Chapter 1. Use of Anticonvulsants During Pregnancy: Teratogenic Risks. Abstract

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1 Chapter 1 Use of Anticonvulsants During Pregnancy: Teratogenic Risks Bengt Källén * Tornblad Institute, Lund University, Sweden * Corresponding Author: Bengt Källén, Tornblad Institute, Lund University, Lund, Sweden, Tel: ; Fax: ; Bengt.Kallen@med. lu.se First Published June 05, 2016 Copyright: 2016 Bengt Källén. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. Abstract The chapter summarizes literature on the teratogenic effects of anticonvulsants and presents data from the Swedish Medical Birth Register. Many anticonvulsants have a teratogenic effect which varies between individual drugs with the highest risk associated with the use of valproic acid and probably topiramide. For some much used drugs like carbamazepine and lamotrigine the risk is not much elevated. Polytherapy is associated with a higher risk than monotherapy and again use of valproic acid is the strongest risk factor. The teratogenic risk of anticonvulsants is not restricted to structural malformations. Brain development can be affected with effects of neuropsychological development. Valproic acid seems to have the most marked effect and milder effects are seen with carbamazepine and perhaps no effect with lamotrigine. Epilepsy in a woman who plans a pregnancy motivates pre-pregnancy information with possible adjustment of drug schedule, reasonably given by her neurologist. When anticonvulsants are used for other indications than epilepsy, trapping down or stopping of therapy should be considered. With the exception of valproic acid (and probably topiramate) the risk is not very high but if use can be reduced without risking the woman s health, this should be done. More information concerning the new anticonvulsants is needed until this has been obtained they should be regarded as potential risks. 2 3

2 Introduction Anticonvulsant drugs were originally only used for epilepsy but have during the last few decades got a much more wide-spread use, e.g., as mode stabilizers at bipolar disease and at treatment of pain, including migraine. Women using anticonvulsants during pregnancy were initially mainly identified from groups of epileptic women. Another source of information is from population registers which contain information on drug use during pregnancy. This information may be obtained by interviews or by the use of registers of prescribed drugs. All methods have their shortcomings the least reliable method makes use of retrospective interviews after the birth of the child in a case-control setting because of the risk for recall and non-participation bias. This Chapter will summarize the pertinent literature and also present data from the Swedish Medical Birth Register [1] on the presence of congenital malformations in infants born of women who had reported the use of anticonvulsants during early pregnancy, Part of this material has been published before [2]. History of the Research on Anticonvulsants During Pregnancy One of the first published studies on the possible risk of using anticonvulsant drugs during pregnancy described 262 women who had used anticonvulsants during pregnancy. The authors found a normal malformation rate but among the five malformed infants observed, three had cleft lip/palate [3]. In 1968, Meadow in a Letter to the Editor in Lancet [4] raised the possibility that maternal epilepsy could be associated with cleft lip/palate in the infant and in a later paper [5] he had collected 32 infants with orofacial clefts (31 cleft lip/palate, one median cleft palate) whose mothers had got anticonvulsant therapy. In 1972 Speidel and Meadow [6] demonstrated an increased incidence of malformations in infants born by women using anticonvulsants. This resulted in a series of communications on small studies of infants born of mothers with epilepsy. The main anticonvulsant drugs which the women in these studies had taken were phenytoin and/ or barbiturates and primidone. Larger studies verified the finding of an increased risk, notably with phenytoin [7-9]. From the very beginning it was discussed to what extent the epilepsy itself could cause the malformations, a confounding by indication. In most studies, women with epilepsy but not using anticonvulsants in early pregnancy had no increased risk to get an infant with a congenital malformation but obviously such women may have another type or a milder form of epilepsy than women who had used anticonvulsants. To-day the general opinion is that the cause of the increased risk is the use of anticonvulsants [10]. Except for the increased risk of structural malformations, a markedly increased risk for dysmorphologi- 4 5

