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Preschool behavioral problems in children prenatally exposed to antiepileptic drugs — A follow-up study
Epilepsy & Behavior 29 (2013) 407–411
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Preschool behavioral problems in children prenatally exposed to antiepileptic drugs — A follow-up study D. Kjaer a,b,c,⁎, J. Christensen c,d, B.H. Bech a, L.H. Pedersen a,e, M. Vestergaard f,g, J. Olsen a a
Section for Epidemiology, Department of Public Health, Aarhus University, Denmark Department of Pathology, Aarhus University Hospital, Denmark Department of Clinical Pharmacology, Aarhus University Hospital, Denmark d Department of Neurology, Aarhus University Hospital, Denmark e Institute of Clinical Medicine, Aarhus University Hospital, Denmark f Research Unit for General Practice, Aarhus University, Denmark g Department of General Practice, School of Public Health, Aarhus University, Denmark b c
a r t i c l e
i n f o
Article history: Received 3 July 2013 Revised 28 August 2013 Accepted 29 August 2013 Available online 3 October 2013 Keywords: Follow-up study Birth cohort Pregnancy Anticonvulsants Maternal epilepsy Strengths and Difficulties Questionnaire Behavioral development
a b s t r a c t We studied the association between maternal epilepsy, antiepileptic drug (AED) treatment, and behavioral problems in preschool children. In the Danish National Birth Cohort, we identified 4- to 5-year-old children whose mothers had epilepsy and received AED treatment (n = 133) or not (n = 304) during pregnancy and compared them with randomly selected children whose mothers did not have epilepsy (n = 1193). The children's behavioral problems were assessed by the use of the Strengths and Difficulties Questionnaire (SDQ). Children prenatally exposed to AEDs more often had an abnormal total SDQ score as compared with children of women without epilepsy (odds ratio (OR) = 4.8 (95% CI: 1.9–12.1)) and as compared with children of women with epilepsy who were not treated with AEDs during their pregnancy (OR = 4.0 (95% CI: 1.3–12.8)). In conclusion, prenatal AED exposure may increase the risk of behavioral problems in preschool children even after adjustments for potential confounders and maternal epilepsy. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Epilepsy is a common neurological disorder affecting 0.3–0.6% of pregnant women [1,2]. Use of antiepileptic drugs (AEDs) during pregnancy in women with epilepsy poses a clinical challenge, since both insufficient therapy leading to seizures and AED treatment itself may harm the developing fetus. The harmful effects of AEDs may range from major congenital abnormalities [3–12] to a subtle delay in measures of normal development [13–25]. Prenatal exposure to carbamazepine, valproate, phenytoin, primidone, or phenobarbital has been associated with learning disabilities [21]; attention, memory, and fine motor impairments [16]; and behavioral problems [22]. Impaired cognitive and behavioral development after AED exposure in utero has been reported in studies of infants [24,25], schoolchildren or teenagers [21–25], and adult men [19]. Other studies have reported normal intelligence in children prenatally exposed to carbamazepine [14] or
Abbreviations: AED, antiepileptic drug; CI, confidence interval; IQ, intelligence quotient; OR, odds ratio; SDQ, Strengths and Difficulties Questionnaire. ⁎ Corresponding author at: Department of Pathology, Aarhus University Hospital, TageHansens Gade 2, DK-8000 Aarhus C, Denmark. Fax: +45 78467499. E-mail address: [email protected] (D. Kjaer). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.08.033
exposed to lamotrigine [25] and in children born to women with epilepsy who did not receive AED treatment during pregnancy [15]. Adverse outcomes in children born to women with epilepsy could be caused by a direct effect of AEDs; the underlying epilepsy; confounding by socioeconomic, lifestyle, or genetic factors; or bias or could be a chance phenomenon. Only a few studies have focused on preschool children (4–5 years old) [13,14,16,25] or included information on potential confounders such as maternal cigarette smoking, alcohol consumption [15,17,19,21,22,25], and folic acid use [20,24,25], although these factors may be important determinants of behavioral problems in children [26–28]. We conducted a cohort study to estimate the association between maternal epilepsy with or without AED treatment and behavioral problems in preschool children, taking potential confounders into consideration. 2. Methods We used data from the Danish National Birth Cohort (1996–2002), a cohort of 101,042 pregnancies and 93,620 children. The women were invited by the general practitioners in Denmark, among whom approximately 50% took part in the recruitment. About 60% of the women, who were invited at the first pregnancy visit, consented to participate in the study [29]. Information on diseases, use of medicine, smoking and
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alcohol habits, education, and employment during pregnancy was collected from the consent form and from computer-assisted telephone interviews during pregnancy and early childhood (at gestational weeks 12 and 30 and six months after birth) [30]. The interviews and questionnaires are available on www.dnbc.dk. For a small group of women (n = 31), we had no interview information on parity and smoking; for these, we used information from the Danish Medical Birth Registry [31]. The databases were linked by means of the civil registration number assigned to all Danish citizens at birth [32].
