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Neurodevelopment in the offspring of Japanese systemic lupus erythematosus patients
Brain & Development 32 (2010) 390–395 www.elsevier.com/locate/braindev
Original article
Neurodevelopment in the offspring of Japanese systemic lupus erythematosus patients Naomi Yoshikawa *, Kyoko Tanaka, Mariko Sekigawa, Noriko Kudo, Yayoi Arai, Yoshikazu Ohtsuka, Toshiaki Shimizu Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan Received 12 March 2009; accepted 22 June 2009
Abstract Objective: To evaluate pregnancy outcome of systemic lupus erythematosus (SLE) and the neuropsychological outcomes in offspring of SLE mothers. Study design: Pregnancy outcomes of SLE patients from 1989 to 2006 were determined and the neuropsychological development of the children born to SLE patients was examined suited for their age; Bayley Scales of Infant Development up to four years and Kauffmann Assessment Battery for Children from four years onwards. Results: Of the 233 deliveries, 58 (24.7%) were preterm, 72 (30.9%) were low-birth-weight, and 46 (19.7%) were IUGR. Twenty-six children enrolled in this study had normal intelligence. The mean MDI and PDI were 95.8 ± 10.1 and 94.6 ± 14.1, respectively. The mean scores for the Sequential Processing scale, Simultaneous Processing scale, and Mental Processing composite were 103.1 ± 13.3, 104.2 ± 10.2, and 104.2 ± 12.2, respectively. In the children with anti-Ro/SS-A antibody-positive mothers, mean gestational age and birth weight were significantly lower (p < 0.05), as a result, the mean score of Sequential Processing and Mental Processing were significantly lower than that of negative mothers. The presence of maternal antiphospholipid antibody was not related to gestational age, birth weight and any score on the intelligence tests, except for the rate of IUGR. Conclusion: The rates of preterm delivery and IUGR were frequent in the SLE patients and careful monitoring and management of the disease during pregnancy are still necessary. We should examine the neurodevelopment of the children born from mothers with anti-Ro/SS-A antibody prospectively. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Pregnancy outcome; Maternal anti Ro/SS-A antibodies; Maternal antiphospholipid antibodies; Neurodevelopment of offspring
1. Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that occurs mainly in women during their childbearing years. The results of pregnancies in women with SLE were once discouraging because of the possible worsening of the disease and negative effects on fetal outcome [1]. Recently, however, the diagnosis * Corresponding author. Address: Department of Pediatrics, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113 8421, Japan. Tel.: +81 3 3813 3111x3640; fax: +81 3 5800 1580. E-mail address: [email protected] (N. Yoshikawa).
0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.06.006
and management of SLE have improved greatly. As a result, the disease can now be controlled sufficiently and SLE patients are not discouraged from bearing children. Therefore, an increasing number of women with SLE are becoming pregnant. However, for SLE patients, the pregnancy outcome commonly includes preterm delivery (21–52%), intrauterine growth retardation (10–30%), and pregnancy loss (10–50%) [2,3]. In particular, women with antiphospholipid antibodies tend to experience recurrent miscarriage and fetal death. Maternal anti-Ro/SS-A antibodies confer a risk of developing congenital heart block (CHB) in the fetus and other clinical manifestations in newborns
N. Yoshikawa et al. / Brain & Development 32 (2010) 390–395
such as skin rashes, hepatic abnormalities, and thrombocytopenia, which are generally referred to as neonatal lupus syndrome (NLS). Now that many women with SLE can expect a safe pregnancy and delivery, they are becoming more interested in the healthy growth and development of their children, rather than the pregnancy itself. Previous studies on the long-term neuropsychological development of children of SLE mothers show that their level of intelligence is normal, but they are more like to have developmental disorders, especially in males, such as left handedness, attention deficit, dyslexia, and learning disabilities (LD) compared to children of mothers who do not have SLE [4,5]. Neri et al. [6] studied neuropsychological development using intelligence tests and specific tests for LD in the children of SLE patients; all children had normal IQs, but 14% of the school-aged children were diagnosed as dyslexic, suggesting that the occurrence of LD is associated with maternal antiphospholipid antibodies. We investigated retrospectively the pregnancy outcome of SLE patients attending our hospital and evaluated the neuropsychological development of the children born to SLE patients with assessments suitable for their age. We focused on the relationship between developmental outcome and maternal autoantibodies during pregnancy. 2. Patients and methods 2.1. Mothers: the pregnancies Between 1998 and 2006, we delivered 233 SLE patients at Juntendo University Hospital, Tokyo, Japan. Our hospital is a tertiary medical care center and has experience with pregnancies in mothers with autoimmune diseases. All of the patients met the adjusted American College of Radiology (ACR) classification criteria for SLE. They were also informed about the criteria for the admission of SLE pregnancies at our institution (Table 1) and underwent blood examinations
391
and echography by experienced obstetricians and specialists in autoimmune diseases at Juntendo Hospital. We excluded patients who had either spontaneous or elective abortions from our analysis. The medical records of SLE mothers were reviewed retrospectively in terms of the following factors: mother’s age, gestational age, birth weight, number of pregnancies lost after 22 weeks of gestational age, neonatal deaths, preterm births, low-birth-weight, intrauterine growth retardation (IUGR), and neonatal lupus syndrome. In addition, data on the presence of maternal autoantibodies, anti-Ro/SS-A antibodies, antiphospholipid antibodies (aPL), detected lupus anticoagulant (LA), and anticardiolipin (aCL) antibodies in assays during pregnancy were obtained retrospectively from the medical records. In 2006, letters were sent to mothers with SLE who had delivered at Juntendo University Hospital informing them of the study details. After receiving informed consent from the parents, 26 children entered this study. 2.2. Children: the sample definition Twenty-six children (16 males, 10 females) aged 6 months to 12 years and 9 months were enrolled in our study: 11 (45%) were classified as premature because they were born before 37 weeks of gestation; 10 (38.4%) were low-birth-weight infants below 2500 g of birth weight; and 5 (19.2%) had IUGR, defined as birth weight less than the 10th percentile for the gestational age. In all cases, the parents were Japanese, and no children had mothers who had psychiatric complications of SLE. 2.3. Children: assessment of physical growth The children were interviewed about their medical conditions, and the physical growth of each child, including measurements of body weight and length, was assessed by a pediatrician. 2.4. Children: assessing intelligence
Table 1 The guidelines of Juntendo Hospital for the pregnancy and delivery of SLE patients. Guideline The patient has been in remission for >10 months and has been given corticosteroids at a dose <15 mg per day The patient has no serious manifestations of SLE such as lupus nephritis The patient has no serious side-effects of corticosteroids The patient is not taking immunosuppressive drugs It is desirable that antiphospholipid antibodies and anti-Ro/SS-A or La/SS-B antibodies are negative* The patient and her family are capable of taking care of the child * When these autoantibodies are positive, the hospital informs the patient of the potential risk and leaves the decision to the patient.