3 cal facial features and digital anomalies were found after maternal use of phenytoin or barbiturates [11-14], an anticonvulsant syndrome. The facial dysmorphology resembles that seen in the fetal alcohol syndrome. Long-term effects on the development of the child have been described. In the early descriptions of children with anticonvulsant syndrome, developmental retardation was often found. A Norwegian study [15] found effects on the intelligence at the military conscription of boys, born in by women with epilepsy. Most of the children were probably exposed to phenytoin, phenobarbital or a combination of them. A meta-analysis [16] of early studies found an effect of valproic acid of child intelligence but none of carbamazepine. Later studies have verified an effect of child IQ, notably of valproic acid [17-20] while results for carbamazepine vary [20-22] and no effect was seen of lamotrigine [22]. A study of school performance of children born by women using anticonvulsants [23] found that such children had a significantly increased risk not to finish compulsory school, statistically significant only for children exposed to polytherapy. Effects of monotherapy could be seen in analyses of grades in sports, mathematics, English and Swedish. In this study only few children had been exposed to valproic acid. A Danish study [24] linked maternal use of valproic acid to an increased risk for autism or autism spectrum disorders in the child. Pattern of Anticonvulsant use in Sweden The pattern of anticonvulsant drug use varies between different populations. In Table 1 data from the Swedish Medical Birth Register ( ) are given. Details of this system are given in Appendix 1. Usage is dominated by three drugs: carbamazepine, valproic acid and lamotrigine. Figure 1 shows how usage of these three drugs has changed during the observation period. The Figure also illustrates the decline in use of an old drug (phenytoin) and the increasing use of a new drug (topiramate). The use of anticonvulsants in early pregnancy is little affected by maternal age but is higher at first parity than at higher parities [2]. Women using such drugs smoke more often and are more often obese than other women. They are also characterized by an increased rate of women with low education, non-cohabitation, and without work outside home. Reporting of anticonvulsant drug use is lower among women born outside Sweden than in Sweden-born women [2]. The socio-economic differences play a minor role for malformation risk in Sweden. In the analyses of the new Swedish data, adjustment has been made for year of birth, maternal age, parity, smoking and BMI. 6 7

4 Table 1: Overview of anticonvulsant use in the Swedish Medical Birth Register., Number of drugs Drug Total Phenobarbitone Primidone Phenytoin Ethosuximide Clonazepam Clobazam Carbamazepine Oxcarbamazepine Valproic acid Vigabatrin Lamotrigine Topiramate Gabapentin Medifoxamine Levitiracetam Zonisamide Pregabalin Lacosamide Unspecified Total number Figure 1: Number of infants whose mothers reported the use of four anticonvulsants for each year of observation, (2013 was incomplete). Monotherapy and Polytherapy Already early it was demonstrated that the teratogenic risk was higher after anticonvulsant polytherapy than after monotherapy. Polytherapy was also much more common at that time than what it is now. In Sweden in the 1970s, nearly half of the treatments of epilepsy in pregnancy were as polytherapy [25]. During the period , the average rate of polytherapy was about 10% - a slight increase was seen during these years (Figure 2). During this period, the risk for any relatively severe congenital malformation 8 9

5 after monotherapy was 1.55 (95% CI ) while after polytherapy it was 3.25 (95% CI ). As we will see later on, the most important cause of teratogenicity is use of valproic acid if such cases were removed, the risk after monotherapy was 1.30 (95% CI ) and after polytherapy 1.95 (95% CI ). The effect of polytherapy is thus not restricted to valproic acid as has been suggested and was also seen in the 1970s when very few valproic acid exposures occurred [25]. Table 2 summarizes the presence of specific congenital malformations after any anticonvulsant exposure in the Swedish data. There seemed to be no increased risk for a chromosome anomaly, but for most of the specific nonchromosomal malformations a risk increase was seen, even though it was not statistically significant for all, perhaps due to low numbers. The lowest risk estimates were for cleft lip/palate, kidney malformations and for limb reduction defects, all groups were relatively small and with large confidence intervals of the risk estimates. During the observation period there is a tendency to a decrease of the malformation risk after anticonvulsant exposure (Figure 3) in spite of the fact that the proportion of polytherapy did not decrease. It was probably due to changes in the proportion of specific anticonvulsants. Table 2: Risk of congenital malformations in singleton infants born of women who used anticonvulsant (AED) drugs in early pregnancy. Odds ratio (OR) or risk ratio (RR) adjusted for year of birth, maternal age, parity, smoking and BMI with 95% confidence intervals (95% CI) were calculated when more than two exposed malformed infants were found. Bold text marks statistical significance. Number of infants exposed to AED = 4969, total number of infants Any Malformation Relatively Severe Malformation Anticonvulsantin monotherapy Total number Number malformed OR/RR 95% CI Number malformed OR/RR 95% CI Phenobarbital # Primidone Phenytoin # Ethosuximide Clonazepam # Carbamazepine Oxcarbamazepine Valproic acid Vigabatrin Lamotrigine Topiramate # # Gabapentin # Feneturid Levatiracetam Zonisamide Pregabalin # # Lakosamide # RR calculated as observed/expected number with exact Poisson confidence interval