report epilepsy or AED use. From the unexposed cohort, we excluded 47 children because of the following reasons: (1) the child had died (n = 2) and (2) the parents had protected addresses or the child was not living with any of the parents (n = 45). For a small group of women (n = 31), we had no interview information on parity and smoking, and for these women, we used the information collected by the midwives during pregnancy and included in the Danish Medical Birth Registry [31]. 2.2. Behavioral data
2.1. Exposure We established an “exposed” cohort of children born to women who reported being diagnosed with epilepsy (Fig. 1). This exposed group was divided into those whose mothers used or did not use AEDs during pregnancy. The information on epilepsy and use of AEDs anytime during pregnancy was collected from the consent form and the interviews. In the first interview, the question on epilepsy was “Have you ever had any other serious diseases such as epilepsy?” In the second interview, the question was “Have you had epilepsy during pregnancy?” In the third interview, the question was “Do you suffer from epilepsy?” We included mothers with epilepsy if they answered yes to any one of these questions, except if they answered yes only in the third interview because this information was collected after pregnancy, and the women may, therefore, not have had epilepsy during pregnancy. Questions on epilepsy in the second and third interviews were followed by the question “Have you taken medicine for epilepsy?” When we initiated our study (February 2006), we identified 437 singletons who were born to women who reported having had epilepsy, were 5 years old or younger at study initiation, and were living in Denmark (exposed cohort) (Fig. 1). Children not living with any of the parents and parents with unknown addresses were excluded (n = 18). The unexposed cohort consisted of 1193 randomly selected singletons from the cohort, who were living in Denmark, were 5 years old or younger at study initiation, and were born to mothers who did not
From February 2006 to May 2007, a questionnaire was sent to the mother around the child's 4th or 5th birthday. If the child was not living with the mother, we contacted the father. The first questionnaire was followed by reminders if the questionnaire was not returned within two months. Data entry was done blinded to the exposure status using EpiData (www.epidata.com). We used the “Strengths and Difficulties Questionnaire” (SDQ) [33] and added additional questions on the child's health (anthropometric measures), the mother's health, and the parents' smoking and drinking habits. The SDQ is a one-page screening questionnaire on the child's development filled out by parents. It covers the child's emotional and behavioral difficulties and has a high specificity (95%) and a moderate sensitivity (63%) [33]. The SDQs were scored in accordance with the official guidelines (www.sdqinfo.com), using 0 point for “not true”, 1 point for “partly true”, and 2 points for “certainly true” in each of the 25 questions. The questions cover five areas of outcome: emotional symptoms (somaticism, anxiety, unhappiness, clinginess, and fear), conduct problems (tantrums, disobedience, fighting, lying, and stealing), hyperactivity/inattention (restlessness, fidgety, distraction, nonreflection, and inattention), peer problems (loner, no friends, not popular, bully victim, and have adult best friends), and social behaviors (considerate, generous, caring, kind, and helpful). Scores were summed up for the five questions in each area (scores: 0–10). The total score (total difficulties) covers the sum of scores including emotional,
Maternal epilepsy N =1,050
Random controls N = 3,000 Abortions, stillborn 52 babies, 183 emigrants, twins or triplets
Liveborn singeltons n = 998
Eligible for the study n = 437
Liveborn singeltons n = 2,789 34
resigned
527
too old* 1,507
89
Protected addresses, not living with parents, or had died (n=2, controls) 18 47
Questionnaire mailed to n = 419 Epilepsy no AED: 294 Epilepsy with AED: 125
Eligible for the study n = 1,193
Questionnaire mailed to n = 1,146 No response 130
Returned n = 289 Epilepsy no AED: 208 Epilepsy with AED: 81
28 already in epilepsy group
318
Returned n = 828
Fig. 1. Inclusion and exclusion in the follow-up study. *Too old: more than 4 or 5 years at the time of the study. Emigrants: families living abroad.
D. Kjaer et al. / Epilepsy & Behavior 29 (2013) 407–411
conduct, hyperactivity, and peer areas (scores: 0–40). For each outcome, we used the officially recommended cutoff values for parentcompleted questionnaires classifying the child as normal (low score), borderline (middle score), or abnormal (high score) (www.sdqinfo. com). The cutoff values for normal and abnormal scores are as follows for the total score — normal: 0–13 and abnormal: N16, for the emotional score — normal: 0–3 and abnormal: N4, for the conduct and peer scores — normal: 0–2 and abnormal: N3, and for the hyperactivity score — normal: 0–5 and abnormal: N6.
Table 1 Characteristics of children and mothers with or without epilepsy. Confounders
Age Gender Maternal age
The data were analyzed using STATA version 9.0 (StataCorp, Texas, USA). A priori, we decided to adjust for the following potential covariates, which, in previous studies, correlated with behavioral and cognitive development in childhood: child's age (4 years, 5 years), gender (boy, girl), folic acid supplementation (yes, no), exclusively breastfed for the first 4 months after birth (yes, no), mother's age (b 30, ≥30 years), parity (1, 2+), smoking and drinking habits during pregnancy (yes, no), and parents' socioeconomic status (high, middle, low). Information on parity came from the Danish Medical Birth Registry [31], a registry that holds information on all pregnancies and births in Denmark since 1974. Information on folic acid use and socioeconomic groups came from interview 1, information on smoking and drinking habits came from interviews 1, 2, and 3 and the Danish Medical Birth Registry, and breast-feeding information came from the 4- and 5-year questionnaires. We included missing responses in the analyses as a separate category. We used logistic regression analyses to estimate the odds ratio (OR) of an abnormal score compared with a normal score for each of the two exposed subgroups (epilepsy with or without AED treatment) compared with the unexposed group. We also compared the two subgroups with epilepsy (with AEDs or without AEDs during pregnancy). Adjusted ORs were reported with 95% confidence intervals (CIs).