The 26 children were divided into two age groups (Table 2). To evaluate the mental development of children younger than 4 years, we used the Bayley Scales of Infant Development second edition (BSID-II) [7]. The BSID-II provides mental development index (MDI) and psychomotor development index (PDI) scores, with a mean of 100 and a standard deviation of 15. Behavior was assessed using the Behavior Rating Scale (BRS), which consists of Orientation/Engagement, Emotional Regulation, and Motor Quality factors. On the BRS, a score of the 26th percentile and above was deemed to be within normal limits, a score between the 11th and 25th percentiles was deemed questionable,
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and a score at or below the 10th percentile was non-optimal. An MDI or PDI > 2 SD below the mean (<70) was defined as mental retardation. Children younger than 3 years with a preterm birth were assessed using their corrected age. For children older than 4 years, we used the Kauffmann Assessment Battery for Children (KABC) [8]. The K-ABC is a measure of intelligence and achievement designed for children aged 2.5 through 12.5 years. This multisubtest battery comprises two scales, i.e., Sequential Processing and Simultaneous Processing, which are hypothesized to reflect the child’s style of problem solving and information processing. These two scales are combined into a Mental Processing Composite, which is a global measure of intellectual functioning that correlates well with other IQ measures and have been used in assessing LD children [9]. Each scale produces a standardized score with a mean of 100 and SD of 15. The intelligence tests were administered a single pediatrician who had a special interest in neuropsychological development. Finally, the parents were interviewed about the children’s growth and learning abilities at school, and the children were diagnosed clinically by another pediatrician who specialized in child development. This study was approved by our institutional review board, and was performed only after obtaining informed consent from the parents of participating patients.
IUGR were frequent: 58 (24.8%) were preterm, 72 (30.9%) were low-birth-weight, and 46 (19.7%) were IUGR. The mean maternal age was 31.5 years (range 19–40). The mean birth weight and gestational age were 2563 g (range 338–3740) and 37.4 weeks (range 24.7– 41.3), respectively. Five children developed neonatal lupus syndrome (NLS): two with congenital heart block (CHB) and three with skin erythema. Pregnancy loss and neonatal death occurred in four and three pregnancies, respectively. The neonatal deaths resulted from heart failure caused by CHB and pulmonary hemorrhage in two extremely low-birth-weight infant. The fetal deaths occurred in mothers who had antiphospholipid antibodies during pregnancy (Table 3).
2.5. Statistical analysis
3.3. Intelligence test results
The results were expressed as the mean ± standard deviation (SD). Proportions were compared using the chi-square test with continuity correction. Means were compared using the Mann–Whitney U-test for independent samples. A P value of less than 0.05 was considered statistically significant.
The mean score on each test was essentially normal. Because mental retardation was defined as a score <70, all 26 children had normal intelligence, and no child had mental retardation. There were eight children in the infant group (<4 years), and their mean age was 1.5 years. The mean birth weight and gestational age were 2407 g (range 1088–3136) and 36.1 weeks of gestation (range 29.6–40.4), respectively. The mean MDI was 95.8 ± 10.1 (mean ± SD). The mean PDI was 94.6 ± 14.1 (Table 5a). The mean BRS was 59, which was within normal limits. There were 18 children older than 4 years and their mean age was 8.8 years. The mean birth weight and gestational age were 2537 g (range 882– 3186) and 37.3 weeks of gestation (range 30.0–40.7), respectively. The mean scores for the Sequential Processing scale, Simultaneous Processing scale, and Mental Processing composite were 103.1 ± 13.3, 104.2 ± 10.2, and 104.2 ± 12.2, respectively, which were within the normal range (Table 5b).
3. Results 3.1. Pregnancy outcomes In the 19 years between 1989 and 2006, we delivered 233 SLE patients at our Hospital. Preterm birth and
Table 2 Distribution of the children for the administration of intelligence tests. Age range
Number of children
Mean age (years)
Intelligence test
6 months–3 years 4 years–12 years
8 18
1.6 8.8
BSID-II* K-ABC**
*
Bayley Scales of Infant Development-II; the children delivered before term were assessed using their corrected age. ** Kaufman Assessment Battery for Children, modified for Japanese children.
3.2. Characteristics of the children Twenty-six children (16 males and 10 females, aged 6 months to 12 years) were enrolled to assess their intelligence. The mean birth weight and gestational age were 2497 g (range 882–3186) and 37.0 weeks of gestation (range 28.1–40.7), respectively. Of the 26 children, 11 were preterm infants (45%) and 5 had IUGR (19.2%; Table 4). None of the children had growth or health problems. The children with IUGR at birth had grown well, and their body weights and heights were within the normal range.