6 Figure 2: Percent polytherapies with 95% confidence intervals according to delivery years (2-year periods). Dotted line is fitted to the percentages each 2-year period. Figure 3: Odds ratio for a relatively severe congenital malformation with 95% confidence intervals for each delivery year. Dotted line is fitted to the yearly odds ratios. The Teratogenic Effect of Specific Anticonvulsants Phenytoin and Barbiturates As is apparent from the previous section, these anticonvulsants dominated the early research which linked exposure to anticonvulsants with an increased malformation risk. These drugs have to a large extent been replaced by other anticonvulsants but are still used, often in polytherapy. In a Swedish study , phenytoin was the dominating drug [25] while in the present data set it represents only 3% of the anticonvulsants used and the rate decreased during the observation period (Figure 1). Among the 142 infants exposed to phenytoin in monotherapy, 13 had a congenital malformation (risk ratio (RR) = 1.72, 95% CI ), 10 of them were relatively severe (RR = 1.82, 95% CI ). Still fewer had been exposed to phenobarbitone in monotherapy: 20 among which 3 had a malformation, 2 of them relatively severe. The present material is not suitable for studies of these drugs. Trimethadione and Paramethadione A first report on a teratogenic effect of these drugs was published in 1970 [26] and was later verified in other studies [e.g., 27]. The risk of embryonic death and severe congenital malformations was high and the drugs were withdrawn from the market in many countries (in Sweden in 1980)

7 Carbamazepine One of the first studies on carbamazepine use during pregnancy and the risk for congenital malformations reported only one malformed among 97 infants exposed to carbamazepine [28]. Most following small studies failed to identify an increased risk for malformations after carbamazepine exposure. Two observations, however, changed this picture. One was a case study [29] indicating a marked risk for facial and digital dysmorphology and developmental delay, the other an analysis of infants born of mothers who had used carbamazepine [30]. Among 107 exposed infants three had spina bifida (but in one of them the mother had also used valproic acid). Other cases of spina bifida after carbamazepine use were reported [31] and a link between maternal use of carbamazepine and infant spina bifida was accepted. A review of the literature on the malformation risk after carbamazepine monotherapy exposure found a total rate of major congenital malformations of 3.3% which is within the expected range [32]. It was concluded that the only association with a specific congenital malformation was with spina bifida, based on six cases among 2680 exposed infants. Table 3: Any congenital malformations and relatively severe malformations after exposure to specific anticonvulsants in monotherapy. Odds ratio (OR) or risk ratio (RR) with 95% confidence interval (95% CI), adjusted for year of delivery, maternal age, parity, smoking and BMI, and calculated when more than two exposed malformed infants were found. Bold text marks statistical significance. Any Malformation Relatively Severe Malformation Anticonvulsantin monotherapy Total number Number malformed OR/RR 95% CI Number malformed OR/RR 95% CI Phenobarbital # Primidone Phenytoin # Ethosuximide Clonazepam # Carbamazepine Oxcarbamazepine Valproic acid Vigabatrin Lamotrigine Topiramate # # Gabapentin # Feneturid Levatiracetam Zonisamide Pregabalin # # Lakosamide # RR calculated as observed/expected number with exact Poisson confidence interval