Parity
Our study was approved by the steering committee of the Danish National Birth Cohort and conducted in accordance with the rules of the Danish Data Protection Agency and “Good Epidemiological Practice” [34]. The Danish National Birth Cohort was approved by the Central Danish Ethic Committee and all regional committees. 3. Results Overall, the questionnaire was returned by parents of 1117 (71%) children of whom 81 (65%) were exposed prenatally to epilepsy and AEDs, 208 (71%) were exposed to epilepsy without AED treatment, and 828 (72%) were unexposed (reference group) (Fig. 1). The children who were prenatally exposed to maternal epilepsy and AEDs were less often girls, firstborn, breast-fed for less than four months, and born to mothers who were older than 30 years and did not consume alcohol (Table 1) as compared with the reference group. The children prenatally exposed to epilepsy and AEDs tended to have the most abnormal SDQ scores, except for emotional symptoms (Table 2). The adjusted ORs for an abnormal total SDQ score among children born to women with epilepsy who took AEDs increased fivefold compared with those of children born to women without epilepsy and fourfold higher compared with those of children born to women with epilepsy without AED exposure during pregnancy. The results did not change significantly when excluding children with missing information on confounders (n = 79) (data not shown). The adjusted ORs of abnormal conduct problem scores were threefold higher in prenatally AEDexposed children of women with epilepsy compared with those in unexposed children and in children of women with epilepsy without AED exposure during pregnancy (Table 2). We found similar abnormal
Epilepsy With AEDsa Without AEDs N = 81 N = 208
2.3. Statistical analyses
2.4. Ethical considerations
409
Folic acidb Breast-feedingb Smoking Alcoholb Socioeconomic statusb a b
4 years 5 years Girl Boy b30 years ≥30 years 1 2+ Yes No ≥4 months No or b4 months No Yes No Yes High Middle Low
Unexposed N = 828
n (%)
n (%)
n (%)
29 (35.8) 52 (64.2) 33 (40.7) 48 (59.3) 30 (37.0) 51 (63.0) 35 (43.2) 46 (56.8) 44 (54.3) 37 (45.7) 44 (54.3) 36 (44.4) 63 (77.8) 18 (22.2) 29 (35.8) 40 (49.4) 55 (67.9) 21 (26.0) 5 (6.2)
73 (35.1) 135 (64.9) 111 (53.4) 97 (46.6) 111 (53.4) 97 (46.6) 103 (49.5) 105 (50.5) 115 (55.3) 92 (44.2) 133 (63.9) 62 (29.8) 161 (77.4) 47 (22.6) 87 (41.8) 106 (51.0) 125 (60.1) 67 (32.2) 11 (5.3)
277 (33.5) 551 (66.6) 399 (48.2) 429 (51.8) 384 (46.4) 444 (53.6) 418 (50.5) 410 (49.5) 416 (50.2) 411 (49.6) 587 (70.9) 212 (25.6) 657 (79.3) 171 (20.7) 364 (44.0) 463 (55.9) 594 (71.7) 198 (23.9) 30 (3.6)
Antiepileptic drugs. Missing left out.
conduct problems when leaving out the children with missing data among confounders (data not shown). 4. Discussion The children born to women with epilepsy who took AEDs during pregnancy had more behavioral problems compared with the children of mothers without epilepsy and the children born to mothers who had epilepsy not treated with AEDs during pregnancy. These results remained after adjustments for potential confounders. Only a few studies have estimated the association between prenatal exposure to AEDs and behavioral problems in preschool children [13,14,16], and our results are in line with a Finnish study on children aged 5–11 years born to women with epilepsy [16]. They found a lower score on attention, memory, and fine motor function measures in children of women with epilepsy, especially following prenatal valproate exposure (n = 22). They also showed an age-dependent auditory attention deficit in 5-year-old children of women with epilepsy [16]. A follow-up study on neurodevelopment in children aged 9– 60 months found no detrimental influence on development in children prenatally exposed to lamotrigine (n = 35) as compared with controls (n = 44) or as compared with those exposed to valproate (n = 58) or carbamazepine (n = 49) [25]. Another developmental study based on prospective data found that infants born to women with epilepsy who received AED treatment during pregnancy had a lower mental development quotient compared with infants born to women with epilepsy who did not take AEDs during pregnancy. The association was strong for polytherapy and for valproate in monotherapy [20]. We did not have sufficient statistical power to study lamotrigine (n = 26), carbamazepine (n = 14), or valproate (n = 11) separately. Our study was based on a cohort study with prospectively collected exposure data obtained before the women were aware of the development of the child. Consequently, any misclassification is, therefore, likely to be nondifferential, which normally will tend to be biased towards the null. However, these results should be interpreted with caution. The association may be confounded by the indication for treatment rather than drug use. We tried to reduce the “confounding-by-indication” problems by using a comparison group of children born to women with epilepsy
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Table 2 Adjusted odds ratios (ORs) for abnormal behavioral scores according to prenatal exposure to epilepsy with or without AED treatment. Abnormal SDQ scoresa
Total Emotion Conduct Hyperactivity Peer a b c
Epilepsy
Unexposed N = 828
Epilepsy with AEDs compared with unexposed
Epilepsy with AEDs compared with epilepsy without AEDs
Epilepsy without AEDs compared with unexposed
n (%)
n (%)
ORc
95% CI
OR
95% CI
OR
95% CI
7 (3.4) 12 (5.8) 12 (5.8) 14 (6.7) 12 (5.8)
21 (2.5) 38 (4.6) 56 (6.8) 38 (4.6) 27 (3.3)
4.8 1.7 2.9 2.1 1.9
1.9–12.1 0.6–5.1 1.4–5.9 0.9–5.1 0.6–5.5
4.0 1.2 3.6 1.6 1.2
1.3–12.8 0.4–4.0 1.5–8.7 0.6–4.1 0.4–3.8
1.2 1.4 0.8 1.4 1.5
0.5–3.0 0.7–2.8 0.4–1.6 0.7–2.7 0.7–3.2
+AEDsb N = 81
−AEDs N = 208
n (%) 8 (9.9) 4 (4.9) 15 (18.5) 8 (9.9) 5 (6.2)
All compared with normal scores in each area. Antiepileptic drugs. Adjusted odds ratios for age and gender of child, mothers' age, parity, folic acid use, breast-feeding, smoking, drinking, and parents' sociooccupational status.