3.4. Correlation between maternal autoantibodies and children’s intelligence The influence of the mother’s autoantibody profile was investigated, considering mothers with or without
N. Yoshikawa et al. / Brain & Development 32 (2010) 390–395 Table 3 Pregnancy outcomes of SLE patients. Variable
Value
Number of deliveries Mean maternal age (range) Mean gestational age (range) Mean birth weight (range) Number of preterm deliveries* Number of low-birth-weight infants* Number of infants with IUGR* Lost pregnancies** Neonatal deaths** Neonatal lupus syndrome
233 31.5 years (19–40) 37.4 weeks (24.7–41.4) 2563 g (338–3740) 58 (24.8%) 72 (30.9%) 46 (19.7%) 4 3 5 (2.1%)
* Preterm delivery is defined as delivery before 37 weeks of gestation, low-birth-weight as below 2500 g of birth weight, IUGR as below tenth percentile for birth weight by gestational age. ** Lost pregnancies are defined as pregnancy loss after 22 weeks of gestation and neonatal deaths are defined as death within 28 days of birth. Two with CHB, three with skin rash.
Table 4 Population of children with SLE patients. Variable
Value
Number of children Male:female Age (range) Mean maternal age Mean gestational age (range) Mean birth weight (range) Number of preterm deliveries Number of low-birth-weight infants < 2500 g Number with IUGR
26 16:10 6.6 years (0.7–12.8) 32.3 years (20–38) 37.0 weeks (28.1–40.7) 2497 g (882–3186) 11 (45%) 10 (38.4%) 5 (19.2%)
Table 5a Results of the Bayley Scales of Infant Development-II (n = 8). Scale
Score (mean ± SD)
MDI PDI BRS Orientation/engagement Emotional regulation Motor quality Total
95.8 ± 10.1 94.6 ± 14.1 47.4 ± 10 45.1 ± 16.4 55.5 ± 14.2 59 ± 20.8
MDI, mental development index; PDI, psychomotor development index; BRS, behavior rating scale.
Table 5b Results of the Kaufman Assessment Battery of Children (n = 18). Scale
Score (mean ± SD)
Sequential processing Simultaneous processing Mental processing
103.1 ± 13.3 104.2 ± 10.2 104.2 ± 12.2
antibodies to Ro/SS-A or one of the other cellular antigens, and to three phospholipids (aCL, anti-b2 GPI, or LA). There were 9 and 17 children of mothers with positive and negative anti-Ro/SS-A antibodies, respectively. The mean gestational age at delivery and birth weight
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Table 6 Correlation between mother’s anti-Ro/SS-A antibodies and children’s characteristics. Child’s characteristic
Positive mothers (n = 9)
Negative mothers (n = 17)
P
Mean gestational age (weeks) Mean birth weight (g) IUGR BSID-II (n = 8) MDI (mean ± SD) PDI K-ABC (n = 18) Simultaneous processing Sequential processing Mental processing
34.3 1914 4 (44%) 4 90 ± 3.4 87.5 ± 14 5 95 ± 17 96 ± 9.6 95 ± 11
38.4 2806 1 (5.8%) 4 101 ± 12 101 ± 11 13 106 ± 11 107 ± 9.1 108 ± 10
<0.05* <0.05* <0.05** ns ns ns <0.05* <0.05*
ns, not significant. * Mann–Whitney U-test. ** Chi-square test.
Table 7 Correlation between mother’s antiphospholipid antibodies and children’s characteristics. Child’s characteristic
Positive mothers (n = 10)
Negative mothers (n = 15)
P
Mean gestational age (weeks) Mean birth weight (g) IUGR BSID-II (n = 8) MDI (mean ± SD) PDI K-ABC (mean ± SD) Simultaneous processing Sequential processing Mental processing
36.3 2243 4 (40%) 1 85 75 9 100 ± 15 103 ± 10 102 ± 13
37.3 2642 1 (6.6%) 7 97 ± 10 97 ± 12 8 107 ± 12 106 ± 11 108 ± 12
ns* ns* 0.04** ns* ns* ns* ns* ns*
ns, not significant. * Mann–Whitney U-test. ** Chi square test.
were significantly lower (p < 0.05) children from the anti-Ro/SS-A antibody-positive mothers. The proportion of children with IUGR was significantly higher in the positive mothers (p < 0.05). On the intelligence tests, all of the children had a normal IQ (>70). Interestingly, however, on the intelligence scores of the children assessed using the K-ABC, the score on the Sequential Processing scale was significantly lower in children with SS-A-positive mothers than in those with SS-A-negative mothers (p < 0.05). There was no significant difference between the score on the MDI and PDI of the children assessed using the BSID-II. The Simultaneous Processing scale was not related to the presence of maternal anti-Ro/SS-A antibodies (Table 6). The presence of maternal aPL was related only to the rate of IUGR and not to differences in any intelligence score (Table 7). Overall, none of the children have been diagnosed with learning disorders or behavior dysfunction such as attention disorder or hyperactivity.
