Prenatal Antiepileptic Drug Exposure Research Articles

Prenatal Pregabalin Exposure Alters Postnatal Pain Sensitivity and Some Behavioral Responses in Adult Offspring Rats.

Prenatal antiepileptic drug exposure could demonstrate both congenital malformations and behavioral impairments in offspring. This study was performed to assess the effects of prenatal exposure to pregabalin (PGB) on pain response, anxiety, motor activity and some behavior of adult offspring rats. Pregnant Wistar rats received PGB (7.5, 15 and 30 mg/kg/ip) during embryonic days 9.5- 15.5. The pain response, anxiety-like behaviors, locomotor activity, motor balance and coordination and anhedonia of adult offspring were examined by tail-flick and hot plate test, open field test, elevated plus maze (EPM), beam balance test and sucrose preference test in their 60th day of life, respectively. Prenatal exposure to PGB revealed significant dose-dependent reduction in pain sensitivity (increase in pain latency response) in the hot plate test, especially in females, while anxiety-like behavior assessed in EPM and open field significantly reduced in males. In the open field, locomotor activity reduced significantly after exposure to PGB 30 mg/kg and motor coordination decreased dose-dependently, especially in males. Anhedonia, as an indication of sucrose preference or pleasure response, was not changed. These findings suggest that prenatal PGB exposure could be associated with significant changes in pain response, anxiety, locomotor activity and coordination in adult offspring rats.

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.

The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds

IntroductionPrenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. Material and methodsData on AED exposure, pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. ResultsFrontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. ConclusionsThese preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information.

Valproic Acid Leads New Neurons Down the Wrong Path.

Ectopic Neurogenesis Induced by Prenatal Antiepileptic Drug Exposure Augments Seizure Susceptibility in Adult Mice Sakai A, Matsuda T, Doi H, Nagaishi Y, Kato K, Nakashima K. Proc Natl Acad Sci U S A. 2018;115(16):4270-4275. doi:10.1073/pnas.1716479115Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs.

Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developmental aberrations associated with prenatal AED exposure could be detected already in infancy and whether effects on visual attention can be observed at this early age. We compared a prospective cohort of infants with in utero exposure to AED (n=56) with infants without drug exposures (n=62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure.

Effects of prenatal antiepileptic drug exposure on newborn brain activity.

Prenatal exposure to antiepileptic drugs (AEDs) is associated with an increased risk of cognitive dysfunction at early school age. Our aim was to investigate whether signs of adverse drug effects on brain function could be detected already during the first 2 weeks of life. We studied prospectively 56 full-term newborns with prenatal exposure to AEDs and 67 unexposed newborns for the following characteristics: Background information, AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, clinical neurologic status with Hammersmith Neonatal Neurological Examination and early cortical activity using electroencephalography (EEG). For EEG assessment, we developed and provide automated quantitation algorithms of several earlier described features: oscillatory bouts at theta and alpha frequencies, frequency spectra, interhemispheric synchrony, and interburst intervals (IBIs). The AED-exposed newborns had lower limb and axial tone and were less irritable than the unexposed newborns. EEG assessment disclosed significant differences in alpha bouts, in the frequency spectra, as well as in the spatial distributions of interhemispheric synchrony and IBIs. The results indicate that fetal AED exposure may affect early neonatal neurologic status and several features of early cortical activity. The findings suggest that interference of activity-dependent network development may be a possible mechanism to explain the link from fetal AED exposure to later neurocognitive sequelae.

Antiepileptic drugs and intrauterine death

To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.

Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study.