who did not report AED use during pregnancy. However, the use of AEDs may indicate more serious epilepsy with uncontrolled seizures which, again, could increase the risk of behavioral difficulties in the offspring, leaving room for residual confounding by indication. Folic acid supplementation in early pregnancy may reduce congenital abnormalities related to AEDs [12,35,36]. Folic acid supplementation influences DNA synthesis and DNA repair and may have an impact on the developing brain, even after the first trimester [26]. It has recently been suggested that folic acid use affects early childhood development as well [24,26]. In our study, we included folic acid intake as a confounder in the analyses. Most studies on maternal epilepsy and AED use related to children's development adjust for socioeconomic status, maternal education, and maternal IQ, or the children were matched on parents' socioeconomic status [14–25,37]. Not all reported associations were found after adjustments for these factors [21]. Few studies include smoking or alcohol consumption as potential confounders [15,17,19,21,22,25], although cigarette smoking and alcohol intake during pregnancy have been associated with impaired behavioral development, especially hyperactivity problems, in several studies [28,38]. However, our results did not change much after adjusting for lifestyle and socioeconomic factors. It has been suggested that lack of breast-feeding by women who used AEDs during pregnancy may delay childhood development (Meador, K.J. Breastfeeding While Taking Seizure Medicine Does Not Appear to Harm Infants. http://www.docguide.com/news/content.nsf/ NewsPrint. August 2008. Ref Type: Internet). Confounding could occur if women in AED treatment avoid breast-feeding because of a perceived risk related to the transferring of drugs to the child via breast milk and if breast-feeding protects against behavioral problems. Studies have shown that prolonged and exclusive breast-feeding improved children's cognitive development [27]. Our study controlled for length of breast-feeding, but as for the other potential confounders, the SDQ score did not change much after adjustments. The validated SDQ is a screening tool covering emotional symptoms, conduct problems, hyperactivity, peer relations, and social problems [33]. Parents may score their child differently from teachers because they lack the comparison with other children that the teachers have access to. This will bias the results if AED-exposed children are scored differently from the unexposed, which is a possibility if persisting epilepsy makes it more difficult to cope with adverse child behavior. We have recently, in the same cohort, used the SDQ to investigate behavior among children of mothers with depression during pregnancy and found no association with SDQ score after prenatal antidepressant exposure [39]. When interpreted cautiously, it at least suggests that an association with childhood SDQ score is not solely a consequence of antidepressant drug use during pregnancy. The Danish National Birth Cohort covers all regions in Denmark and had an overall participation rate of approximately 30%, since only half of the general practitioners in the country took part in the study.
However, this need not impact internal comparisons [29] as this would only bias the results if the AED used was related to the response. The response rate in our follow-up study was high but not high enough to exclude selection bias, which would occur if nonparticipation was related to both exposure to epilepsy and AEDs and behavioral problems in childhood. Despite the very large population-based pregnancy cohort including more than 100,000 pregnancies, the informative sample size was small. The child's IQ may be a potential confounder or – for some of the drugs – an intermediate, as it was reported in several studies that prenatal exposure to valproate was associated with significantly lower verbal or fullscale IQ in the child [22–25]. We have no data on the children's IQ in this study. We had no information on subtypes of epilepsy, which could hide important information on the genetic factors involved, as would be expected, for example, with idiopathic generalized epilepsy. However, results from a recent study adjusting for types of epilepsy (localization-related, idiopathic generalized, and generalized tonic–clonic) suggest that the adverse outcome of AEDs is associated with the use of anticonvulsant drugs during pregnancy rather than with the epilepsy type itself [15]. Genetic factors, mothers' IQ, and psychiatric disease may also confound the results. All these factors may be important when considering the association between AED exposure during pregnancy and behavioral development of the child. 5. Conclusion Our results suggest that AED exposure in prenatal life may increase the risk of behavioral problems in preschool children even after adjustments for potential confounders and maternal epilepsy. Disclosure JC received honoraria for serving on the scientific advisory board of UCB Nordic and Eisai AB, received honoraria from UCB Nordic and Eisai AB for giving lectures, and received funding for a trip from UCB Nordic. Acknowledgments The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is, furthermore, supported by a major grant from the Danish National Research Foundation and grants from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defect Foundation, the Augustinus Foundation, and the Health Foundation. DK was supported by grants from the Augustinus Foundation, the Aarhus University Research Foundation, and the Lennart Gram Memorial Foundation.