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4. Discussion The overall prevalence of pregnancy outcomes in SLE patients was similar to those in previous reports. The rates of preterm delivery and IUGR were 24.8% and 19.7%, respectively, which fall within the reported ranges [10,11]. The rates of preterm delivery and IUGR are affected by the disease activity, maternal antiphospholipid antibodies, and drugs such as high doses of corticosteroids or immunosuppressive drugs, which cause ovarian insufficiency, hypertensive complications in the second trimester, and oligohydramnios, all likely factors contributing to preterm delivery and IUGR [12–14]. Chakravarty et al. [15] reported that women with SLE had significantly increased rates of hypertensive disorders, longer hospital stays, higher risk of cesarean delivery, and were older than women in the general obstetric population for a large number of patients in 35 states in the United States. Therefore, given the increasing number of pregnancies in SLE patients, careful monitoring and management of the disease during pregnancy are still necessary [16]. The pregnancy outcome of women with anti-Ro/SS-A antibodies included a significantly lower gestational age and birth weight and a higher rate of IUGR than in women without anti-Ro/SS-A antibodies. All 26 children had normal IQs, although, interestingly, the Sequential Processing score was significantly lower in children of anti-Ro/SS-A antibody-positive mothers than in those of negative mothers. In a recent study, the presence of anti-Ro/SS-A antibodies was associated with LD in boys born from SLE mothers, and maternal antibodies might affect the developing brains of male fetuses, with the subsequent expression of learning and other developmental disorders [5]. However, another study found no association between the neurodevelopment of children and maternal anti-Ro/SS-A antibodies [17]. In our study, we think that the lower Sequential Processing score in the children with Ro/SS-A-positive mothers showed that maternal autoantibodies especially Ro/SS-A might affect cognitive development of the children. Our study also showed the higher incidence of preterm infant and IUGR of children born from mothers with Ro/SS-A. So, we should follow the development of these children with Ro/SS-A positive mothers because of the possible development of LD and so on, although preterm or not. Antiphospholipid antibodies are recognized as the most frequent acquired risk factor for recurrent thrombosis; they are a treatable cause of recurrent pregnancy loss and are also associated with fetal death, IUGR, and early preeclampsia [18,19]. A previous study found that exposure to aPL might be related to CNS dysfunction and hyperactive behavior because the aPL induces a hypercoagulable state, interacting with clotting factors and activating platelets, monocytes, and endothelial cells, thereby causing micro-thrombi at many sites in
the brain in an animal model [20,21]. In our sample population, fetal death occurred in 4 of 233 deliveries in which the mothers developed aPL. In addition, the pregnancy outcome of mothers with aPL was not related to gestational age or birth weight, except for the rate of IUGR in comparison with the mothers without aPL. Moreover, the presence of aPL was not related to any score on the intelligence tests. In the neurodevelopment of the children of SLE mothers, all 26 children examined had scores within the normal ranges on the intelligence tests. Previous studies also reported that the offspring of SLE patients had normal IQs, despite the higher rate of preterm delivery [5,9]. To ensure that none of the children examined had developmental disorders such as LD, dyslexia, or attention deficit hyperactivity disorder (ADHD), the pregnant women with SLE were treated strictly following our criteria (Table 1). In particular, the pregnant women were given corticosteroids at doses < 15 mg/ day, which reflected the disease activity and resulted in the normal development of children. Therefore, we postulate that the admission protocol for SLE mothers used at our institute has no negative effects on the physical growth and cognitive development of children, although there was no difference in the rate of IUGR and pregnancy loss. However, we need to examine forms of the disease activity of SLE such as SLEPDI, modified as pregnant patients [22], which might affect the development of children in utero and during infancy. The cognitive development of children is affected by various factors such as parental education and the socioeconomic environment in which the children are raised, in addition to maternal disease. Patients with chronic, unpredictable diseases such as SLE may experience secondary psychiatric disorders, acute confusional states, stress, and anxiety, which might influence the attachment between the mother and infant during infancy. It has been reported that SLE mothers worry about the disease itself and are anxious about transmitting the disease and effect of the disease on the growth of their children [23–25]. Therefore, we should investigate the confounding variables that influence the cognitive development of children of women with SLE, especially the maternal mental state.
Acknowledgement We are indebted to Professor Yoshinari Takasaki; Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan; for his advice on the autoimmune diseases, to Dr Toshitaka Tanaka; Department of Obstetric and Gynecology, Juntendo University School of Medicine; for his help in the investigation of pregnancy outcomes. We also wish to acknowledgement all the families for their kind participation in our study.
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Sponsor and grant: We had no any grant and sponsor for this paper. References [1] Petri M, Howard D, Repke J. Frequency of Lupus flare in pregnancy. Arthritis Rheum 1991;34:1538–45. [2] Yasmeen S, Wilkins EE, Field NT, Sheikh RA, Gilbert WM. Pregnancy outcomes in women with systemic lupus erytehematosus. J Matern Fetal Med 2001;10:91–6. [3] Branch DW, Silver RM, Blackwell JL, Reading JC, Scott TR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obestet Gynecol 1992;80:614–20. [4] McAllister DL, Kaplan BJ, Edworthy SM. The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends. J Int Neuropsychol Soc 1997;3:370–6. [5] Ross G, Sammaritano L, Nass R, Lockshin M. Effects of mothers’ autoimmune disease during pregnancy on learning disabilities and hand preference in their children. Arch Pediatr Adolesc Med 2003;157:397–402. [6] Neri F, Chimini L, Bonomi F, Filippini E, Motta M, Faden D, et al. Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus 2004;13:805–11. [7] Nancy Bayley. Bayley scales of infant development second edition manual. The Psychological Corporation; 1993. [8] Kaufman AS, Kaufman NL. The Kaufman assessment battery for children: interpretive manual. American Guidance Service; 1983. [9] Stephan RH, George WH. Performance of normal and dyslexic readers on the Kaufman assessment battery for children (KABC): a discriminate analysis. J Learn Disabil 1986;19:206–10. [10] Clark CA, Spizer KA, Nadler JN, Laskin CA. Preterm deliveries in women with systemic lupus erythematosus. J Rheumatol 2003;30:2127–32. [11] Petri M. Prospective study of systemic lupus erythematosus pregnancies. Lupus 2004;13:688–9. [12] Clowse MEB, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 2005;52:514–21.
