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RESULTS |
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The Risk for Second-Degree and Third-Degree AVB Is Increased in Older Mothers and Higher Parity But Does Not Correlate With Fetal Gender
The observed anti-Ro52-positive pregnancies included 7 cases of second-degree or third-degree AVB (AVB II-III), 8 cases of first-degree AVB (AVB I), and 17 cases with signs of NC. Analyzing maternal factors influencing the development of congenital heart block, we noticed that women giving birth to infants with midtrimester signs of AVB II-III were older than mothers of fetuses without signs of AVB II-III (P < .05; Table 2). This difference in maternal age was more pronounced when compared with AVB I pregnancies (P < .05) than with NC pregnancies where it did not reach statistical significance. The age of women with fetal signs of AVB I did not deviate significantly from that found in NC pregnancies. There were no differences in age between the women with SS (33.3 ± 4.6 years [mean ±SD]), SLE (30.5 ± 5.1 years), or other connective tissue diseases (31.5 ± 6.7 years).
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The risk of having a fetus with AVB II-III seemed to increase with increasing parity, both compared with the NC and AVB I groups (Table 2). Fetuses with AVB II-III were, on average, born as the 2.4 ± 1.0 child, whereas fetuses with AVB I were born as the 1.4 ± 0.7 child and fetuses with NC as the 1.6 ± 0.9 child (P < .05). The maternal diagnosis could not be related to any differences in parity. Fetal gender did not predict AVB (Table 3).
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AVB II-III Pregnancies Are <40 weeks, Whereas AVB I and NC Pregnancies Have a Normal Duration
Pregnancies where mothers gave birth to an infant with fetal signs of AVB II-III were
2.5 weeks shorter than a pregnancy with an AVB I or NC fetus (P < .05; Table 3) and significantly <40 completed weeks (Fig 1). Gestational ages were similar in AVB I and NC pregnancies (Table 3). Five infants in the study were born preterm (Fig 1). One was born by a normal vaginal delivery after 36 weeks of pregnancy. Four were born by cesarean section: 2 on maternal indication at 33 weeks and 2 on fetal indication at 34 and 35 weeks of gestation. Cesarean section was also used to give birth to the 4 term fetuses with complete heart block. Although the group of 31 anti-Ro52-positive pregnancies resulting in a live born child had a gestational age (271 ± 16.6 days; P < .01) that was <40 completed weeks, this was no longer true when AVB II-III pregnancies were excluded. When grouped according to maternal diagnosis, mothers with SLE (270 ± 18.4 days; P < .05) but not those with SS had a pregnancy <40 weeks.
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Newborns With Second-Degree or Third-Degree Heart Block Are Retarded in Growth and Do Not Show Any Catch-Up During Infancy
Newborn infants with fetal signs of AVB II-III did not only have a shorter stay in utero than newborns with midtrimester findings of AVB I or NC, but also a lower weight, shorter length, and smaller head circumference (Table 3). By using national Swedish reference charts to correct for differences in gestational age and convert each individual body measurement to a standardized score, the AVB II-III group obtained an average birth weight z score –0.98 ± 0.77 below the population standard (P < .05; Fig 1). Still, all of the individual observations were found within the ±2-SD normal reference range. Length and head circumference were not significantly different from population standards. The groups of newborn infants with fetal signs of AVB I or NC did not deviate significantly from population standards in weight, length, or head circumference. Notably, 23 of all 31 of the infants had a birth weight z score below the population mean (Fig 1), and also after excluding those with AVB II-III, the remaining had a z score of –0.51 ± 1.01 below population standards (P < .05). This was also true for infants of mothers with SS (–0.86 ± 1.13; P < .05) but not for those with SLE. Newborn infants without fetal signs of AVB II-III could not be shown to diverge from population standards in length or head circumference.
