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We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

The impact of certain medication exposures in utero can be observed in the physical development of the fetus (e.g. patterns of congenital malformations or dysmorphic features) or in the form of growth disruption. Developmental trajectories within the fetal brain can also be susceptible to alteration and can manifest as lifelong neurodevelopmental impairments. Despite growing recognition of its importance as an outcome, a lack of coherence within the investigation of the neurodevelopmental outcomes remains. Important methodological clarity could be gained through reviewing published data regarding neurodevelopmental outcomes within the context of confirmed structural teratogens. This scoping review will use systematic searches to identify neurodevelopmental outcome data for medications demonstrated to alter the physical development of the fetus (i.e. structural malformations or growth disruption). Searches will be conducted in MEDLINE, EMBASE, and the specialized database Reprotox. Identified abstracts will be doubly reviewed against the eligibility criteria and data extracted. A narrative review will be undertaken, reporting on the key neurodevelopmental areas frequently altered, methodological features of completed studies (e.g. study designs, child characteristics, dose relationships, etc) and, importantly, the relationship between the structural alterations associated with the exposure and the observed neurodevelopmental outcomes.

Report describing core data elements for the collection of pregnancy, immediate child outcomes and longer-term child outcomes in medication exposed pregnancies.

By describing a sequence of reviews, this report aims to document current practice from which routes for improvement can be identified and implemented into future endeavours of the ConcePTION project. The reviews emphasize present regulatory frameworks regarding the collection of data on exposed pregnancies, on large-scale data collection schemes, and on how data reported through industry pharmacovigilance systems are coded and communicated to regulators.

Summary sheet for General Practitioners. (PPTX 115 kb)

Summary sheet for Psychologists. (PPTX 102 kb)

Summary sheet for Educators. (PPTX 114 kb)

Summary sheet for Patients and Parents. (PPTX 102 kb)

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.

To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5).Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills.Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

OBJECTIVE: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. METHODS: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. RESULTS: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p 800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p

Prenatal exposure to sodium valproate and levetiracetam: consequences for neurodevelopmental outcomes? Rebecca L. Bromley, PhD. For the award: Doctorate of Clinical Psychology. Submitted to the University of Manchester June 2012.Research has demonstrated that prenatal exposure to antiepileptic drugs is associated with an increased risk of physical malformations. The potential risk such exposure conveys to the developing brain and therefore the later cognitive functioning of the child is now the focus of both national and international research. This thesis investigated the relationship between prenatal exposure to antiepileptic drugs and child cognitive functioning. This investigation was undertaken in three phases: a systematic review of the published literature; an original research piece investigating prenatal exposure to sodium valproate and levetiracetam and finally a critical review of the research undertaken as part of this thesis and in the wider published literature.The systematic review identified 30 studies which had investigated the cognitive abilities of children with a history of prenatal exposure to antiepileptic drugs. Methodological quality of the studies was considered against the criteria of the Newcastle Ottawa Scale. Differential findings were noted across the antiepileptic drug types, with the largest number of studies documenting increased risks associated with prenatal exposure to sodium valproate. A lack of high quality research across all antiepileptic drugs, and in particular the more recently licensed antiepileptic drugs is highlighted. In the research paper presented here children aged between five and nine years of age exposed to either levetiracetam (n=37), sodium valproate (n=40) or who were born to women with epilepsy but did not require medication (n=43) were recruited from throughout the UK. Demographic and health information was collected from prospective records and supplemented with maternal interview. Formal standardised neuropsychological assessments were undertaken to inform on the child’s current level of intellectual, memory, language, attentional and executive functioning. Following adjustment for variables likely to influence child cognitive ability, prenatal exposure to sodium valproate was found to be associated with poorer intellectual and language functioning in a dose dependent manner. When stratified by dose, 57.9% of children exposed to doses of sodium valproate above 800mg daily scored below the average range for their global intellectual ability. Prenatal exposure to levetiracetam was not found to be associated with poorer cognitive functioning. The critical review highlighted a number of methodological strengths of this research, despite time and resource implications. However, consideration should be given to the retrospective nature of this cohort and the potential for recruitment bias.This thesis concludes that women who require continuation of their treatment during pregnancy to control their seizures should be counselled regarding the risks and the benefits of their treatment to allow them to make informed decisions. Prenatal exposure to sodium valproate and levetiracetam: consequences for neurodevelopmental outcomes? Rebecca L. Bromley, PhD. For the award: Doctorate of Clinical Psychology. Submitted to the University of Manchester June 2012.Research has demonstrated that prenatal exposure to antiepileptic drugs is associated with an increased risk of physical malformations. The potential risk such exposure conveys to the developing brain and therefore the later cognitive functioning of the child is now the focus of both national and international research. This thesis investigated the relationship between prenatal exposure to antiepileptic drugs and child cognitive functioning. This investigation was undertaken in three phases: a systematic review of the published literature; an original research piece investigating prenatal exposure to sodium valproate and levetiracetam and finally a critical review of the research undertaken as part of this thesis and in the wider published literature.The systematic review identified 30 studies which had investigated the cognitive abilities of children with a history of prenatal exposure to antiepileptic drugs. Methodological quality of the studies was considered against the criteria of the Newcastle Ottawa Scale. Differential findings were noted across the antiepileptic drug types, with the largest number of studies documenting increased risks associated with prenatal exposure to sodium valproate. A lack of high quality research across all antiepileptic drugs, and in particular the more recently licensed antiepileptic drugs is highlighted. In the research paper presented here children aged between five and nine years of age exposed to either levetiracetam (n=37), sodium valproate (n=40) or who were born to women with epilepsy but did not require medication (n=43) were recruited from throughout the UK. Demographic and health information was collected from prospective records and supplemented with maternal interview. Formal standardised neuropsychological assessments were undertaken to inform on the child’s current level of intellectual, memory, language, attentional and executive functioning. Following adjustment for variables likely to influence child cognitive ability, prenatal exposure to sodium valproate was found to be associated with poorer intellectual and language functioning in a dose dependent manner. When stratified by dose, 57.9% of children exposed to doses of sodium valproate above 800mg daily scored below the average range for their global intellectual ability. Prenatal exposure to levetiracetam was not found to be associated with poorer cognitive functioning. The critical review highlighted a number of methodological strengths of this research, despite time and resource implications. However, consideration should be given to the retrospective nature of this cohort and the potential for recruitment bias.This thesis concludes that women who require continuation of their treatment during pregnancy to control their seizures should be counselled regarding the risks and the benefits of their treatment to allow them to make informed decisions.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3. years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain. © 2011 Elsevier Inc.

Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97).Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE.On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p0.001).Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age.

Purpose: In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230). Methods: The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child's mother had epilepsy and to antiepileptic drug type. Results: Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child's overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ. Discussion: Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary. © 2010 International League Against Epilepsy.