8 In the new Swedish material the effect of carbamazepine monotherapy on any congenital malformation is statistically significant while significance is not reached for relatively severe malformations (Table 3). During the first nine years, however, the latter OR was 1.43 (95% CI ), during the last nine years 0.92 (95% CI ). The difference between these two estimates can, however, be random (p=0.14). After carbamazepine monotherapy no increase was seen of some common malformations, typically associated with anticonvulsant use, notably cardiovascular defects (OR = 0.80, 95% CI ). The only specific malformation group with an apparently significant increased risk was CNS defects other than neural tube defects with five observed cases, RR = 4.54, 95% CI Two cases had agenesis of corpus callosum, two brain reductions and one hydrocephaly. Other high risk estimates, based on small numbers and not statistically significant, referred to esophageal atresia, pylorostenosis, and poly/syndactyly. Valproic Acid The first indications that valproic acid had a strong teratogenic effect were obtained in animal experiments [33]. In a Letter to the Editors in Lancet an association between maternal use of valproic acid and infant spina bifida was pointed out [34] and this finding has been verified repeatedly [e.g., 35], even though some initial comments doubted the association. In a review [36] no firm evidence was found for specific effects on other malformations than spina bifida. Bradai and Robert [37], however, found evidence for an increased risk also of hypospadias and of limb reduction defects. One paper estimated that nearly 11% of infants exposed to valproic acid in monotherapy had a major malformation while only 3% of infants exposed to other anticonvulsants had such malformations [38]. The study included only 149 women exposed to valproic acid. A study from EUROCAT [39] described increased risks for spina bifida, atrial septum defects, cleft palate, hypospadias, polydactyly, and craniostenosis. It also summarized eight cohort studies with a total of 1565 exposures and a major malformation rate of 7%. Mawhinney et al. [40] reported on 1109 pregnancies exposed to valproic acid in monotherapy and found a difference in teratogenic effect according to daily dosage with an 1.7 times higher risk at 1000 mg/day compared with <1000 mg/day. In a meta-analysis [41] outcomes after valproic acid exposure were compared with outcomes after other anticonvulsants and increased risks were identified for any major malformation, neural tube defects, congenital heart defects, genitourinary anomalies and musculoskeletal anomalies. The total risk of a major malformation after valproic acid is about 10%. A valproic acid embryopathy has been described; resembling what has been seen after other anticonvulsants with facial characteristics [42] and was noted in nearly half of children exposed to valproic acid [17]. The practical consequences of the teratogenic effect of val

9 proic acid were discussed recently [43]. As seen in Table 3, there is a clear-cut increased risk for any congenital malformation and a similar risk increase for a relatively severe malformation in the recent Swedish data. Table 4 shows that many different types of congenital malformations were increased, notably CNS malformations including neural tube defects, orofacial clefts (median cleft palate), cardiovascular defects, hypospadias, pes equinovarus, and craniostenosis even though actual numbers were low for most conditions. Table 4: Some congenital malformation groups in 720 infants exposed to valproic acid in monotherapy. RR = risk ratio with exact Poisson confidence interval. Bold text marks statistical significance. Malformation Number RR 95% CI Note Neural tubedefects Spina bifida Other CNS malformations Two microcephaly (one with agenesis of corpus callosum), one unspecified. Orofacialclefts All median cleftpalate Congenitalheartdefects Amongthemseptumdefects Alimentarytractatresia/stenosis One esophageal atresia, one pyloric stenosis Diaphragmatic hernia Hypospadias Pesequinovarus Cranostenosis Clonazepam and Ethosuximide Only small studies have been published on the possible teratogenic effect of clonazepam [44]. Only one among 75 infants exposed to clonazepam in monotherapy (collected from the literature) had malformations but those were similar to what has been seen with other anticonvulsants: dysmorphic face, growth retardation, and a major cardiac defect (tetralogy of Fallot). In the recent Swedish material there were only 117 monotherapy exposures (Table 3). The RR was similar to that after carbamazepine but not statistically significant. Still fewer reports exist on the use of ethosuximide in monotherapy, e.g., 12 exposures in [45] and 12 in the present data from Sweden. Lamotrigine Lamotrigine was introduced in 1991 and has become much used, among other things because of its apparently favorable records with respect to teratogenic risks. Holmes and Hernandez-Diaz [46] summarized published experiences with this drug when used during pregnancy. They identified three studies with risk estimates of 1.8 (95% CI ), 1.18 (95% CI ) and 1.20 (95% CI ), based on 31, 38 and 12 malformed cases, respectively. In a later Norwegian study [47] a slightly increased but not statistically significant risk after lamotrigine monotherapy was found (odds ratio (OR) = 1.26, 95% CI ) based on 28 malformed among 833 exposed infants compared with infants born without exposure to maternal epilepsy. The estimates are thus of the same order of magnitude although individually not statistically significant. At lamotrigine polytherapy (4 malformed among 150 exposed infants) no increased risk was seen (OR = 1.02, 95% CI ) but the confidence interval was wide [47]. The possibility of a specific effect of lamotrigine on orofacial clefts was raised by Holmes et al. [48]. Among 684 studied infants which had been exposed to lamotrigi

