The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Neurodevelopment of babies born to mothers with epilepsy: A prospective observational cohort study.

OBJECTIVE: Despite widespread monotherapy use of lamotrigine or levetiracetam during pregnancy, prospectively collected, blinded child development data are still limited. The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study prospectively recruited a new cohort of women with epilepsy and their offspring for longitudinal follow-up. METHODS: Pregnant women of <21 weeks gestation (n = 401) were recruited from 21 hospitals in the UK. Data collection occurred during pregnancy (recruitment, trimester 3) and at 12 and 24 months of age. The primary outcome was blinded assessment of infant cognitive, language, and motor development on the Bayley Scales of Infant and Toddler Development (3rd edition) at 24 months of age with supplementary parent reporting on the Vinelands Adaptive Behavior Scales (2nd edition). RESULTS: There were 394 live births, with 277 children (70%) completing the Bayley assessment at 24 months. There was no evidence of an association of prenatal exposure to monotherapy lamotrigine (-.74, SE = 2.9, 95% confidence interval [CI] = -6.5 to 5.0, p = .80) or levetiracetam (-1.57, SE = 3.1, 95% CI = -4.6 to 7.7, p = .62) with poorer infant cognition, following adjustment for other maternal and child factors in comparison to nonexposed children. Similar results were observed for language and motor scores. There was no evidence of an association between increasing doses of either lamotrigine or levetiracetam. Nor was there evidence that higher dose folic acid supplementation (≥5 mg/day) or convulsive seizure exposure was associated with child development scores. Continued infant exposure to antiseizure medications through breast milk was not associated with poorer outcomes, but the number of women breastfeeding beyond 3 months was low. SIGNIFICANCE: These data are reassuring for infant development following in utero exposure to monotherapy lamotrigine or levetiracetam, but child development is dynamic, and future follow-up is required to rule out later emerging effects.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required. OBJECTIVES: To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child. SEARCH METHODS: For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy. DATA COLLECTION AND ANALYSIS: Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases. AUTHORS' CONCLUSIONS: Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.

ANTECEDENTES: La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC. OBJETIVOS: Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa. RESULTADOS PRINCIPALES: De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médicos fueron limitados. En cuanto a la exposición a la fenitoína, la prevalencia de MCG fue elevada en los datos de los estudios de cohortes (5,4%; IC del 95%: 3,6 a 8,1) y en los datos rutinarios de los historiales médicos (6,8%; IC del 95%: 0,1 a 701,2). La prevalencia de MCG fue mayor en los niños expuestos a la fenitoína en comparación con los hijos de mujeres sin epilepsia (RR 3,81; IC del 95%: 1,91 a 7,57) y los hijos de mujeres con epilepsia que no reciben tratamiento (RR 2,01; IC del 95%: 1,29 a 3,12); no hubo datos procedentes de estudios con datos rutinarios de los historiales médicos. Los datos agrupados de los estudios de cohortes indicaron un riesgo significativamente mayor de MCG en los niños expuestos a lamotrigina en comparación con los niños nacidos de mujeres sin epilepsia (RR 1,99; IC del 95%: 1,16 a 3,39); con una diferencia de riesgos (DR) que indica un riesgo 1% mayor de MCG (DR 0,01. IC del 95%: 0,00 a 0,03). Esto no se repitió en la comparación con los hijos de las mujeres con epilepsia que no reciben tratamiento (RR 1,04; IC del 95%: 0,66 a 1,63), que contenía el mayor grupo de niños expuestos a la lamotrigina (> 2700). Además, también se encontró una diferencia no significativa tanto en comparación con los hijos de mujeres sin epilepsia (RR 1,19; IC del 95%: 0,86 a 1,64) como con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,00; IC del 95%: 0,79 a 1,28) a partir de los estudios con datos rutinarios. Para la exposición al levetiracetam, los datos agrupados proporcionaron razones de riesgos similares a las de las mujeres sin epilepsia en los estudios de cohortes (RR 2,20; IC del 95%: 0,98 a 4,93) y en los estudios con datos rutinarios de los historiales médicos (RR 0,67; IC del 95%: 0,17 a 2,66). Los resultados agrupados de los estudios de cohortes (RR: 0,71; IC del 95%: 0,39 a 1,28) y de los estudios con datos rutinarios de los historiales médicos (RR: 0,82; IC del 95%: 0,39 a 1,71) respaldan esta afirmación cuando se comparan con los hijos de las mujeres con epilepsia que no reciben tratamiento. En el caso del topiramato, la prevalencia de MCG fue del 3,9% (IC del 95%: 2,3 a 6,5) a partir de los datos de los estudios de cohortes y del 4,1% (0,0 a 27.050,1) a partir de los estudios con datos rutinarios de los historiales médicos. Las razones de riesgos fueron significativamente más altas para los niños expuestos al topiramato en comparación con los hijos de mujeres sin epilepsia en estudios de cohortes (RR 4,07; IC del 95%: 1,64 a 10,14), pero no en una comparación más pequeña con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,37; IC del 95%: 0,57 a 3,27); actualmente se dispone de pocos datos a partir de estudios con datos rutinarios de los historiales médicos. La exposición en el útero al topiramato también se asoció con RR significativamente mayores en comparación con otros FAC para las hendiduras orofaciales. Los datos de todos las demás FAC fueron extremadamente limitados. Debido a los diseños observacionales, todos los estudios presentaron un alto riesgo de ciertos sesgos, pero los sesgos observados en los estudios de obtención de datos primarios y el uso secundario de historiales médicos rutinarios fueron diferentes y, en parte, complementarios. Los sesgos estaban equilibrados entre los FAC investigados, y es poco probable que los resultados diferenciales observados entre los FAC se expliquen únicamente por estos sesgos. CONCLUSIONES DE LOS AUTORES: La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

