IJE Advance Access originally published online on November 9, 2005
International Journal of Epidemiology 2006 35(2):280-287; doi:10.1093/ije/dyi234
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Article |
Congenital structural anomalies in offspring of women with epilepsy—a population-based cohort study in Finland
1 Tampere School of Public Health, University of Tampere, Tampere, Finland
2 The Finnish Register of Congenital Malformations, National Research and Development Centre for Welfare and Health, Helsinki, Finland
3 Social Welfare and Health Care Statistics, National Research and Development Centre for Welfare and Health, Helsinki, Finland
4 Department of Neurology, University of Oulu, Oulu, Finland
5 Pediatric Research Center, Tampere University Hospital, Tampere, Finland
* Corresponding author. School of Public Health, FIN-33014 University of Tampere, Finland. E-mail: miia.artama{at}uta.fi
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Abstract |
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Background Offspring of women with epilepsy may have an increased risk for congenital malformations, probably attributable to maternal antiepileptic medication. We conducted this population-based study to obtain valid and accurate estimates on major congenital malformations in the offspring of women with epilepsy, based on a large and representative patient cohort.
Methods We identified all women (n = 6535) entitled to full reimbursement for antiepileptic medication indicated for epilepsy for the first time between 1985 and 1994 from the Social Insurance Institution of Finland database. A reference cohort (n = 14 704) was identified from the Finnish Population Register Centre. Information on children born between 1993 and 2000 (patient cohort, n = 2162; reference cohort, n = 5413) was obtained from the Medical Birth Register. Information on children born with malformation (patient cohort, n = 116; reference cohort, n = 151) was obtained from the Finnish Register of Congenital Malformations.
Results The prevalence of major malformation was 54/1000 births among patients with epilepsy and 28/1000 births among mothers without epilepsy, corresponding to a 2-fold overall risk for malformation in the offspring of women with epilepsy. The risk for spina bifida [odds ratio (OR) = 11.3, 95% confidence interval (CI) 2.34–108] and congenital anomalies of genital organs (OR = 8.38, 95% CI 2.15–47.4) was substantially elevated in the offspring of mothers with epilepsy.
Conclusions The absolute excess in the prevalence of major malformations was 26/1000 births in the offspring of mothers with epilepsy in relation to the offspring of reference mothers. The highest relative risk was observed in spina bifida and congenital anomalies of genital organs. However, these malformations cover only a small proportion of all major malformations.
Keywords Children, cohort studies, congenital anomalies, epilepsy, prevalence
Accepted 5 October 2005
Maternal use of antiepileptic medication during pregnancy increases the risk for congenital malformations in offspring. Teratogenicity of older antiepileptic drugs (AEDs) has been well established.1–3 In the 1960s, Hanson and Smith2 recognized the fetal hydantoin syndrome, which comprises facial abnormalities, spina bifida, cardiac defects, and limb anomalies among children exposed to phenytoin in utero. DiLiberti et al.3 described the valproate syndrome, consisting of cranial–facial defects, cleft palate, radial ray defects, cardiac anomalies, and opthalmological, learning, and behavioural problems. Carbamazepine and valproate increase, especially, the risk of spina bifida.4,5
In most previous studies, risk of malformations has not been elevated in the offspring of mothers without medication.6–8 Some studies suggest that genetic factors underlying epilepsy may increase the risk for congenital malformations in offspring,9–11 but the evidence for this hypothesis is not strong.12
Most previous studies on major congenital malformations in the offspring of women with epilepsy have been based on small numbers and, therefore, they lack statistical power.13,14 Moreover, the majority have been hospital-based including patients with complicated epilepsy unlikely to be representative of all patients.15,16 We conducted this population-based study to obtain more valid and accurate estimates of major congenital malformations in the offspring of women with epilepsy, based on a large and representative patient cohort with comprehensive assessment of major congenital anomalies. Furthermore, we were able to use comprehensive assessment of congenital anomalies and analyse the risks by type of malformation.