Longitudinal data systematically collected at standardized postnatal ages and converted to z scores after correction for gestational age are presented in Fig 2. Infants with fetal signs of AVB II-III seemed to have some catch-up in weight during the first 2 months after birth but thereafter showed a slowly progressing negative divergence from population standards. From 8 months onward, the weight z score was significantly lower than normal, and at 1 year of age it was even lower than at birth. Analysis of the length of children with AVB II-III shows the same tendency, although without significant deviation from the reference population. Infants in the AVB I and NC groups had weight and length measurements that compared well with normal standards all through the study period. BMI increased with postnatal age in all of the infants. As could be expected from the observed differences in weight and length z scores between groups, a lower BMI could be demonstrated from 4 months onward in infants of the AVB II-III group compared with those belonging to the other 2 groups. Infants with fetal signs of AVB I did not show any differences in BMI compared with those with NC. All of the infants had a head circumference within the ±2-SD normal reference range from birth to 1 year of age. The group of infants with fetal signs of AVB II-III did not demonstrate any deviation from the population standard, whereas the groups of infants with fetal AVB I or NC both had a period between 2 and 6 months of age where head circumference measurements were significantly higher than expected. All of the children developed well without any obvious signs of delayed performance in communicational skills, fine and basic motor skills, or cognitive skills as judged from the basic routine methods used in their local childhood health centers.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Based on our clinical observation of feeding problems and failure to thrive in infants affected by complete heart block, we initiated this study to evaluate the clinical outcome with regard to growth and development in infants fetally exposed to anti-Ro52 antibodies. We also specifically aimed at investigating the outcome in our recently identified group of fetuses developing indirect signs of AVB I in utero, because the long-term clinical relevance of this condition has not been established.
Our study included 32 fetuses (31 surviving infants) of 30 anti-Ro52-positive mothers. Women giving birth to infants with prenatal AVB II-III were significantly older than mothers of fetuses with AVB I or NC. The risk of having a fetus with AVB II-III also increased with parity compared with the AVB I and NC groups. Increasing maternal age and parity are obviously linked, and our cohort did not allow independent analysis of the 2 variables because of sample size. In a previous study of a larger series of families with 1 child diagnosed with complete AVB, birth order could not be demonstrated to predict the occurrence of heart block, indicating that the more important factor may be maternal age.33
An increased risk for AVB II-III in older mothers and with increasing parity could depend on several different factors of immunologic or nonimmunologic origin. Both epitope spreading and antibody affinity maturation may contribute to an increased risk, either related to increasing age or cumulative pregnancies. Thus, higher titers and higher affinity antibody after affinity maturation may develop after autoantigen exposure during tissue and cell rupture during pregnancy or at birth, as well as epitope spreading, with the formation of new specificities to adjacent epitopes by the same mechanism, which may lead to the development and production of pathogenic specificities. Nonimmune-related factors could include placental development and function, especially in the pregnancy of women with SLE, where thromboembolic events may lead to placental infarction and disturbed support of the fetus.
Contrary to most other autoimmune diseases, we found no gender bias in the development of AVB. That fetal gender does not predict occurrence of AVB is an observation made by previous investigators3,33 and indicates that gender relates to the induction of an autoimmune response and not the pathogenic effector phase.
The whole group of anti-Ro52-positive pregnancies resulting in a live-born child had a gestational age of <40 completed weeks. When subgrouped according to maternal disease, this finding could still be demonstrated in women with SLE but not in those with SS, supporting observations made by previous investigators.3,4,6 All of the fetuses with AVB II-III were delivered before 40 weeks of gestation, 2 preterm because of maternal or fetal complications and 4 by elective cesarean section at 37 to 38 weeks. The remaining infants with AVB I or NC did not show any differences in gestational age and could not be demonstrated to have a gestation of <40 weeks, indicating that the presence of AVB I does not affect the duration of pregnancy and that AVB II-III was an important predictor of reduced length of pregnancy in our group of patients.