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Preschool behavioral problems in children prenatally exposed to antiepileptic drugs — A follow-up study D. Kjaer a,b,c,⁎, J. Christensen c,d, B.H. Bech a, L.H. Pedersen a,e, M. Vestergaard f,g, J. Olsen a a
Section for Epidemiology, Department of Public Health, Aarhus University, Denmark Department of Pathology, Aarhus University Hospital, Denmark Department of Clinical Pharmacology, Aarhus University Hospital, Denmark d Department of Neurology, Aarhus University Hospital, Denmark e Institute of Clinical Medicine, Aarhus University Hospital, Denmark f Research Unit for General Practice, Aarhus University, Denmark g Department of General Practice, School of Public Health, Aarhus University, Denmark b c
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Article history: Received 3 July 2013 Revised 28 August 2013 Accepted 29 August 2013 Available online 3 October 2013 Keywords: Follow-up study Birth cohort Pregnancy Anticonvulsants Maternal epilepsy Strengths and Difficulties Questionnaire Behavioral development
a b s t r a c t We studied the association between maternal epilepsy, antiepileptic drug (AED) treatment, and behavioral problems in preschool children. In the Danish National Birth Cohort, we identified 4- to 5-year-old children whose mothers had epilepsy and received AED treatment (n = 133) or not (n = 304) during pregnancy and compared them with randomly selected children whose mothers did not have epilepsy (n = 1193). The children's behavioral problems were assessed by the use of the Strengths and Difficulties Questionnaire (SDQ). Children prenatally exposed to AEDs more often had an abnormal total SDQ score as compared with children of women without epilepsy (odds ratio (OR) = 4.8 (95% CI: 1.9–12.1)) and as compared with children of women with epilepsy who were not treated with AEDs during their pregnancy (OR = 4.0 (95% CI: 1.3–12.8)). In conclusion, prenatal AED exposure may increase the risk of behavioral problems in preschool children even after adjustments for potential confounders and maternal epilepsy. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Epilepsy is a common neurological disorder affecting 0.3–0.6% of pregnant women [1,2]. Use of antiepileptic drugs (AEDs) during pregnancy in women with epilepsy poses a clinical challenge, since both insufficient therapy leading to seizures and AED treatment itself may harm the developing fetus. The harmful effects of AEDs may range from major congenital abnormalities [3–12] to a subtle delay in measures of normal development [13–25]. Prenatal exposure to carbamazepine, valproate, phenytoin, primidone, or phenobarbital has been associated with learning disabilities [21]; attention, memory, and fine motor impairments [16]; and behavioral problems [22]. Impaired cognitive and behavioral development after AED exposure in utero has been reported in studies of infants [24,25], schoolchildren or teenagers [21–25], and adult men [19]. Other studies have reported normal intelligence in children prenatally exposed to carbamazepine [14] or
Abbreviations: AED, antiepileptic drug; CI, confidence interval; IQ, intelligence quotient; OR, odds ratio; SDQ, Strengths and Difficulties Questionnaire. ⁎ Corresponding author at: Department of Pathology, Aarhus University Hospital, TageHansens Gade 2, DK-8000 Aarhus C, Denmark. Fax: +45 78467499. E-mail address: [email protected] (D. Kjaer). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.08.033
exposed to lamotrigine [25] and in children born to women with epilepsy who did not receive AED treatment during pregnancy [15]. Adverse outcomes in children born to women with epilepsy could be caused by a direct effect of AEDs; the underlying epilepsy; confounding by socioeconomic, lifestyle, or genetic factors; or bias or could be a chance phenomenon. Only a few studies have focused on preschool children (4–5 years old) [13,14,16,25] or included information on potential confounders such as maternal cigarette smoking, alcohol consumption [15,17,19,21,22,25], and folic acid use [20,24,25], although these factors may be important determinants of behavioral problems in children [26–28]. We conducted a cohort study to estimate the association between maternal epilepsy with or without AED treatment and behavioral problems in preschool children, taking potential confounders into consideration. 2. Methods We used data from the Danish National Birth Cohort (1996–2002), a cohort of 101,042 pregnancies and 93,620 children. The women were invited by the general practitioners in Denmark, among whom approximately 50% took part in the recruitment. About 60% of the women, who were invited at the first pregnancy visit, consented to participate in the study [29]. Information on diseases, use of medicine, smoking and
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alcohol habits, education, and employment during pregnancy was collected from the consent form and from computer-assisted telephone interviews during pregnancy and early childhood (at gestational weeks 12 and 30 and six months after birth) [30]. The interviews and questionnaires are available on www.dnbc.dk. For a small group of women (n = 31), we had no interview information on parity and smoking; for these, we used information from the Danish Medical Birth Registry [31]. The databases were linked by means of the civil registration number assigned to all Danish citizens at birth [32].