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Methods |
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All the Finnish citizens are entitled to reimbursement of medications for certain conditions. The reimbursement system of the Social Insurance Institution (SII) of Finland is organized through the National Health Insurance, which is maintained by the state, and financed through tax revenues. The costs of prescribed medicines are reimbursable partly or completely.17 The patient pays a fixed deductible per purchase, and of the balance remaining, reimbursement is percentage-based and divided into three categories: basic (50%), lower special (75%), and higher special (100%). The pharmaceutical reimbursement system currently covers
50 chronic diseases in higher special refund category at the moment, including epilepsy. Reimbursement requires a medical certificate demonstrating that the epilepsy diagnosis is based on clinical examinations, fulfils international criteria, and is made by a board-certified neurologist. Medical certificate is submitted to the SII when the medical treatment for epilepsy is started. Women entitled to fully reimbursable antiepileptic medication for epilepsy were identified from the SII of Finland (Figure 1). The information covered personal identification number and date of eligibility approval. The female epilepsy patient cohort (n = 6535) consisted of all women who were approved as eligible for reimbursement for antiepileptic medication from the SII for the first time between January 1, 1985 and December 31, 1994, were in fertile ages (15–49 years), and were alive on January 1, 1990. Persons, who had died before January 1, 1990, had been removed from the SII database and information on them was not available. We did not have any information on maternal use of antiepileptic or any other medication.
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The reference cohort (n = 14 704) was formed as a stratified random sample of all women alive and resident in Finland on January 1, 1990. The subjects were identified from the Finnish Population Register Centre with frequency-matching by 5 year age group to the epilepsy patient cohort. For assessment of maternal age at reimbursement and time since reimbursement, the mean starting date of reimbursement in the patients with epilepsy in that 5 year age group was used as a surrogate for index date (date of reimbursement) in the reference cohort.
Children were identified from the Medical Birth Register maintained by STAKES—the National Research and Development Centre for Welfare and Health. Information included personal identification numbers of mothers, and of their live or stillborn children, as well as the numbers of babies born in case of multiple births. Information on previous pregnancies, deliveries, and previous stillbirths (with fetal weight of at least 500 g or gestational age of at least 22 weeks) was also available. Information on previous stillbirths was missing for 106 births. In women with epilepsy, only children born after reimbursement were included in the analyses. In women without epilepsy, only children born after the index date were included in the analyses.
Information on congenital anomalies was obtained from the Finnish Register of Congenital Malformations maintained by STAKES. Information on malformations in the register is completed over the first year of life. The method of compiling the Finnish Register of Congenital Malformations was revised in 199318 and case ascertainment of the register improved substantially. Therefore, information on malformations before and after 1993 is not directly comparable. Only births between January 1, 1993 and December 31, 2000 were included in the analyses in this study.
Information covered the personal identification number of the mother and the live or stillborn children, as well as diagnosis according to ICD-9 (International Classification of Diseases, ninth revision). Only major congenital malformations were included in the analyses. Minor anomalies were excluded according to the exclusion list of European Registration of Congenital Anomalies (EUROCAT).19 If a child had more than one major congenital malformation of one organ system, those malformations were treated as one outcome in the analyses by organ system.
Information from the registers was merged through computerized record linkage based on the unique personal identification number assigned to all residents of Finland.
The study protocol was approved by the ethical committee of the Pirkanmaa Hospital District. Register-based studies were conducted with permission from STAKES, SII of Finland, and the Finnish Population Register Centre. Because the study subjects were not contacted, informed consent to participate was not required according to the Finnish data protection legislation.
In the statistical analyses, factors considered potential confounders were maternal age at delivery and number of previous parities. Factors considered potential effect modifiers were maternal age at reimbursement for antiepileptic medication and maternal age at delivery. The analyses were performed using exact logistic regression in LogXact 4.120 with major congenital anomaly as the outcome. Confidence intervals (CIs) for differences in prevalence proportions were calculated with Stata 7.0.21
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The number of births during the study period was 2162 among the women with epilepsy (n = 1422) and 5413 among the reference women without epilepsy (n = 3533). The gender ratio of newborns in the female patients with epilepsy was similar to the women without epilepsy: 48.2% of the offspring were girls among women with epilepsy and 48.9% among women without epilepsy. The mean maternal age at delivery was lower among the mothers with epilepsy (
28.1) than among the mothers without epilepsy ( 28.7) (P < 0.01). The mean number of previous live births in the mothers with epilepsy ( 0.92) was comparable with the mothers without epilepsy ( 0.96) (P = 0.16), as was the mean number of previous stillbirths (patients: 0.01; referents: 0.01) (P = 0.92). The prevalence of births with major malformation was 54/1000 births (n = 116) among the mothers with epilepsy and 28/1000 births (n = 151) among the mothers without epilepsy (Table 1). In terms of absolute difference between the offspring of mothers with and without epilepsy ranging from 3.5/1000 to 7.0/1000 births, the greatest excess was observed in the prevalence of bulbus cordis anomalies and cardiac septal closure, congenital anomalies of the urinary system, other congenital anomalies of limbs, other congenital anomalies, congenital anomalies of genital organs, spina bifida, and other congenital anomalies of the circulatory system in the offspring of mothers with epilepsy. No obvious differences between the cohorts were observed in congenital anomalies of the skin, hair and nails, other anomalies of upper alimentary tract, other congenital anomalies of the heart, other congenital anomalies of the digestive system, and chromosomal anomalies.