Neurodevelopmental outcomes in children exposed to newer antiseizure medications: A systematic review.

As prenatal exposure to certain older antiseizure medications (ASMs) has been linked with poorer neurodevelopmental outcomes in children, the use of newer ASMs throughout pregnancy has increased. The current review aimed to delineate the impact of in utero exposure to these newer ASMs on child neurodevelopment. A systematic search of MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature Plus, and PsycINFO was conducted, limiting results to articles available in English and published after the year 2000. Studies investigating neurodevelopmental outcomes following in utero exposure to the following ASMs were eligible for inclusion in the review: eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, topiramate, and zonisamide. Thirty-five publications were identified, and a narrative synthesis was undertaken. Methodological quality was variable, with distinct patterns of strengths/weaknesses attributable to design. Most studies examined lamotrigine exposure and reported nonsignificant effects on child neurodevelopment. Comparatively fewer high-quality studies were available for levetiracetam, limiting conclusions regarding findings to date. Data for topiramate, gabapentin, and oxcarbazepine were so limited that firm conclusions could not be drawn. Concerningly, no studies investigated eslicarbazepine, lacosamide, perampanel, or zonisamide. Exposure to certain newer ASMs, such as lamotrigine and levetiracetam, does not thus far appear to impact certain aspects of neurodevelopment, but further delineation across the different neurodevelopmental domains and dosage levels is required. A lack of data cannot be inferred to represent safety of newer ASMs, which are yet to be investigated.

Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: The NEAD prospective observational study.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

Changing antiepilepsy drug-prescribing trends in women with epilepsy in the UK and Ireland and the impact on major congenital malformations.

OBJECTIVES: After 20 years of data collection, pregnancy registers have informed prescribing practice. Various populations show trends for a reduction in valproate prescribing, which is associated with an increased risk of anatomical teratogenesis and neurodevelopmental effects in those exposed in utero. Our aim was to determine if any shifts in prescribing trends have occurred in the UK and Ireland Epilepsy and Pregnancy Register cohort and to assess if there had been any change in the overall major congenital malformation (MCM) rate over time. METHODS: The UK and Ireland Epilepsy and Pregnancy Register, a prospective, observational, registration and follow-up study established in 1996, was used to determine the changes in antiepileptic drugs (AEDs) utilised during pregnancy and the MCM rate between 1996 and 2016. Linear regression analysis was used to assess changes in AED utilisation, and Poisson regression was used for the analysis of trends in the MCM rates. RESULTS: Outcome data for 9247 pregnancies showed a stable percentage of monotherapy to polytherapy prescribing habits over time. After Bonferroni correction, statistically significant (p<0.003) changes were found in monotherapy prescribing with increases in lamotrigine and levetiracetam and decreases in valproate and carbamazepine use. Between 1996 and 2016, the total MCM rate showed a 2.1% reduction per year (incidence risk ratio 0.979 (95% CIs 0.956 to 1.002) but Poisson regression analysis showed that this was not statistically significant p=0.08). CONCLUSION: Significant changes are seen in the prescribing habits in this cohort over 20 years, but a statistically significant change in the MCM rate was not detected. This work should be replicated on a larger scale to determine if significant changes are occurring in the MCM rate, which would allow a robust economic estimate of the benefits of improvements in prescribing practice and the personal effect of such changes.

