Adaptive behaviour in children exposed to topiramate in the womb: An observational cohort study

Knight, Rebecca A.; Craig, John; Irwin, B.; Wittkowski, Anja; Bromley, Rebecca

doi:10.1016/j.seizure.2023.01.008

Cited by 19 publications

(15 citation statements)

References 23 publications

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“…In that study, the associations of prenatal topiramate exposure with ASD and intellectual disability were slightly stronger than in the current study (and reached statistical significance), which is explained by the former study applying a narrower exposure window (ie, not including the 30 days before the last menstrual period), which will tend to increase HRs due to higher specificity of exposure classification (but lower sensitivity) . Findings from the 2 SCAN-AED studies contrast a few prior studies reporting no reductions in child cognitive abilities and no increased risk of neurodevelopmental disorders associated with prenatal topiramate exposure but align with a few others . More evidence is therefore needed, but our findings strengthen the increasing concerns about the use of topiramate in pregnancy.…”

Section: Discussioncontrasting

confidence: 83%

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders

et al. 2023

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ImportancePrenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.ObjectiveTo examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy.Design, Setting, and ParticipantsThis prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023.ExposuresPrenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth.Main Outcomes and MeasuresThe main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported.ResultsAmong the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07).Conclusions and RelevanceFindings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.

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Section: Discussioncontrasting

confidence: 83%

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders

et al. 2023

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“…This could be achieved through updates to the ICH-E2BR3 data standards [ 57 ], with these CDE recommendations providing a valuable basis for the development of pregnancy optimised clinical trial databases. This would align with the current work plan and recognition of the importance of including pregnant women in clinical trials [ 22 , 53 , 58 ].…”

Section: Discussionmentioning

confidence: 77%

“…Many PregPV systems are not structured to investigate longer-term child health or neurodevelopmental outcomes. Recently, experts within the field have recommended the inclusion of child neurodevelopment outcomes more centrally, to reduce the latency between a medication's approval and the development of conclusive evidence regarding neurodevelopmental risk [22]. Child health and neurodevelopmental outcomes are numerous, can vary over time, and can be investigated to different levels of sensitivity.…”

Section: Longer-term Child Health and Neurodevelopmental Outcome Detailsmentioning

confidence: 99%

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

et al. 2023

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Introduction and ObjectiveThe risks and benefits of medication use in pregnancy are typically established through postmarketing 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. ResultsThe 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.

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“…Raw scores were converted into age-adjusted standard scores (mean = 100, SD = 15). 27 The Vinelands has been demonstrated to be sensitive to the pattern of difficulties that can be associated with in utero exposure to ASMs 17,32 and was conducted by one of three interviewers blinded to the exposure group. Breastfeeding information was collected from maternal report at 12 months or at the 24-month visit, if contact had not been made at 12 months.…”

Section: Methodsmentioning

confidence: 99%

“…Both valproate and phenobarbital convey an increased risk of neurodevelopmental difficulties, including reduced intelligence quotient (IQ) 5–9 and language functioning, 10,11 with an increased rate of autistic spectrum disorder 12–14 and attention‐deficit/hyperactivity disorder 15 for valproate exposure. Recently, evidence of neurodevelopmental risk following topiramate has also been presented 16,17 . Prescribing practices have shifted in the past two decades, and use of lamotrigine and levetiracetam has increased internationally 1 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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ObjectiveDespite 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.MethodsPregnant 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).ResultsThere 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.SignificanceThese 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.

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Adaptive behaviour in children exposed to topiramate in the womb: An observational cohort study

Cited by 19 publications

References 23 publications

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders

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

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

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