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The overall risk for major congenital malformation was clearly elevated in the offspring of mothers with epilepsy (OR = 1.98, 95% CI 1.53–2.55) (Table 1). The risk for spina bifida (OR = 11.3, 95% CI 2.34–108) and congenital anomalies of genital organs (OR = 8.38, 95% CI 2.15–47.4) was substantially higher in the offspring of mothers with epilepsy than the mothers without epilepsy. In addition, the offspring of women with epilepsy had a statistically significantly higher risk for other congenital anomalies of the circulatory system (OR = 4.19, 95% CI 1.38–14.0), other congenital anomalies (OR = 3.20, 95% CI 1.35–7.80), and other congenital anomalies of limbs (OR = 2.66, 95% CI 1.29–5.51). Adjustment for maternal age at delivery did not materially affect the results. Adjustment for previous parities had no substantial effect on the risk estimates with the exception of other congenital anomalies of the nervous system.
No clear trend was observed in the risk for major congenital anomalies by maternal age at delivery (P = 0.07 for trend) (Table 2). Regardless of the number of previous parities, the offspring of women with epilepsy had a 2-fold risk for malformations in relation to the offspring of women without epilepsy. The risk increased with time since reimbursement for antiepileptic medication (P = 0.02 for trend). Six confirmed and two suspected valproate syndromes were observed in the offspring of women with epilepsy.
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Discussion |
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Few large population-based studies on malformations in offspring of women with epilepsy have been conducted16,22 (Table 3). Most of the previous studies have been based on small numbers of live births without a population-based reference group.7,8,23–26 In this study, comprehensive and nationwide material consisting of 2162 children of whom 116 were malformed, enabled evaluation of risks for most common types of malformations in offspring of mothers with epilepsy.
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The comprehensive register-based approach offers extensive information on births and malformations in a nationwide study population. Coverage of the Birth Register is >99% and its information is supplemented by the Population Register Centre information on live births and by Statistics Finland information on stillbirths and infant deaths to attempt to ensure completeness.18
Certain major congenital malformations are not always identified at birth (e.g. major congenital malformations of the cardiovascular or genitourinary system).24 Therefore, the prevalence of these major congenital malformations is underestimated in studies where only malformations diagnosed at birth are included. In Finland, coverage of the Register of Congenital Malformations is 100% of the births27 and information on malformations in the register is completed over the first year of life.
In previous studies, the overall proportion of children born with malformations to mothers with epilepsy has varied from 37/1000 to 155/1000 births.6,8,15,16,23,28–30 In this study, the prevalence of births with malformation (54/1000 births) in patients with epilepsy was lower than in most previous studies. The definition of major congenital anomaly differs between the studies.31 Also, most of the previous studies are hospital-based and, therefore, women with complicated epilepsy and polytherapy may be overrepresented in these studies.
Regarding the risk for different types of malformations, the offspring of women with epilepsy have the highest risk for cardiovascular and urogenital malformations, spina bifida, and cleft lip/palate.8,24,29,31,32 Our results were mainly consistent with the previous studies, though, we did not find a clearly increased risk for cleft lip/palate in the offspring of women with epilepsy. However, we could not analyse the offspring of mothers on different antiepileptic medication separately.