report epilepsy or AED use. From the unexposed cohort, we excluded 47 children because of the following reasons: (1) the child had died (n = 2) and (2) the parents had protected addresses or the child was not living with any of the parents (n = 45). For a small group of women (n = 31), we had no interview information on parity and smoking, and for these women, we used the information collected by the midwives during pregnancy and included in the Danish Medical Birth Registry [31]. 2.2. Behavioral data
2.1. Exposure We established an “exposed” cohort of children born to women who reported being diagnosed with epilepsy (Fig. 1). This exposed group was divided into those whose mothers used or did not use AEDs during pregnancy. The information on epilepsy and use of AEDs anytime during pregnancy was collected from the consent form and the interviews. In the first interview, the question on epilepsy was “Have you ever had any other serious diseases such as epilepsy?” In the second interview, the question was “Have you had epilepsy during pregnancy?” In the third interview, the question was “Do you suffer from epilepsy?” We included mothers with epilepsy if they answered yes to any one of these questions, except if they answered yes only in the third interview because this information was collected after pregnancy, and the women may, therefore, not have had epilepsy during pregnancy. Questions on epilepsy in the second and third interviews were followed by the question “Have you taken medicine for epilepsy?” When we initiated our study (February 2006), we identified 437 singletons who were born to women who reported having had epilepsy, were 5 years old or younger at study initiation, and were living in Denmark (exposed cohort) (Fig. 1). Children not living with any of the parents and parents with unknown addresses were excluded (n = 18). The unexposed cohort consisted of 1193 randomly selected singletons from the cohort, who were living in Denmark, were 5 years old or younger at study initiation, and were born to mothers who did not
From February 2006 to May 2007, a questionnaire was sent to the mother around the child's 4th or 5th birthday. If the child was not living with the mother, we contacted the father. The first questionnaire was followed by reminders if the questionnaire was not returned within two months. Data entry was done blinded to the exposure status using EpiData (www.epidata.com). We used the “Strengths and Difficulties Questionnaire” (SDQ) [33] and added additional questions on the child's health (anthropometric measures), the mother's health, and the parents' smoking and drinking habits. The SDQ is a one-page screening questionnaire on the child's development filled out by parents. It covers the child's emotional and behavioral difficulties and has a high specificity (95%) and a moderate sensitivity (63%) [33]. The SDQs were scored in accordance with the official guidelines (www.sdqinfo.com), using 0 point for “not true”, 1 point for “partly true”, and 2 points for “certainly true” in each of the 25 questions. The questions cover five areas of outcome: emotional symptoms (somaticism, anxiety, unhappiness, clinginess, and fear), conduct problems (tantrums, disobedience, fighting, lying, and stealing), hyperactivity/inattention (restlessness, fidgety, distraction, nonreflection, and inattention), peer problems (loner, no friends, not popular, bully victim, and have adult best friends), and social behaviors (considerate, generous, caring, kind, and helpful). Scores were summed up for the five questions in each area (scores: 0–10). The total score (total difficulties) covers the sum of scores including emotional,
Maternal epilepsy N =1,050
Random controls N = 3,000 Abortions, stillborn 52 babies, 183 emigrants, twins or triplets
Liveborn singeltons n = 998
Eligible for the study n = 437
Liveborn singeltons n = 2,789 34
resigned
527
too old* 1,507
89
Protected addresses, not living with parents, or had died (n=2, controls) 18 47
Questionnaire mailed to n = 419 Epilepsy no AED: 294 Epilepsy with AED: 125
Eligible for the study n = 1,193
Questionnaire mailed to n = 1,146 No response 130
Returned n = 289 Epilepsy no AED: 208 Epilepsy with AED: 81
28 already in epilepsy group
318
Returned n = 828
Fig. 1. Inclusion and exclusion in the follow-up study. *Too old: more than 4 or 5 years at the time of the study. Emigrants: families living abroad.
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conduct, hyperactivity, and peer areas (scores: 0–40). For each outcome, we used the officially recommended cutoff values for parentcompleted questionnaires classifying the child as normal (low score), borderline (middle score), or abnormal (high score) (www.sdqinfo. com). The cutoff values for normal and abnormal scores are as follows for the total score — normal: 0–13 and abnormal: N16, for the emotional score — normal: 0–3 and abnormal: N4, for the conduct and peer scores — normal: 0–2 and abnormal: N3, and for the hyperactivity score — normal: 0–5 and abnormal: N6.
Table 1 Characteristics of children and mothers with or without epilepsy. Confounders
Age Gender Maternal age
The data were analyzed using STATA version 9.0 (StataCorp, Texas, USA). A priori, we decided to adjust for the following potential covariates, which, in previous studies, correlated with behavioral and cognitive development in childhood: child's age (4 years, 5 years), gender (boy, girl), folic acid supplementation (yes, no), exclusively breastfed for the first 4 months after birth (yes, no), mother's age (b 30, ≥30 years), parity (1, 2+), smoking and drinking habits during pregnancy (yes, no), and parents' socioeconomic status (high, middle, low). Information on parity came from the Danish Medical Birth Registry [31], a registry that holds information on all pregnancies and births in Denmark since 1974. Information on folic acid use and socioeconomic groups came from interview 1, information on smoking and drinking habits came from interviews 1, 2, and 3 and the Danish Medical Birth Registry, and breast-feeding information came from the 4- and 5-year questionnaires. We included missing responses in the analyses as a separate category. We used logistic regression analyses to estimate the odds ratio (OR) of an abnormal score compared with a normal score for each of the two exposed subgroups (epilepsy with or without AED treatment) compared with the unexposed group. We also compared the two subgroups with epilepsy (with AEDs or without AEDs during pregnancy). Adjusted ORs were reported with 95% confidence intervals (CIs).
Parity
Our study was approved by the steering committee of the Danish National Birth Cohort and conducted in accordance with the rules of the Danish Data Protection Agency and “Good Epidemiological Practice” [34]. The Danish National Birth Cohort was approved by the Central Danish Ethic Committee and all regional committees. 3. Results Overall, the questionnaire was returned by parents of 1117 (71%) children of whom 81 (65%) were exposed prenatally to epilepsy and AEDs, 208 (71%) were exposed to epilepsy without AED treatment, and 828 (72%) were unexposed (reference group) (Fig. 1). The children who were prenatally exposed to maternal epilepsy and AEDs were less often girls, firstborn, breast-fed for less than four months, and born to mothers who were older than 30 years and did not consume alcohol (Table 1) as compared with the reference group. The children prenatally exposed to epilepsy and AEDs tended to have the most abnormal SDQ scores, except for emotional symptoms (Table 2). The adjusted ORs for an abnormal total SDQ score among children born to women with epilepsy who took AEDs increased fivefold compared with those of children born to women without epilepsy and fourfold higher compared with those of children born to women with epilepsy without AED exposure during pregnancy. The results did not change significantly when excluding children with missing information on confounders (n = 79) (data not shown). The adjusted ORs of abnormal conduct problem scores were threefold higher in prenatally AEDexposed children of women with epilepsy compared with those in unexposed children and in children of women with epilepsy without AED exposure during pregnancy (Table 2). We found similar abnormal
Epilepsy With AEDsa Without AEDs N = 81 N = 208
2.3. Statistical analyses
2.4. Ethical considerations
409
Folic acidb Breast-feedingb Smoking Alcoholb Socioeconomic statusb a b
4 years 5 years Girl Boy b30 years ≥30 years 1 2+ Yes No ≥4 months No or b4 months No Yes No Yes High Middle Low
Unexposed N = 828
n (%)
n (%)
n (%)
29 (35.8) 52 (64.2) 33 (40.7) 48 (59.3) 30 (37.0) 51 (63.0) 35 (43.2) 46 (56.8) 44 (54.3) 37 (45.7) 44 (54.3) 36 (44.4) 63 (77.8) 18 (22.2) 29 (35.8) 40 (49.4) 55 (67.9) 21 (26.0) 5 (6.2)
73 (35.1) 135 (64.9) 111 (53.4) 97 (46.6) 111 (53.4) 97 (46.6) 103 (49.5) 105 (50.5) 115 (55.3) 92 (44.2) 133 (63.9) 62 (29.8) 161 (77.4) 47 (22.6) 87 (41.8) 106 (51.0) 125 (60.1) 67 (32.2) 11 (5.3)
277 (33.5) 551 (66.6) 399 (48.2) 429 (51.8) 384 (46.4) 444 (53.6) 418 (50.5) 410 (49.5) 416 (50.2) 411 (49.6) 587 (70.9) 212 (25.6) 657 (79.3) 171 (20.7) 364 (44.0) 463 (55.9) 594 (71.7) 198 (23.9) 30 (3.6)
Antiepileptic drugs. Missing left out.
conduct problems when leaving out the children with missing data among confounders (data not shown). 4. Discussion The children born to women with epilepsy who took AEDs during pregnancy had more behavioral problems compared with the children of mothers without epilepsy and the children born to mothers who had epilepsy not treated with AEDs during pregnancy. These results remained after adjustments for potential confounders. Only a few studies have estimated the association between prenatal exposure to AEDs and behavioral problems in preschool children [13,14,16], and our results are in line with a Finnish study on children aged 5–11 years born to women with epilepsy [16]. They found a lower score on attention, memory, and fine motor function measures in children of women with epilepsy, especially following prenatal valproate exposure (n = 22). They also showed an age-dependent auditory attention deficit in 5-year-old children of women with epilepsy [16]. A follow-up study on neurodevelopment in children aged 9– 60 months found no detrimental influence on development in children prenatally exposed to lamotrigine (n = 35) as compared with controls (n = 44) or as compared with those exposed to valproate (n = 58) or carbamazepine (n = 49) [25]. Another developmental study based on prospective data found that infants born to women with epilepsy who received AED treatment during pregnancy had a lower mental development quotient compared with infants born to women with epilepsy who did not take AEDs during pregnancy. The association was strong for polytherapy and for valproate in monotherapy [20]. We did not have sufficient statistical power to study lamotrigine (n = 26), carbamazepine (n = 14), or valproate (n = 11) separately. Our study was based on a cohort study with prospectively collected exposure data obtained before the women were aware of the development of the child. Consequently, any misclassification is, therefore, likely to be nondifferential, which normally will tend to be biased towards the null. However, these results should be interpreted with caution. The association may be confounded by the indication for treatment rather than drug use. We tried to reduce the “confounding-by-indication” problems by using a comparison group of children born to women with epilepsy
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Table 2 Adjusted odds ratios (ORs) for abnormal behavioral scores according to prenatal exposure to epilepsy with or without AED treatment. Abnormal SDQ scoresa
Total Emotion Conduct Hyperactivity Peer a b c
Epilepsy
Unexposed N = 828
Epilepsy with AEDs compared with unexposed
Epilepsy with AEDs compared with epilepsy without AEDs
Epilepsy without AEDs compared with unexposed
n (%)
n (%)
ORc
95% CI
OR
95% CI
OR
95% CI
7 (3.4) 12 (5.8) 12 (5.8) 14 (6.7) 12 (5.8)
21 (2.5) 38 (4.6) 56 (6.8) 38 (4.6) 27 (3.3)
4.8 1.7 2.9 2.1 1.9
1.9–12.1 0.6–5.1 1.4–5.9 0.9–5.1 0.6–5.5
4.0 1.2 3.6 1.6 1.2
1.3–12.8 0.4–4.0 1.5–8.7 0.6–4.1 0.4–3.8
1.2 1.4 0.8 1.4 1.5
0.5–3.0 0.7–2.8 0.4–1.6 0.7–2.7 0.7–3.2
+AEDsb N = 81
−AEDs N = 208
n (%) 8 (9.9) 4 (4.9) 15 (18.5) 8 (9.9) 5 (6.2)
All compared with normal scores in each area. Antiepileptic drugs. Adjusted odds ratios for age and gender of child, mothers' age, parity, folic acid use, breast-feeding, smoking, drinking, and parents' sociooccupational status.