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[13] Meroni PL, Shimone N, Testoni C, D’Asta M, Acaia B, Caruso A. Antiphospholipid antibodies as cause of pregnancy loss. Lupus 2004;13:649–52. [14] Parke A. Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and chronic autoimmune disease. Lupus 2006;16:808–13. [15] Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalization in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;54:899–907. [16] Branch DW. Pregnancy in patients with rheumatic diseases: obstetric management and monitoring. Lupus 2004;13:696–8. [17] Brucato A, Astori MG, Cimaz R, Villa P, Destri ML, Chimini L, et al. Normal neuropsychological development in children with congenital complete heart block who may or may not be exposed to dexamethasone in utero. Ann Rheum Dis 2006;65:1422–6. [18] Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–63. [19] Di Simone N, Meroni PL, Del papa N. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by biding directly and through adhered b2–glycoprotein II. Arthritis Rheum 2000;43:140–50. [20] Ziporen L, Soenfeld Y, Levy Y, Kerezyn AD. Neurological dysfunctions and hyperactive behavior associated with antiphospholipid antibodies. J Clin Invesst 1997;100:613–9. [21] Shrot S, Katzav A, Korezyn AD, et al. Behavioral and cognitive deficits occur only after prolonged exposure of mice to antiphospholipid antibodies. Lupus 2002;11:736–43. [22] Buyon JP, Kalunian KC, Ramsey-Goldman R, Petri MA, Lockshin MD, Ruiz-Irastorza G, et al. Assessing disease activity in SLE patients during pregnancy. Lupus 1999;8:677–84. [23] Sgui J, Ramos-Casals M, Garcia-Carrasco M, de Flores T, Cervera R, Valdes M, et al. Psychiatric and psychosocial disorders in patients with systemic lupus erythematosus: a longitudinal study of active and inactive stages of the disease. Lupus 2000;9:584–8. [24] Neri F, Chimini L, Filippini E, Motta M, Faden D, Tincani A. Pregnancy in patients with rheumatic disease: psychological implication of a chronic disease and neuropsychological evaluation of the children. Lupus 2004;13:666–8. [25] Omdal R, Waterloo K, Koldingsnes W, Husby G, Mellgren SI. Fatigue in patients with systemic lupus erythematosus: the psychosocial aspects. J Rheumatol 2003;30:283–7.
Original article
Neurodevelopment in the offspring of Japanese systemic lupus erythematosus patients Naomi Yoshikawa *, Kyoko Tanaka, Mariko Sekigawa, Noriko Kudo, Yayoi Arai, Yoshikazu Ohtsuka, Toshiaki Shimizu Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan Received 12 March 2009; accepted 22 June 2009
Abstract Objective: To evaluate pregnancy outcome of systemic lupus erythematosus (SLE) and the neuropsychological outcomes in offspring of SLE mothers. Study design: Pregnancy outcomes of SLE patients from 1989 to 2006 were determined and the neuropsychological development of the children born to SLE patients was examined suited for their age; Bayley Scales of Infant Development up to four years and Kauffmann Assessment Battery for Children from four years onwards. Results: Of the 233 deliveries, 58 (24.7%) were preterm, 72 (30.9%) were low-birth-weight, and 46 (19.7%) were IUGR. Twenty-six children enrolled in this study had normal intelligence. The mean MDI and PDI were 95.8 ± 10.1 and 94.6 ± 14.1, respectively. The mean scores for the Sequential Processing scale, Simultaneous Processing scale, and Mental Processing composite were 103.1 ± 13.3, 104.2 ± 10.2, and 104.2 ± 12.2, respectively. In the children with anti-Ro/SS-A antibody-positive mothers, mean gestational age and birth weight were significantly lower (p < 0.05), as a result, the mean score of Sequential Processing and Mental Processing were significantly lower than that of negative mothers. The presence of maternal antiphospholipid antibody was not related to gestational age, birth weight and any score on the intelligence tests, except for the rate of IUGR. Conclusion: The rates of preterm delivery and IUGR were frequent in the SLE patients and careful monitoring and management of the disease during pregnancy are still necessary. We should examine the neurodevelopment of the children born from mothers with anti-Ro/SS-A antibody prospectively. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Pregnancy outcome; Maternal anti Ro/SS-A antibodies; Maternal antiphospholipid antibodies; Neurodevelopment of offspring
1. Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that occurs mainly in women during their childbearing years. The results of pregnancies in women with SLE were once discouraging because of the possible worsening of the disease and negative effects on fetal outcome [1]. Recently, however, the diagnosis * Corresponding author. Address: Department of Pediatrics, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113 8421, Japan. Tel.: +81 3 3813 3111x3640; fax: +81 3 5800 1580. E-mail address: [email protected] (N. Yoshikawa).