Our results regarding risk for malformation in the offspring of women with epilepsy were consistent with the previous population-based studies. In a British study, the risk for malformations in the offspring of women with epilepsy was 2.2-fold relative to the general population.33 In a study conducted in Iceland, the risk for malformations was 2.7-fold (95% CI 1.4–4.5) in the offspring of patients on AEDs and 2.2-fold (95% CI 0.3–8.0) in the offspring of patients without AEDs in relation to the general population.16 Overall risk, regardless of maternal AED use, was not reported in this study. In accordance with these findings, our results indicate that approximately half of the malformed children born to mothers with epilepsy were attributable to maternal epilepsy and/or AED use. We did not find an association between the occurrence of malformations in newborn and maternal age at delivery in women with epilepsy. This result was consistent with the previous studies.6,8,34
Information on epilepsy types or medication was not available in this study, but we were able to assess one modifier of antiepileptic medication. Discontinuation of medication increases with duration of epilepsy, and therefore, the risk for malformations is expected to decrease. However, in the analysis by time since reimbursement for antiepileptic medication, the highest risk was observed for 
10 years after start of reimbursement. In contrast to this finding, Lander and Eadie34 did not find an association between the incidence of malformations in the offspring and duration of maternal epilepsy. One possible explanation for our results is that despite the discontinuation of medication in many women, the proportion of patients with refractory epilepsy and polytherapy increases with long duration of epilepsy, which elevates the risk for malformations.
Because of epilepsy, medical follow-up during and after pregnancy may be more intensive in epilepsy patients than in other women. Therefore, malformations may be detected more comprehensively in the offspring of mothers with epilepsy than in other children. Also, reporting of major malformations for registration may be more complete and more detailed in the offspring of mothers with epilepsy than in other children. More extensive surveillance may lead to information bias and overestimation of the risk. As would be expected, the mean number of reported major anomalies/child with anomaly was higher in the patients with epilepsy than the referents (1.8 vs 1.5, P = 0.07) in our study. However, the difference was larger (2.2 vs 1.6, P < 0.01) when minor anomalies were included. The offspring of patients with epilepsy may have more multiple malformations including minor anomalies than the offspring of mothers without epilepsy.
Periconceptional folic acid supplementation is known to reduce the risk for malformations, especially neural tube defects in the offspring.35 Because the offspring of women with antiepileptic medication have an elevated risk for neural tube defects, the Finnish Ministry of Social Affairs and Health has recommended, since 1995, that all women on antiepileptic medication take 0.4 mg of extra folic acid supplements daily, 4 weeks prior to conception and during the first 12 weeks of pregnancy.36 Information on folic acid use was not available in this study.
Women with epilepsy are at a higher risk for early pregnancy losses and spontaneous abortions than women in general.37 We did not evaluate these aspects, and, therefore, the effect of epilepsy on prevalence of major congenital malformations in offspring of epilepsy patients may have been underestimated. We did, however evaluate stillbirths and their inclusion or exclusion did not alter the results.
In our study, the risk for spina bifida was substantially elevated in the offspring of patients with epilepsy. In 1993–2002, one-third of all spina bifida pregnancies and nearly 90% of anencephaly pregnancies were terminated in Finland.18 Overall, 226 pregnancies were terminated because of fetal congenital structural anomalies in Finland in 2002.18 We did not have information on selective pregnancy terminations performed for fetal indications. Pregnant women with epilepsy are considered a high-risk group and are commonly under intensive obstetric surveillance. Therefore, structural anomalies may be more likely to be detected at an early stage, increasing also possibility of induced abortion. This may have underestimated the risk for congenital anomalies in the offspring of patients with epilepsy in our study, if the proportion of terminated pregnancies due to these types of malformations differs between patients with epilepsy and other population.
Identification of patients with epilepsy may have been incomplete. However, costs of antiepileptic medication are high in Finland. Therefore, few people with epilepsy do not seek reimbursement of antiepileptic medication. If an epilepsy diagnosis was made for an institutionalized patient, information on reimbursement is not necessarily in the SII database. Probably those patients are underrepresented in our study. Furthermore, the proportion of institutionalized epilepsy patients is overall small and the effect of exclusion of these persons is not likely to substantially affect our results, because they have a low birth rate. Information on epilepsy patients who have not wanted reimbursement for antiepileptic medication was not available.
Use of some antiepileptic medications during pregnancy may be associated with certain types of malformations. We did not have information on maternal use of AEDs. Although we did not find an association between maternal epilepsy and e.g. cleft palate and/or cleft lip, this does not exclude a possible association within subgroups of patients with specific medication.
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Conclusions |
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Risk for major congenital malformations is 2-fold in the offspring of women with epilepsy in relation to the offspring of women without epilepsy. The highest relative risk was observed in spina bifida and congenital anomalies of genital organs. However, these malformations cover only a small proportion of all major malformations. These results pertain to follow-up on average of 7.3 years since diagnosis of epilepsy, regardless of antiepileptic medication usage.
KEY MESSAGES
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Acknowledgments |
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The work of M.A. was conducted during the fellowship of the Doctoral Programs of Public Health with funding from the Ministry of Education.
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