who did not report AED use during pregnancy. However, the use of AEDs may indicate more serious epilepsy with uncontrolled seizures which, again, could increase the risk of behavioral difficulties in the offspring, leaving room for residual confounding by indication. Folic acid supplementation in early pregnancy may reduce congenital abnormalities related to AEDs [12,35,36]. Folic acid supplementation influences DNA synthesis and DNA repair and may have an impact on the developing brain, even after the first trimester [26]. It has recently been suggested that folic acid use affects early childhood development as well [24,26]. In our study, we included folic acid intake as a confounder in the analyses. Most studies on maternal epilepsy and AED use related to children's development adjust for socioeconomic status, maternal education, and maternal IQ, or the children were matched on parents' socioeconomic status [14–25,37]. Not all reported associations were found after adjustments for these factors [21]. Few studies include smoking or alcohol consumption as potential confounders [15,17,19,21,22,25], although cigarette smoking and alcohol intake during pregnancy have been associated with impaired behavioral development, especially hyperactivity problems, in several studies [28,38]. However, our results did not change much after adjusting for lifestyle and socioeconomic factors. It has been suggested that lack of breast-feeding by women who used AEDs during pregnancy may delay childhood development (Meador, K.J. Breastfeeding While Taking Seizure Medicine Does Not Appear to Harm Infants. http://www.docguide.com/news/content.nsf/ NewsPrint. August 2008. Ref Type: Internet). Confounding could occur if women in AED treatment avoid breast-feeding because of a perceived risk related to the transferring of drugs to the child via breast milk and if breast-feeding protects against behavioral problems. Studies have shown that prolonged and exclusive breast-feeding improved children's cognitive development [27]. Our study controlled for length of breast-feeding, but as for the other potential confounders, the SDQ score did not change much after adjustments. The validated SDQ is a screening tool covering emotional symptoms, conduct problems, hyperactivity, peer relations, and social problems [33]. Parents may score their child differently from teachers because they lack the comparison with other children that the teachers have access to. This will bias the results if AED-exposed children are scored differently from the unexposed, which is a possibility if persisting epilepsy makes it more difficult to cope with adverse child behavior. We have recently, in the same cohort, used the SDQ to investigate behavior among children of mothers with depression during pregnancy and found no association with SDQ score after prenatal antidepressant exposure [39]. When interpreted cautiously, it at least suggests that an association with childhood SDQ score is not solely a consequence of antidepressant drug use during pregnancy. The Danish National Birth Cohort covers all regions in Denmark and had an overall participation rate of approximately 30%, since only half of the general practitioners in the country took part in the study.
However, this need not impact internal comparisons [29] as this would only bias the results if the AED used was related to the response. The response rate in our follow-up study was high but not high enough to exclude selection bias, which would occur if nonparticipation was related to both exposure to epilepsy and AEDs and behavioral problems in childhood. Despite the very large population-based pregnancy cohort including more than 100,000 pregnancies, the informative sample size was small. The child's IQ may be a potential confounder or – for some of the drugs – an intermediate, as it was reported in several studies that prenatal exposure to valproate was associated with significantly lower verbal or fullscale IQ in the child [22–25]. We have no data on the children's IQ in this study. We had no information on subtypes of epilepsy, which could hide important information on the genetic factors involved, as would be expected, for example, with idiopathic generalized epilepsy. However, results from a recent study adjusting for types of epilepsy (localization-related, idiopathic generalized, and generalized tonic–clonic) suggest that the adverse outcome of AEDs is associated with the use of anticonvulsant drugs during pregnancy rather than with the epilepsy type itself [15]. Genetic factors, mothers' IQ, and psychiatric disease may also confound the results. All these factors may be important when considering the association between AED exposure during pregnancy and behavioral development of the child. 5. Conclusion Our results suggest that AED exposure in prenatal life may increase the risk of behavioral problems in preschool children even after adjustments for potential confounders and maternal epilepsy. Disclosure JC received honoraria for serving on the scientific advisory board of UCB Nordic and Eisai AB, received honoraria from UCB Nordic and Eisai AB for giving lectures, and received funding for a trip from UCB Nordic. Acknowledgments The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is, furthermore, supported by a major grant from the Danish National Research Foundation and grants from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defect Foundation, the Augustinus Foundation, and the Health Foundation. DK was supported by grants from the Augustinus Foundation, the Aarhus University Research Foundation, and the Lennart Gram Memorial Foundation.
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