Newborns with fetal signs of AVB II-III had a significantly lower weight, shorter length, and smaller head circumference than those with AVB I or NC, who, in turn, did not demonstrate any differences in any of these measurements. Although the reduction in length and head circumference at birth seemed to be an effect of the shorter gestation in AVB II-III pregnancies, birth weight still remained close to 1 SD below Swedish reference standards after correction for gestational age. The whole group of anti-Ro52-exposed fetuses, even after excluding those with AVB II-III, also had a significant but smaller retardation in weight compared with our population standards. Although intrauterine growth retardation in pregnant women with connective tissue disease has been well documented,1–4 the impact of fetal cardiac involvement in this respect has been less satisfactorily investigated. In a recent neurodevelopmental follow-up of 13 children with fetal AVB, 6 had a birth weight below the 10th centile and 3 had a birth weight at or below the third centile.22 Five of the 6 had, however, been prenatally exposed to dexamethasone, making it difficult to distinguish effects of steroids from effects of the fetal disease. Fetal dexamethasone treatment has, on one hand, not only been associated with a slight reduction in birth weight when administered to promote lung maturation23 but also severe intrauterine growth retardation and fetal death in a few cases of prophylactic treatment of pregnant women with a previous history of fetal AVB.24 Prenatal dexamethasone treatment of congenital adrenal hyperplasia has, on the other hand, not been found to have any negative effect on fetal growth.34 Furthermore, in an outcome analysis of 37 consecutive cases of fetal AVB, the degree of intrauterine growth retardation was not reported, but the birth weight and gestational age were found not to change between 2 time periods, 1990–1996 and 1997–2003, with different prenatal management.35 During the first time period 2 of 12 live-born infants were fetally treated with dexamethasone, whereas during the second time period almost all (17 of 18) infants were treated, indirectly suggesting that this treatment does not have a major impact on fetal growth, as birth weight and gestational age did not change.
In our cohort, 4 fetuses received steroid treatment in an attempt to improve atrioventricular conduction. Three fetuses, 1 with AVB III and 2 with AVB II, received treatment with fluorinated steroids from diagnosis to birth. In an additional fetus with AVB III, it was not possible to exclude periods of second-degree AVB, and betamethasone was given for <1 week, leaving only 2 surviving fetuses with AVB III who did not receive any transplacental steroid treatment. Even if these 2 did not differ with regard to birth weight compared with the other 4, the numbers are too small to speculate whether transplacental treatment contributed to the retarded growth demonstrated in our group of newborns with fetal AVB II-III or not.
Infants with fetal signs of AVB II-III did not show any signs of catch-up, but remained 1 SD below population standards in weight all through their first year of life. These infants also tended to be somewhat shorter than average but not to the same extent as the reduction in weight, as reflected by their lower BMI compared with infants in the AVB I and NC groups. The combined group of infants without signs of AVB III had a catch-up in weight during their first 2 months after birth, and thereafter both groups with signs of AVB I and NC followed our national standard growth charts. Our clinical impression is that this lack of catch-up in the AVB II-III group was more related to problems with feeding and nutrition than problems of cardiac origin. Actually, 2 of these infants were in sinus rhythm, 3 received a pacemaker already as neonates, and the last had a good ventricular escape rhythm. All had a good cardiac function without any signs of circulatory compromise.
None of the groups of children investigated in our study showed signs of retarded development in communication skills, cognitive development, or motor skills with the rather blunt methods used within the study.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study suggests that the risk of giving birth to a child with heart block increases with age in anti-Ro52 antibody-positive women. Our findings also demonstrate that fetuses with AVB II-III were
1 SD retarded in weight and did not show any catch-up during infancy. Even if almost all remained within our national reference range of ± 2 SD, we believe that this observation, combined with our clinical experience of these infants, should be taken as a signal that these patients need close observation also of their nutrition and growth. Fetuses without AVB II-III had a significant but smaller weight retardation at birth. These infants, however, showed a quick catch-up during the first 2 postnatal months, indicating that they, even in the presence of fetal signs of AVB I, have a good prognosis.
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ACKNOWLEDGMENTS |
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This study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, Karolinska Institutet, Prof Nanna Svartz' Foundation, King Gustaf V's 80-Year Foundation, the Heart-Lung Foundation, the Swedish Rheumatism Association, Stiftelsen Frimurare Barnhuset, and the Stockholm City Council.
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FOOTNOTES |
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Accepted Sep 4, 2007.
Address correspondence to Sven-Erik Sonesson, MD, PhD, Fetal Cardiology Unit, Pediatric Cardiology Q1:03, Astrid Lindgrens Children's Hospital, Karolinska Hospital, SE-171 76 Stockholm, Sweden. E-mail: sven-erik.sonesson{at}karolinska.se
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject The objective of the present study was to analyze outcome with focus on growth in infants fetally exposed to heart block-associated maternal anti-Ro52/SSA autoantibodies, which has not been systematically investigated before.
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| What This Study Adds This report documents that newborns with autoantibody-mediated second-degree or third-degree atrioventricular block are retarded in growth, with no catch-up during infancy, whereas fetuses with first-degree atrioventricular block or normal atrioventricular conduction have a normal growth soon after birth.
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