0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.06.006
and management of SLE have improved greatly. As a result, the disease can now be controlled sufficiently and SLE patients are not discouraged from bearing children. Therefore, an increasing number of women with SLE are becoming pregnant. However, for SLE patients, the pregnancy outcome commonly includes preterm delivery (21–52%), intrauterine growth retardation (10–30%), and pregnancy loss (10–50%) [2,3]. In particular, women with antiphospholipid antibodies tend to experience recurrent miscarriage and fetal death. Maternal anti-Ro/SS-A antibodies confer a risk of developing congenital heart block (CHB) in the fetus and other clinical manifestations in newborns
N. Yoshikawa et al. / Brain & Development 32 (2010) 390–395
such as skin rashes, hepatic abnormalities, and thrombocytopenia, which are generally referred to as neonatal lupus syndrome (NLS). Now that many women with SLE can expect a safe pregnancy and delivery, they are becoming more interested in the healthy growth and development of their children, rather than the pregnancy itself. Previous studies on the long-term neuropsychological development of children of SLE mothers show that their level of intelligence is normal, but they are more like to have developmental disorders, especially in males, such as left handedness, attention deficit, dyslexia, and learning disabilities (LD) compared to children of mothers who do not have SLE [4,5]. Neri et al. [6] studied neuropsychological development using intelligence tests and specific tests for LD in the children of SLE patients; all children had normal IQs, but 14% of the school-aged children were diagnosed as dyslexic, suggesting that the occurrence of LD is associated with maternal antiphospholipid antibodies. We investigated retrospectively the pregnancy outcome of SLE patients attending our hospital and evaluated the neuropsychological development of the children born to SLE patients with assessments suitable for their age. We focused on the relationship between developmental outcome and maternal autoantibodies during pregnancy. 2. Patients and methods 2.1. Mothers: the pregnancies Between 1998 and 2006, we delivered 233 SLE patients at Juntendo University Hospital, Tokyo, Japan. Our hospital is a tertiary medical care center and has experience with pregnancies in mothers with autoimmune diseases. All of the patients met the adjusted American College of Radiology (ACR) classification criteria for SLE. They were also informed about the criteria for the admission of SLE pregnancies at our institution (Table 1) and underwent blood examinations
391
and echography by experienced obstetricians and specialists in autoimmune diseases at Juntendo Hospital. We excluded patients who had either spontaneous or elective abortions from our analysis. The medical records of SLE mothers were reviewed retrospectively in terms of the following factors: mother’s age, gestational age, birth weight, number of pregnancies lost after 22 weeks of gestational age, neonatal deaths, preterm births, low-birth-weight, intrauterine growth retardation (IUGR), and neonatal lupus syndrome. In addition, data on the presence of maternal autoantibodies, anti-Ro/SS-A antibodies, antiphospholipid antibodies (aPL), detected lupus anticoagulant (LA), and anticardiolipin (aCL) antibodies in assays during pregnancy were obtained retrospectively from the medical records. In 2006, letters were sent to mothers with SLE who had delivered at Juntendo University Hospital informing them of the study details. After receiving informed consent from the parents, 26 children entered this study. 2.2. Children: the sample definition Twenty-six children (16 males, 10 females) aged 6 months to 12 years and 9 months were enrolled in our study: 11 (45%) were classified as premature because they were born before 37 weeks of gestation; 10 (38.4%) were low-birth-weight infants below 2500 g of birth weight; and 5 (19.2%) had IUGR, defined as birth weight less than the 10th percentile for the gestational age. In all cases, the parents were Japanese, and no children had mothers who had psychiatric complications of SLE. 2.3. Children: assessment of physical growth The children were interviewed about their medical conditions, and the physical growth of each child, including measurements of body weight and length, was assessed by a pediatrician. 2.4. Children: assessing intelligence
Table 1 The guidelines of Juntendo Hospital for the pregnancy and delivery of SLE patients. Guideline The patient has been in remission for >10 months and has been given corticosteroids at a dose <15 mg per day The patient has no serious manifestations of SLE such as lupus nephritis The patient has no serious side-effects of corticosteroids The patient is not taking immunosuppressive drugs It is desirable that antiphospholipid antibodies and anti-Ro/SS-A or La/SS-B antibodies are negative* The patient and her family are capable of taking care of the child * When these autoantibodies are positive, the hospital informs the patient of the potential risk and leaves the decision to the patient.
The 26 children were divided into two age groups (Table 2). To evaluate the mental development of children younger than 4 years, we used the Bayley Scales of Infant Development second edition (BSID-II) [7]. The BSID-II provides mental development index (MDI) and psychomotor development index (PDI) scores, with a mean of 100 and a standard deviation of 15. Behavior was assessed using the Behavior Rating Scale (BRS), which consists of Orientation/Engagement, Emotional Regulation, and Motor Quality factors. On the BRS, a score of the 26th percentile and above was deemed to be within normal limits, a score between the 11th and 25th percentiles was deemed questionable,
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and a score at or below the 10th percentile was non-optimal. An MDI or PDI > 2 SD below the mean (<70) was defined as mental retardation. Children younger than 3 years with a preterm birth were assessed using their corrected age. For children older than 4 years, we used the Kauffmann Assessment Battery for Children (KABC) [8]. The K-ABC is a measure of intelligence and achievement designed for children aged 2.5 through 12.5 years. This multisubtest battery comprises two scales, i.e., Sequential Processing and Simultaneous Processing, which are hypothesized to reflect the child’s style of problem solving and information processing. These two scales are combined into a Mental Processing Composite, which is a global measure of intellectual functioning that correlates well with other IQ measures and have been used in assessing LD children [9]. Each scale produces a standardized score with a mean of 100 and SD of 15. The intelligence tests were administered a single pediatrician who had a special interest in neuropsychological development. Finally, the parents were interviewed about the children’s growth and learning abilities at school, and the children were diagnosed clinically by another pediatrician who specialized in child development. This study was approved by our institutional review board, and was performed only after obtaining informed consent from the parents of participating patients.
IUGR were frequent: 58 (24.8%) were preterm, 72 (30.9%) were low-birth-weight, and 46 (19.7%) were IUGR. The mean maternal age was 31.5 years (range 19–40). The mean birth weight and gestational age were 2563 g (range 338–3740) and 37.4 weeks (range 24.7– 41.3), respectively. Five children developed neonatal lupus syndrome (NLS): two with congenital heart block (CHB) and three with skin erythema. Pregnancy loss and neonatal death occurred in four and three pregnancies, respectively. The neonatal deaths resulted from heart failure caused by CHB and pulmonary hemorrhage in two extremely low-birth-weight infant. The fetal deaths occurred in mothers who had antiphospholipid antibodies during pregnancy (Table 3).
2.5. Statistical analysis
3.3. Intelligence test results
The results were expressed as the mean ± standard deviation (SD). Proportions were compared using the chi-square test with continuity correction. Means were compared using the Mann–Whitney U-test for independent samples. A P value of less than 0.05 was considered statistically significant.