10 ne, five had orofacial clefts: three with cleft palate, one with isolated cleft lip, and two with cleft lip/palate. One also identified 1623 exposed infants from other registers with four clefts. A study from EUROCAT [49] compared lamotrigine exposure in infants with orofacial clefts against infants with other congenital malformations but found no specificity (OR = 0.67, 95% CI ). In the recent material from the Swedish Medical Birth Register, a large number of monotherapies of lamotrigine exists. The ORs for any malformation or a relatively severe malformation are increased (Table 3) but do not reach statistical significance. Among specific groups of malformations, only congenital heart defects showed a significant risk increase: OR = 1.67 (95% CI ), based on 21 cases, among which 14 were septal defects and two unspecified cardiac defects. Among the remaining five cases, three were valve malformations, one a transposition of the great vessels, and one a PDA in a term infant. The association with heart defects was apparently mainly due to relatively mild conditions. Topiramate This drug was introduced in Holmes and Hernandez-Dias [46] summarized the limited literature on topiramate and congenital malformations. Among 709 infants exposed to topiramate in monotherapy, there were 26 with congenital malformations (3.7%). One study compared malformation risk after topiramate with unexposed infants and found an OR = 1.44 (95% CI ) based on 5 cases among 108 exposed infants [50]. Another study found a rate of major congenital malformations (n=37) of 4.3% among 870 infants exposed to topiramate, slightly but not significantly higher than in infants exposed to other anticonvulsants (OR =1.33, 95% CI ) or were unexposed (OR = 1.13, 95% CI ) [51]. A comparison with lamotrigine exposure gave an RR of 2.2 ( ) [52]. In a large study of 1945 topiramate exposed infants, 107 had a congenital malformation (5.5%) [53]. The rate was higher than among infants whose mothers did not use topiramate during pregnancy but had done so before pregnancy (4.0%) or among unexposed infants whose mothers had a similar medical profile (3.4%). In a study from Norway [47] a malformation rate of 4.2% (two malformed among 48 exposed infants) was noticed and in a study from England there were three malformed infants among 70 exposed for topiramate in monotherapy [54]. A specific association with orofacial clefts has been described [54, 55]. In the recent Swedish data, there are only 59 monotherapy cases (Table 3). Seven infants had any malformation, six of which were relatively severe. The RRs were high and statistically significant. Among the six infants one was multi-malformed with cleft lip/palate, atrium and ventricular septum defect and toe syndactyly, one infant had hypospadias, two had polydactyly (one of them with a hand deformity), one had coarctatio of aorta, and one Down syndrome

11 Gabapentin Only small studies are available on gabapentin use during pregnancy, A gabapentin pregnancy register [56] reported on 17 pregnancies with gabapentin in monotherapy and 30 in polytherapy with two major and one minor malformation. A prospective study of 223 pregnancies exposed to gabapentin (mainly as pain treatment but in 34% because of epilepsy) found among 170 live births seven with a major malformation [57]. A review [58] identified 254 first trimester exposures from the literature with five major malformations. In the Swedish data (Table 3) there were 128 gabapentin monotherapy exposures with only two infants with a relatively severe malformation: one had a cleft lip/palate, the other pylorostenosis. Levetiracetam One large study from the UK and Ireland epilepsy register [40] identified 671 pregnancies exposed to levetiracetam among which 307 were in monotherapy. Only two infants with major malformations were identified in the monotherapy group (0.7%) but 19 in the polytherapy group with high rates when levetiracetam had been combined with carbamazepine (9.4%) or valproate (6.9%). There were only 86 infants exposed to levetiracetamin monotherapy in the recent Swedish data (Table 3) two had mild malformations (hip subluxations). Pregabalin Very little data exist in the literature on pregabalin use. In the recent Swedish data (Table 3) there was a slight increase in malformation rate after pregabalin in monotherapy but the OR was not statistically significant. Among the six infants with relatively severe malformations, two had atrium septum defects and one a ventricular septum defect; one had hypospadias, one encephalocele, and one scoliosis with dextrocardia. Teratogenic Effects of Some Combinations of Anticonvulsants There were 70 different combinations of two or more anticonvulsants in the recent Swedish material but most were represented with only few cases. Only three combinations occured in more than 50 infants. The most common combination was valproic acid and lamotrigine: 97 cases among which 15 had any malformation (RR = 3.80, 95% CI ), 13 of them relatively severe (RR = 4.85, 95% CI ). The risk estimates are thus higher than for valproic acid alone (see Table 3) but the difference is not statistically significant. A combination of carbamazepine and lamotrigine occurred in 74 cases. There were only five malformed infants (RR = 1.53, 95% CI ), four of them were relatively severe (RR = 1.76, 95% CI )