We studied the potential impact of antiepileptic drugs (AEDs) on fetal growth and gestational age at birth. In the Danish Medical Birth Registry, we identified all pregnancies with birth outcomes from 1997 to 2008 and linked with data from the Danish National Prescription Register. We used binomial regression to study preterm birth (<37weeks), low birth weight (<2,500g), and small for gestational age (SGA), adjusted for potential confounding factors including maternal age, smoking, substance abuse, cohabitation, income, education, and parity. We identified 679,762 singletons, and 2,928 (0.4%) of these had been exposed to AEDs. Exposure to AEDs was associated with a risk of preterm birth (adjusted risk ratio (aRR) 1.32; 95% confidence interval [CI] 1.16-1.50) when compared to unexposed children. However, when stratifying on maternal epilepsy, there was no association between AED exposure and preterm birth in offspring of women with epilepsy (aRR 1.00; 95% CI 0.82-1.21), whereas there was a risk associated with AED exposure in offspring of women without epilepsy (aRR 1.56; 95% CI 1.27-1.92). AED exposure was associated with a risk of being born with low birth weight (aRR 1.40; 95% CI 1.22-1.60) both for children born of women with epilepsy (aRR 1.32; 95% CI 1.06-1.63) and children born of women without epilepsy (aRR 1.61; 95% CI 1.28-2.02). The risk of being born SGA associated with AED exposure (aRR 1.21; 95% CI 1.10-1.34) was found both in offspring of women with epilepsy (aRR 1.19; 95% CI 1.02-1.37) and without epilepsy (aRR 1.21; 95% CI 1.01-1.45). Prenatal AED exposure was associated with low birth weight and risk of being born SGA, but only with preterm birth among women without epilepsy.

Breastfeeding and antiepileptic drugs.

IMPORTANCE Exposure to antiepileptic drugs during pregnancy is associated with adverse effects on psychomotor development. OBJECTIVES To determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. DESIGN, SETTING, AND PARTICIPANTS Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009. The mothers reported on their child’s motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n = 78 744), 18 months (n = 61 351), and 36 months (n = 44 147) of age. The mothers also provided detailed information on breastfeeding during the first year. MAIN OUTCOMES AND MEASURES The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child. RESULTS At age 6 months, infants of mothers using antiepileptic drugs (n = 223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio = 2.1; 95% CI, 1.3–3.2). Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome for both fine motor skills (25.0% vs 4.8%, respectively; odds ratio = 4.3; 95% CI, 2.0–9.1) and social skills (22.5% vs 10.2%, respectively; odds ratio = 2.6; 95% CI, 1.2–5.5). Continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year. Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months. CONCLUSIONS AND RELEVANCE Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment.

Early Child Development and Exposure to Antiepileptic Drugs Prenatally and Through Breastfeeding

Exposure to antiepileptic drugs during pregnancy is associated with adverse effects on psychomotor development. To determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009. The mothers reported on their child's motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n = 78,744), 18 months (n = 61,351), and 36 months (n = 44,147) of age. The mothers also provided detailed information on breastfeeding during the first year. MAIN OUTCOMES AND MEASURES The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child. At age 6 months, infants of mothers using antiepileptic drugs (n = 223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio = 2.1; 95% CI, 1.3-3.2). Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome for both fine motor skills (25.0% vs 4.8%, respectively; odds ratio = 4.3; 95% CI, 2.0-9.1) and social skills (22.5% vs 10.2%, respectively; odds ratio = 2.6; 95% CI, 1.2-5.5). Continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year. Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months. Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment.

Preschool behavioral problems in children prenatally exposed to antiepileptic drugs — A follow-up study

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.

1508 Spectrum of Neural Tube Defects after Prenatal Antiepileptic Drug Exposure: Extensive Case Series

BackgroundMost pregnant women with chronic active epilepsy need to use antiepileptic drugs (AEDs) during pregnancy to prevent epileptic seizures that may threaten maternal and fetal well-being. Valproic acid (VPA) and...

Prenatal antiepileptic exposure associates with neonatal DNA methylation differences

Antiepileptic drugs (AEDs) are used to treat a variety of neuropsychiatric illnesses commonly encountered in women during their reproductive years, including epilepsy and bipolar disorder. Despite their widespread use, the impact of prenatal exposure on fetal development remains obscure. To evaluate whether AEDs taken by pregnant mothers influence DNA methylation patterns in their neonates, DNA was extracted from the umbilical cord blood of 201 neonates whose mothers were treated for neuropsychiatric illness during pregnancy and interrogated across 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip. The association of each methylation value with the cumulative duration of prenatal AED exposure was examined using a linear mixed model. The average methylation level across all CpG sites was calculated for each subject, and this global methylation measure was evaluated similarly. Neonates with a longer duration of AED exposure in pregnancy showed a decrease in average global methylation (p = 0.0045). Further, DNA methylation of CpG sites in 14 genes significantly decreased with the duration of prenatal AED exposure even after adjusting for multiple comparisons (FDR < 0.05). For a small subset (n = 19) of these neonates, a second tissue, placenta, was available in addition to cord blood. Methylation of 3 of these 14 CpG sites was also significantly decreased in placental tissue. These novel data suggest decreased DNA methylation in neonates of mothers who took AEDs during pregnancy. The long-term stability and potential impact of these changes warrant further attention, and caution may be warranted before prescribing AEDs to pregnant women.