The mean score on each test was essentially normal. Because mental retardation was defined as a score <70, all 26 children had normal intelligence, and no child had mental retardation. There were eight children in the infant group (<4 years), and their mean age was 1.5 years. The mean birth weight and gestational age were 2407 g (range 1088–3136) and 36.1 weeks of gestation (range 29.6–40.4), respectively. The mean MDI was 95.8 ± 10.1 (mean ± SD). The mean PDI was 94.6 ± 14.1 (Table 5a). The mean BRS was 59, which was within normal limits. There were 18 children older than 4 years and their mean age was 8.8 years. The mean birth weight and gestational age were 2537 g (range 882– 3186) and 37.3 weeks of gestation (range 30.0–40.7), respectively. The mean scores for the Sequential Processing scale, Simultaneous Processing scale, and Mental Processing composite were 103.1 ± 13.3, 104.2 ± 10.2, and 104.2 ± 12.2, respectively, which were within the normal range (Table 5b).
3. Results 3.1. Pregnancy outcomes In the 19 years between 1989 and 2006, we delivered 233 SLE patients at our Hospital. Preterm birth and
Table 2 Distribution of the children for the administration of intelligence tests. Age range
Number of children
Mean age (years)
Intelligence test
6 months–3 years 4 years–12 years
8 18
1.6 8.8
BSID-II* K-ABC**
*
Bayley Scales of Infant Development-II; the children delivered before term were assessed using their corrected age. ** Kaufman Assessment Battery for Children, modified for Japanese children.
3.2. Characteristics of the children Twenty-six children (16 males and 10 females, aged 6 months to 12 years) were enrolled to assess their intelligence. The mean birth weight and gestational age were 2497 g (range 882–3186) and 37.0 weeks of gestation (range 28.1–40.7), respectively. Of the 26 children, 11 were preterm infants (45%) and 5 had IUGR (19.2%; Table 4). None of the children had growth or health problems. The children with IUGR at birth had grown well, and their body weights and heights were within the normal range.
3.4. Correlation between maternal autoantibodies and children’s intelligence The influence of the mother’s autoantibody profile was investigated, considering mothers with or without
N. Yoshikawa et al. / Brain & Development 32 (2010) 390–395 Table 3 Pregnancy outcomes of SLE patients. Variable
Value
Number of deliveries Mean maternal age (range) Mean gestational age (range) Mean birth weight (range) Number of preterm deliveries* Number of low-birth-weight infants* Number of infants with IUGR* Lost pregnancies** Neonatal deaths** Neonatal lupus syndrome
233 31.5 years (19–40) 37.4 weeks (24.7–41.4) 2563 g (338–3740) 58 (24.8%) 72 (30.9%) 46 (19.7%) 4 3 5 (2.1%)
* Preterm delivery is defined as delivery before 37 weeks of gestation, low-birth-weight as below 2500 g of birth weight, IUGR as below tenth percentile for birth weight by gestational age. ** Lost pregnancies are defined as pregnancy loss after 22 weeks of gestation and neonatal deaths are defined as death within 28 days of birth. Two with CHB, three with skin rash.
Table 4 Population of children with SLE patients. Variable
Value
Number of children Male:female Age (range) Mean maternal age Mean gestational age (range) Mean birth weight (range) Number of preterm deliveries Number of low-birth-weight infants < 2500 g Number with IUGR
26 16:10 6.6 years (0.7–12.8) 32.3 years (20–38) 37.0 weeks (28.1–40.7) 2497 g (882–3186) 11 (45%) 10 (38.4%) 5 (19.2%)
Table 5a Results of the Bayley Scales of Infant Development-II (n = 8). Scale
Score (mean ± SD)
MDI PDI BRS Orientation/engagement Emotional regulation Motor quality Total
95.8 ± 10.1 94.6 ± 14.1 47.4 ± 10 45.1 ± 16.4 55.5 ± 14.2 59 ± 20.8
MDI, mental development index; PDI, psychomotor development index; BRS, behavior rating scale.
Table 5b Results of the Kaufman Assessment Battery of Children (n = 18). Scale
Score (mean ± SD)
Sequential processing Simultaneous processing Mental processing
103.1 ± 13.3 104.2 ± 10.2 104.2 ± 12.2
antibodies to Ro/SS-A or one of the other cellular antigens, and to three phospholipids (aCL, anti-b2 GPI, or LA). There were 9 and 17 children of mothers with positive and negative anti-Ro/SS-A antibodies, respectively. The mean gestational age at delivery and birth weight
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Table 6 Correlation between mother’s anti-Ro/SS-A antibodies and children’s characteristics. Child’s characteristic
Positive mothers (n = 9)
Negative mothers (n = 17)
P
Mean gestational age (weeks) Mean birth weight (g) IUGR BSID-II (n = 8) MDI (mean ± SD) PDI K-ABC (n = 18) Simultaneous processing Sequential processing Mental processing
34.3 1914 4 (44%) 4 90 ± 3.4 87.5 ± 14 5 95 ± 17 96 ± 9.6 95 ± 11
38.4 2806 1 (5.8%) 4 101 ± 12 101 ± 11 13 106 ± 11 107 ± 9.1 108 ± 10
<0.05* <0.05* <0.05** ns ns ns <0.05* <0.05*
ns, not significant. * Mann–Whitney U-test. ** Chi-square test.
Table 7 Correlation between mother’s antiphospholipid antibodies and children’s characteristics. Child’s characteristic
Positive mothers (n = 10)
Negative mothers (n = 15)
P
Mean gestational age (weeks) Mean birth weight (g) IUGR BSID-II (n = 8) MDI (mean ± SD) PDI K-ABC (mean ± SD) Simultaneous processing Sequential processing Mental processing
36.3 2243 4 (40%) 1 85 75 9 100 ± 15 103 ± 10 102 ± 13
37.3 2642 1 (6.6%) 7 97 ± 10 97 ± 12 8 107 ± 12 106 ± 11 108 ± 12
ns* ns* 0.04** ns* ns* ns* ns* ns*
ns, not significant. * Mann–Whitney U-test. ** Chi square test.
were significantly lower (p < 0.05) children from the anti-Ro/SS-A antibody-positive mothers. The proportion of children with IUGR was significantly higher in the positive mothers (p < 0.05). On the intelligence tests, all of the children had a normal IQ (>70). Interestingly, however, on the intelligence scores of the children assessed using the K-ABC, the score on the Sequential Processing scale was significantly lower in children with SS-A-positive mothers than in those with SS-A-negative mothers (p < 0.05). There was no significant difference between the score on the MDI and PDI of the children assessed using the BSID-II. The Simultaneous Processing scale was not related to the presence of maternal anti-Ro/SS-A antibodies (Table 6). The presence of maternal aPL was related only to the rate of IUGR and not to differences in any intelligence score (Table 7). Overall, none of the children have been diagnosed with learning disorders or behavior dysfunction such as attention disorder or hyperactivity.
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4. Discussion The overall prevalence of pregnancy outcomes in SLE patients was similar to those in previous reports. The rates of preterm delivery and IUGR were 24.8% and 19.7%, respectively, which fall within the reported ranges [10,11]. The rates of preterm delivery and IUGR are affected by the disease activity, maternal antiphospholipid antibodies, and drugs such as high doses of corticosteroids or immunosuppressive drugs, which cause ovarian insufficiency, hypertensive complications in the second trimester, and oligohydramnios, all likely factors contributing to preterm delivery and IUGR [12–14]. Chakravarty et al. [15] reported that women with SLE had significantly increased rates of hypertensive disorders, longer hospital stays, higher risk of cesarean delivery, and were older than women in the general obstetric population for a large number of patients in 35 states in the United States. Therefore, given the increasing number of pregnancies in SLE patients, careful monitoring and management of the disease during pregnancy are still necessary [16]. The pregnancy outcome of women with anti-Ro/SS-A antibodies included a significantly lower gestational age and birth weight and a higher rate of IUGR than in women without anti-Ro/SS-A antibodies. All 26 children had normal IQs, although, interestingly, the Sequential Processing score was significantly lower in children of anti-Ro/SS-A antibody-positive mothers than in those of negative mothers. In a recent study, the presence of anti-Ro/SS-A antibodies was associated with LD in boys born from SLE mothers, and maternal antibodies might affect the developing brains of male fetuses, with the subsequent expression of learning and other developmental disorders [5]. However, another study found no association between the neurodevelopment of children and maternal anti-Ro/SS-A antibodies [17]. In our study, we think that the lower Sequential Processing score in the children with Ro/SS-A-positive mothers showed that maternal autoantibodies especially Ro/SS-A might affect cognitive development of the children. Our study also showed the higher incidence of preterm infant and IUGR of children born from mothers with Ro/SS-A. So, we should follow the development of these children with Ro/SS-A positive mothers because of the possible development of LD and so on, although preterm or not. Antiphospholipid antibodies are recognized as the most frequent acquired risk factor for recurrent thrombosis; they are a treatable cause of recurrent pregnancy loss and are also associated with fetal death, IUGR, and early preeclampsia [18,19]. A previous study found that exposure to aPL might be related to CNS dysfunction and hyperactive behavior because the aPL induces a hypercoagulable state, interacting with clotting factors and activating platelets, monocytes, and endothelial cells, thereby causing micro-thrombi at many sites in
the brain in an animal model [20,21]. In our sample population, fetal death occurred in 4 of 233 deliveries in which the mothers developed aPL. In addition, the pregnancy outcome of mothers with aPL was not related to gestational age or birth weight, except for the rate of IUGR in comparison with the mothers without aPL. Moreover, the presence of aPL was not related to any score on the intelligence tests. In the neurodevelopment of the children of SLE mothers, all 26 children examined had scores within the normal ranges on the intelligence tests. Previous studies also reported that the offspring of SLE patients had normal IQs, despite the higher rate of preterm delivery [5,9]. To ensure that none of the children examined had developmental disorders such as LD, dyslexia, or attention deficit hyperactivity disorder (ADHD), the pregnant women with SLE were treated strictly following our criteria (Table 1). In particular, the pregnant women were given corticosteroids at doses < 15 mg/ day, which reflected the disease activity and resulted in the normal development of children. Therefore, we postulate that the admission protocol for SLE mothers used at our institute has no negative effects on the physical growth and cognitive development of children, although there was no difference in the rate of IUGR and pregnancy loss. However, we need to examine forms of the disease activity of SLE such as SLEPDI, modified as pregnant patients [22], which might affect the development of children in utero and during infancy. The cognitive development of children is affected by various factors such as parental education and the socioeconomic environment in which the children are raised, in addition to maternal disease. Patients with chronic, unpredictable diseases such as SLE may experience secondary psychiatric disorders, acute confusional states, stress, and anxiety, which might influence the attachment between the mother and infant during infancy. It has been reported that SLE mothers worry about the disease itself and are anxious about transmitting the disease and effect of the disease on the growth of their children [23–25]. Therefore, we should investigate the confounding variables that influence the cognitive development of children of women with SLE, especially the maternal mental state.
Acknowledgement We are indebted to Professor Yoshinari Takasaki; Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan; for his advice on the autoimmune diseases, to Dr Toshitaka Tanaka; Department of Obstetric and Gynecology, Juntendo University School of Medicine; for his help in the investigation of pregnancy outcomes. We also wish to acknowledgement all the families for their kind participation in our study.
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