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. 2023 Jun 1;80(6):568-577.
doi: 10.1001/jamaneurol.2023.0674.

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

Julie Werenberg Dreier  1   2 , Marte-Helene Bjørk  2   3 , Silje Alvestad  2   4 , Mika Gissler  5   6   7 , Jannicke Igland  8   9 , Maarit K Leinonen  5 , Yuelian Sun  1   10   11   12 , Helga Zoega  13   14 , Jacqueline M Cohen  15   16 , Kari Furu  15   16 , Torbjörn Tomson  17 , Jakob Christensen  1   10   12
Affiliations

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

Julie Werenberg Dreier et al. JAMA Neurol. .

Abstract

Importance: Prenatal 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.

Objective: To 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 participants: This 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.

Exposures: Prenatal 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 measures: The 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.

Results: Among 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 relevance: Findings 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bjørk reported receiving fees paid to her institution by valproate market authorization holders for EMA-mandated contract research; personal fees from Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, Teva, Lilly, and Lundbeck; and grants from the Research Council of Norway outside the submitted work. Dr Alvestad reported receiving speaker honoraria from Eisai. Dr Igland reported receiving support for contracted research from Pfizer (drug utilization study) and from Sanofi (PASS study) outside the submitted work. Dr Leinonen reported receiving grants from Innovative Medicines Initiative, IMI ConcePTION, and Finnish Medicines Agency outside the submitted work. Dr Zoega reported receiving grants from AbbVie Australia and being employed by the Centre for Big Data Research in Health, University of New South Wales, Sydney, which received funding from AbbVie Australia to conduct research unrelated to this study. Dr Cohen reported receiving grants from the Research Council of Norway during the conduct of the study. Dr Furu reported receiving grants from the Research Council of Norway during the conduct of the study. Dr Tomson reported receiving grant support to the International Registry of Antiepileptic Drugs and Pregnancy from Eisai, GSK, UCB, Bial, Sanofi, Teva, GW Pharma, and Angelini Pharma and personal fees from Sanofi, Sun Pharma, Arvelle, GW Pharma, Eisai, and UCB outside the submitted work. Dr Christensen reported receiving honoraria from UCB Nordic and personal fees from Eisai during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cumulative Incidence of the Combined Psychiatric End Point According to Prenatal Antiseizure Medication (ASM) Exposure
The cumulative incidence curves are unadjusted. Different lengths of the curves reflect differences in available follow-up data for the ASMs. NA indicates not applicable.
Figure 2.
Figure 2.. Hazard Ratios (HRs) of Psychiatric Disorders According to Maternal Antiseizure Medication (ASM) Use in Pregnancy for Valproate, Lamotrigine, Levetiracetam, and Carbamazepine Monotherapies
The HRs are adjusted for sex of the child, maternal age, parity, educational level, smoking in pregnancy, use of antidepressants in pregnancy, and maternal psychiatric comorbidity, with separate baseline hazards for country and year of birth. ADHD indicates attention-deficit/hyperactivity disorder; NA, not applicable; ODD/CD, oppositional defiant disorder and conduct disorder.
Figure 3.
Figure 3.. Hazard Ratios (HRs) of Psychiatric Disorders According to Maternal Antiseizure Medication (ASM) Use in Pregnancy for Clonazepam Monotherapy, Polytherapy Without Valproate, and Polytherapy With Valproate
Associations are not shown for pregabalin and gabapentin because of insufficient numbers. The HRs are adjusted for sex of the child, maternal age, parity, educational level, smoking in pregnancy, use of antidepressants in pregnancy, and maternal psychiatric comorbidity, with separate baseline hazards for country and year of birth. ADHD indicates attention-deficit/hyperactivity disorder; NA, not applicable; ODD/CD, oppositional defiant disorder and conduct disorder.
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