12 The third combination was between lamotrigine and levetiracetam with 58 cases. Three infants had a congenital malformation (RR = 1.28, 95% CI ), two of them were relatively severe. Conclusion Anticonvulsants represent the most commonly used drug category with a known teratogenic capacity. There is also ample evidence that such drugs can affect brain differentiation with long-term neuropsychological effects. The harmful effects vary strongly with the actual drug use and are higher in anticonvulsive polytherapy than in monotherapy. The anticonvulsant with the highest risk is valproic acid and if possible this drug should be stopped before pregnancy. Also topiramate appears to be strongly teratogenic but the amount of available data is much smaller than for valproic acid. Much weaker effects are seen for carbamazepine and lamotrigine, but an effect of the latter drug was found on the risk for congenital heart defects also in monotherapy, and there are some uncertainty concerning carbamazepine and some specific malformations including spina bifida. Enough data on teratogenicity are not available for many new anticonvulsants. So far gabapentin seems to be free of teratogenic properties. Until further large enough data are available which indicate non-teratogenicity, it is probably wise to regard also the new anticonvulsant drugs as potentially carrying a risk. Epilepsy in women of fertile age and planning a pregnancy should get pre-pregnancy information, perhaps best from her neurologist. If possible, treatment with valproic acid or topiramate should be stopped before a planned pregnancy. If possible, polytherapy should be avoided and the lowest effective dose should be given. If a woman becomes pregnant during such therapy (especially with valproic acid) detailed prenatal diagnosis should be recommended but the risk for a non-detectable severe malformation is hardly high enough to motivate a pregnancy interruption but the effect on the neuropsychological development is a concern. Such effects may be the result of relatively late pregnancy exposures. Appendix 1: Data from the Swedish Medical Birth Register on Congenital Malformations. A Short Description of the Register The Swedish Medical Birth Register started in 1973 and covers practically all deliveries which take place in Sweden (a few percent are missing), at present about each year. It contains information from the free prenatal care, from the delivery unit, and from the pediatric examination of the newborn. Since 1982, information in the register is based on copies of the original medical documents and is nowadays mainly transmitted electronically to the National Board of Health. With a beginning 24 25

13 during 1994, information on maternal drug use in early pregnancy was included in the register. This information was obtained from midwife interviews at the first prenatal care visit, usually towards the end of the first trimester. The drug names were written down in clear text and were later centrally transferred into ATC codes. Details of the system can be obtained from [56] and from an internet site [1]. Information on congenital malformations in the infants born is obtained from the pediatric examination of the newborn, from a special register of congenital malformations, and from discharge diagnoses from hospitalizations of the child [57]. Malformation diagnoses are given as ICD codes, up to 1997 as ICD-9, since then as ICD-10. The number of infants with any malformation is determined and among these the number of infants with relatively severe malformations. This concept is defined by exclusion of infants with only had one or more of the following minor and variably recorded diagnoses: preauricular appendix, tongue tie, single umbilical artery, patent ductus in preterm infants, undescended testis, hip (sub) luxation, nevus. Risk estimates were made with adjustment for year of delivery, maternal age, parity, smoking habits in early pregnancy, and body mass index. When the expected number of malformations in the exposed group was 10 or more, Mantel-Haenszel odds ratios (OR) was determined with 95% confidence interval (95% CI). When the expected number was <10 a risk ratio (RR) was calculated instead with its 95% CI based on Poisson distributions. In the present study a restriction has been made to singleton pregnancies as the malformation risk in the two members of a twin pair are not independent. References 1. National Board of Health and Welfare. Centre for Epidemiology. The Swedish Medical Birth Register a summary of content and quality. 2003; Källén B. Drugs during Pregnancy. Nova Biochemical Books, New York Janz D, Fuchs U. Is antiepileptic drugs during pregnancy harmful?. Dtsch Med Wochenschr. 1964; 89: Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet. 1968; 2: Meadow SR. Congenital abnormalities and anticonvulsant drugs. Proc R Soc Med. 1970; 63: Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet. 1972; 2: Bjerkedal T, Bahna SL. The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand. 1973; 52:

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