Maternal Use of Antiepileptic Agents During Pregnancy and Major Congenital Malformations in Children.

CLINICAL QUESTION: Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children? BOTTOM LINE: Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available. OBJECTIVES: To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference abstracts (2010-2015) without language restriction. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. DATA COLLECTION AND ANALYSIS: Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: We included 50 studies, with 31 contributing to meta-analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random-effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro-facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose-response association for the other AEDs remained less clear. AUTHORS' CONCLUSIONS: Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.

Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child.

BACKGROUND: Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy. OBJECTIVES: To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies. SELECTION CRITERIA: Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. DATA COLLECTION AND ANALYSIS: Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible. MAIN RESULTS: Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of -5.58 (95% confidence interval (CI) -10.83 to -0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD -7.22, 95% CI -12.76 to - 1.67, P = 0.01). Further analysis using a random-effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD -0.03, 95% CI -3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI -2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD -8.72, 95% -14.31 to -3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD -8.94, 95% CI -11.96 to -5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD -8.17, 95% CI -12.80 to -3.55, P = 0.0005).In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI -0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD -1.62, 95% CI -5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI -2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD -3.30, 95% CI -7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses. AUTHORS' CONCLUSIONS: The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy.

Importance: Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child. Objective: To examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children. Design, Setting, and Participants: This prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023. Exposure: Redeemed prescription for an ASM from 30 days before pregnancy until birth. Main Outcomes and Measures: The main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses. Results: This cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05). Conclusions and Relevance: In this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child's risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs.

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.

Exposure to medication for neurological disease in pregnancy - time to consider the long-term implications?

A range of long-term neurological conditions may be diagnosed in young adulthood. These conditions are generally not curable, and most people need to take ongoing treatment for symptom control and/or disease modification. When chronic diseases are diagnosed before people have completed their families, there is a need to balance the potential benefits of treatment for the mother against potential risk(s) to the fetus from exposure to medications during pregnancy. Whilst available data regarding short-term fetal outcomes following treatment exposures during pregnancy is rapidly increasing, information regarding longer-term outcomes is more limited. The association of fetal exposure to valproate with serious long-term neurodevelopmental outcomes has highlighted the importance of capturing and evaluating long-term data. In this review we examine available evidence around the long-term effects of treatments used for the most common long-term neurological conditions diagnosed in early adulthood, namely epilepsy, migraine and neuroinflammatory disorders. We draw from existing literature across a range of diseases and discuss strategies to improve future knowledge.

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods: Recommendations from the IMI ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities. METHODS: This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems. RESULTS: The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde ). DISCUSSION: With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.

An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION project.

BACKGROUND: Studies on medication safety in pregnancy are increasingly focusing on child neurodevelopmental outcomes. Establishing neurodevelopmental safety is complex due to the range of neurodevelopmental outcomes and the length of follow-up needed for accurate assessment. The aim of this study was to provide an inventory of European data sources for use in pharmacoepidemiologic studies investigating neurodevelopment following maternal medication exposure. METHOD: The EUROmediSAFE inventory of data sources in Europe for evaluating perinatal and long-term childhood risks associated with in-utero exposure to medication was updated by contacting colleagues across 31 European countries, literature review and internet searches. Included data sources must record at least one neurodevelopmental outcome and maternal medication use in pregnancy must be available, either in the data source itself or through linkage with another data source. Information on the domain of neurodevelopment, measure/scale used and the approach to measurement were recorded for each data source. RESULTS: Ninety data sources were identified across 14 countries. The majority (63.3%) were created for health surveillance and research with the remaining serving administrative purposes (21.1% healthcare databases,15.6% other administrative databases). Five domains of neurodevelopment were identified-infant development (36 data sources,13 countries), child behaviour (27 data sources, 10 countries), cognition (29 data sources, 12 countries), educational achievement (20 data sources, 7 countries), and diagnostic codes for neurodevelopmental disorders (42 data sources, 11 countries). Thirty-nine data sources, in 12 countries, had information on more than one domain of neurodevelopment. CONCLUSION: This inventory is invaluable to future studies planning to investigate the neurodevelopmental impact of medication exposures during pregnancy. Caution must be used when combining varied approaches to neurodevelopment outcome measurement, the age of children in the data source, and the sensitivity and specificity of the outcome measure selected should be borne in mind.

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

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.

Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert.

BACKGROUND: The pharmacoepidemiology of the long-term benefits and harms of medicines in pregnancy and breastfeeding has received little attention. The impact of maternal medicines on children is increasingly recognised as a source of avoidable harm. The focus of attention has expanded from congenital anomalies to include less visible, but equally important, outcomes, including cognition, neurodevelopmental disorders, educational performance, and childhood ill-health. Breastfeeding, whether as a source of medicine exposure, a mitigator of adverse effects or as an outcome, has been all but ignored in pharmacoepidemiology and pharmacovigilance: a significant 'blind spot'. WHOLE-POPULATION DATA ON BREASTFEEDING: WHY WE NEED THEM: Optimal child development and maternal health necessitate breastfeeding, yet little information exists to guide families regarding the safety of medicine use during lactation. Breastfeeding initiation or success may be altered by medicine use, and breastfeeding may obscure the true relationship between medicine exposure during pregnancy and developmental outcomes. Absent or poorly standardised recording of breastfeeding in most population databases hampers analysis and understanding of the complex relationships between medicine, pregnancy, breastfeeding and infant and maternal health. The purpose of this paper is to present the arguments for breastfeeding to be included alongside medicine use and neurodevelopmental outcomes in whole-population database investigations of the harms and benefits of medicines during pregnancy, the puerperium and postnatal period. We review: 1) the current situation, 2) how these complexities might be accommodated in pharmacoepidemiological models, using antidepressants and antiepileptics as examples; 3) the challenges in obtaining comprehensive data. CONCLUSIONS: The scarcity of whole-population data and the complexities of the inter-relationships between breastfeeding, medicines, co-exposures and infant outcomes are significant barriers to full characterisation of the benefits and harms of medicines during pregnancy and breastfeeding. This makes it difficult to answer the questions: 'is it safe to breastfeed whilst taking this medicine', and 'will this medicine interfere with breastfeeding and/ or infants' development'?

Cognitive and neurodevelopmental effects of antiepileptic drugs.

This article primarily represents the contributions of two young investigators to the understanding of the neuropsychological consequences of epilepsy and its treatment. The authors have reviewed two key areas of importance: the complex relationship between cognitive dysfunction and epilepsy and the risks of cognitive dysfunction in children as a consequence of in utero exposure to antiepileptic drug treatment. The work of two young investigators is presented and future research needs are outlined.

Prenatal exposure to anti-epileptic drugs: the need for preconception counselling.

There is accumulating evidence that prenatal exposure to antiepileptic drugs (AEDs) poses an increased risk to the fetus. There is robust evidence surrounding the incidence of major congenital malformations following exposure to some commonly prescribed AEDs, and growing evidence that prenatal exposure to certain AEDs is also associated with a reduction in cognitive functioning and an increase in neurodevelopmental disorders in childhood. This article discusses some of the findings in regards to pregnancy outcome after exposure to AEDs, the possible implications for the child and, given recent findings, the need for preconception counselling for women with epilepsy of childbearing potential.

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review.

Exposure in the womb to antiseizure medications and their potential impact on the brain of the developing child has long been researched. Despite this long period of interest, this review highlights that above the well-known risks associated with valproate exposure, there are more data required for conclusions regarding all other antiseizure medications. Limited experience with phenytoin and phenobarbital in monotherapy makes clearly defining the risk to later child postnatal functioning difficult, although the evidence of an impact is stronger for phenobarbital than for phenytoin. The widely prescribed lamotrigine is limited in its investigation in comparison to unexposed control children, and whilst it has been demonstrated to carry a lower risk than valproate for certain outcomes, whether it is associated with a more moderate impact on wider aspects of neurodevelopmental functioning is still to be understood. Data for levetiracetam, topiramate and oxcarbazepine are too limited to confidently draw conclusions for most neurodevelopmental outcomes. This slow accumulation of evidence impacts on the safest use of medications in pregnancy and makes counseling women regarding the risks and benefits of specific antiseizure medications difficult. Improved focus, funding, and research methodologies are urgently needed.