Neurobehavioral Consequences of Prenatal Antiepileptic Drug Exposure

Despite elevated rates of birth defects associated with prenatal antiepileptic drug exposure, pharmacotherapy is typically continued throughout pregnancy because of the risks posed to mother and child by recurrent seizures. Emerging data suggest that prenatal exposure to valproate or polytherapy may also be associated with increased risk of cognitive impairment. However, our understanding of the longer-term sequelae of prenatal antiepileptic drug exposure remains incomplete. Improved understanding of the neurobehavioral consequences of prenatal antiepileptic drug exposure is essential to ensure accurate information is available for women with epilepsy planning a pregnancy, and to achieve optimal outcomes for mothers and children.

Long-term neurocognitive adverse effects of prenatal antiepileptic drug exposure

Most women with epilepsy use antiepileptic medication during pregnancy because of seizure-related risks to mother and fetus. Most of the children exposed prenatally to antiepileptic medication are born healthy; however, there is increased risk for major congenital malformations and also unfavorable neurocognitive long-term development of the offspring. The increased risk has been correlated mainly with prenatal exposure to polytherapy and certain antiepileptic medications. Many confounding risk factors make it difficult to correlate the prenatal exposure and neurodevelopmental problems, and data of newer antiepileptic medications are lacking. In the future, larger prospective, controlled studies with extended follow-up are required to evaluate the long-term neurocognitive effects of prenatal antiepileptic medication exposure.

Retrospective case series of birth defects can predict malformation patterns associated with prenatal antiepileptic drug exposure

Retrospective case series of birth defects can predict malformation patterns associated with prenatal antiepileptic drug exposure

The frequency of neonatal morbidity after exposure to antiepileptic drugs in utero

To investigate the frequency of malformations, fetal growth retardation, cerebral hemorrhage and neonatal withdrawal symptoms in newborns exposed to antiepileptic drugs (AEDs) in utero. Population of the northeastern part of Slovenia (pregnant women and newborns between 1998 and 2002). Data on newborns born between 1998 and 2002 of 37 epileptic mothers taking AEDs in pregnancy, of 32 epileptic mothers not taking AEDs in pregnancy and of 211 mothers healthy in pregnancy were ascertained from hospital obstetric and neonatal records and included in the study. The health status of 270 newborns was assessed. frequency of congenital malformations, growth retardation (SFD), intracranial hemorrhage, feeding problems and withdrawal symptoms. In the group not exposed to antiepileptic drugs (32 neonates), two (2.9%) had germinal matrix hemorrhage grade I, one (1.4%) was small for date (SFD) and one (1.4%) had feeding problems. In the group exposed to antiepileptic drugs (37 neonates), nine (13%) had germinal matrix hemorrhage grade I, six (8.6%) were SFD, five (7.24%) had feeding problems, four (5.8%) had withdrawal symptoms and three (4.3%) "macro" congenital anomalies. Among neonatal problems in the control non-exposed group of newborns of 211 healthy women we identified 23 (10.9%) newborns who were SFD, 5 (2.4%) cases with germinal matrix hemorrhage grade I, 5 (2.4%) cases with major congenital malformations and 7 (3.3%) cases with feeding problems. Prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with increased risk of neonatal morbidity. In our study a particularly significant connection was established between carbamazepine therapy during pregnancy and cerebral hemorrhage in the neonates.

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.

In Utero Effects of AEDs.

Long-term Health and Neurodevelopment in Children Exposed to Antiepileptic Drugs Before Birth Dean JC, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. J Med Genet 2002;39:251–259 Objective To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero. Design Retrospective population-based study. SETTING: Population of the Grampian region of Scotland. Participants Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records, and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed. Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood-onset medical problems, developmental delay, and behaviour disorders. Results Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs (AEDs). Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of nonexposed sibs, and developmental delay in 24% of exposed children, compared with 11% of nonexposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of nonexposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of nonexposed sibs), and 20% had behaviour disorders (5% of nonexposed). Conclusion Prenatal AED exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation.