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

Julie Werenberg Dreier; Marte-Helene Bjørk; Silje Alvestad; Mika Gissler; Jannicke Igland; Maarit K Leinonen; Yuelian Sun; Helga Zoega; Jacqueline M Cohen; Kari Furu; Torbjörn Tomson; Jakob Christensen

doi:10.1001/jamaneurol.2023.0674

. 2023 Apr 17;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

¹National Centre for Register-Based Research, School of Business and Social Science, Aarhus University, Aarhus, Denmark

²Department of Clinical Medicine, University of Bergen, Bergen, Norway

³Department of Neurology, Haukeland University Hospital, Bergen, Norway

⁴National Center for Epilepsy, Oslo University Hospital, Oslo, Norway

⁵Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland

⁶Region Stockholm, Academic Primary Health Care Centre, Stockholm, Sweden

⁷Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden

⁸Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

⁹Department of Health and Caring Sciences, Western Norway University of Applied Sciences, Bergen

¹⁰Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

¹¹Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

¹²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

¹³School of Population Health, Faculty of Medicine & Health, University of New South Wales, Sydney, Australia

¹⁴Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland

¹⁵Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway

¹⁶Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

¹⁷Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Accepted for Publication: February 10, 2023.

Published Online: April 17, 2023. doi:10.1001/jamaneurol.2023.0674

^✉

Corresponding author: Julie Werenberg Dreier, PhD, National Centre for Register-Based Research, School of Business and Social Science, Aarhus University, Fuglesangs Allé 26, 8210 Aarhus V, Denmark (jwdreier.ncrr@au.dk).

Author Contributions: Drs Dreier and Igland had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Dreier, Bjørk, Alvestad, Igland, Sun, Zoega, Cohen, Furu, Tomson, Christensen.

Acquisition, analysis, or interpretation of data: Dreier, Bjørk, Alvestad, Gissler, Igland, Leinonen, Sun, Zoega, Cohen, Furu, Christensen.

Drafting of the manuscript: Dreier, Christensen.

Critical revision of the manuscript for important intellectual content: Bjørk, Alvestad, Gissler, Igland, Leinonen, Sun, Zoega, Cohen, Furu, Tomson, Christensen.

Statistical analysis: Dreier, Igland.

Obtained funding: Dreier, Bjørk, Zoega, Furu, Tomson, Christensen.

Administrative, technical, or material support: Bjørk, Gissler, Zoega, Cohen, Furu, Christensen.

Supervision: Gissler, Christensen.

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.

Funding/Support: This work was funded by grants 83796 (Drs Gissler, Leinonen, Zoega, and Furu) and 83539 (Drs Bjørk, Gissler, Leinonen, Tomson, and Christensen) from the NordForsk Nordic Program on Health and Welfare and grant 1133-00026B from the Independent Research Fund Denmark (Dr Dreier).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC10111234 PMID: 37067807

Key Points

Question

What are the associations between prenatal exposure to antiseizure medications and psychiatric disorders with onset in childhood and adolescence?

Findings

In this cohort study of 38 661 children of mothers with epilepsy, prenatal valproate exposure was associated with an increased risk of psychiatric disorders. 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 and levetiracetam with attention-deficit/hyperactivity disorder.

Meaning

This study strengthens the evidence for the warning against the use of valproate in pregnancy, supports concerns about the use of topiramate, and provides a preliminary indication for caution with the use of levetiracetam in pregnancy.

This cohort study of children of mothers with epilepsy examines whether prenatal exposure to common prenatal antiseizure medication is associated with a broad spectrum of psychiatric disorders in childhood and adolescence.

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.

Introduction

The use of antiseizure medication (ASM) among pregnant women has increased during recent decades, and today between 0.5% and 2% of all children are born to women using ASMs during pregnancy.¹ In pregnancy, ASMs are used mainly for epilepsy but may be prescribed for other indications, such as mood disorders, migraine, and neuropathic pain.^2,3

There are increasing concerns of adverse effects in offspring after prenatal ASM exposure. The evidence of harm is most definitive for valproate⁴ and shows increased risk of congenital anomalies⁵ and adverse neurodevelopment, including autism spectrum disorder (ASD),^6,7,8,9,10 attention-deficit/hyperactivity disorder (ADHD),^7,11,12 and impaired cognitive function.^{9,10,13,14,15,16,17,18} Other ASMs influence fetal growth and development,¹⁹ yet our understanding of the potential link with psychiatric disorders in childhood is limited. Even in studies^6,11,17,18 based on nationwide cohorts, data are insufficient to examine associations with less frequently used ASMs, warranting studies combining data from multiple countries. Current evidence is further limited to some neurodevelopmental outcomes, such as ASD and intellectual disability, but it is unclear whether the potential adverse behavioral effects of prenatal ASM exposure is limited to these end points. To inform clinicians and patients about the potential risks, there is a need to systematically compare different ASMs with respect to a broader spectrum of psychiatric disorders. In this Nordic cohort study of more than 38 000 children of mothers with epilepsy, we examined the association between prenatal exposure to common ASMs with a broad spectrum of psychiatric disorders in childhood and adolescence.

Methods

Study Design, Setting, and Population

We performed a prospective, population-based register study within the SCAN-AED project, which is a study of ASM teratogenicity based on children born in Denmark, Finland, Iceland, Norway, and Sweden. The SCAN-AED cohort was established by pooling and harmonizing individual-level data from the nationwide health and social registers from each of the 5 countries. This process was possible because of the similarity of the structure and contents of the registers and included data on all births (medical birth registers), maternal and child diagnoses (patient and hospital registers), dispensed prescription medications (prescription registers), vital status and place of residence (population registers), and socioeconomic measures (eg, education registers). Accurate linkage between the registers was ensured using a unique personal identification number. The relevant ethical and/or data protection authorities in all countries approved the project and granted a waiver of informed consent because no informed consent is required for a register-based study using anonymized data according to legislation in the Nordic countries. None of the participants received a stipend. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

This study was based on live-born singleton children of mothers with epilepsy in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2005-2017), and Sweden (2006-2017) for the years with full coverage of all relevant registers (eFigure in Supplement 1). Maternal epilepsy was defined by a hospital contact with epilepsy before birth (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes G40-G41, all countries), use of ASM with epilepsy as an indication or reason for reimbursement before birth (Denmark since 2004, Norway, and Finland), or any registered diagnosis of epilepsy in the Medical Birth Register (all countries except Denmark) (eTable 1 in Supplement 1).

Maternal Use of ASM in Pregnancy

Information on use of ASM was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code. Children were considered prenatally exposed to ASM if the mother had redeemed 1 or more prescriptions for medications with ATC codes N03A (ASM), N05BA09 (clobazam), or S01EC01 (acetazolamide, data not available from Finland) during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. We defined monotherapy with valproate, lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, topiramate, clonazepam, pregabalin, and gabapentin as having redeemed 1 or more prescriptions for that specific ASM and no other prescriptions for ASMs in the exposure window. We defined polytherapy as having redeemed 1 or more prescriptions for 2 or more different ASMs during the exposure window and divided polytherapy into combinations with and without valproate. This definition did not distinguish between true polytherapy and those switching from one ASM to another, but even among switchers, transitional polytherapy is often necessary in the up-titration and tapering phase.

Child Psychiatric Disorders

Information on psychiatric disorders was retrieved from the patient registers, which contain diagnostic information from inpatient admissions and outpatient visits in specialist care. We considered the children to have a psychiatric or neurodevelopmental disorder if they were registered with any main or secondary diagnosis from the ICD-10 F-chapter (excluding F00-09) and classified disorders further into 13 groups²⁰ (eTable 2 in Supplement 1). For the combined psychiatric end point and for each subgroup, we defined the date of onset as the first day of the first inpatient or outpatient contact with that disorder.

Statistical Analysis

The children were followed up from birth until onset of the psychiatric disorder of interest, death, emigration, or the end of follow-up, whichever came first. We estimated 3 main measures of the risk of psychiatric disorders associated with prenatal ASM exposure: (1) incidence rates expressed as the number of affected children per 10 000 person-years, (2) hazard ratios (HRs) as relative risk measures of the association between prenatal ASM exposure and psychiatric disorders, and (3) cumulative incidences of psychiatric disorders across age, as an absolute measure of risk. Because this study was considered explorative, we did not adjust for multiple testing, but all main analyses were prespecified. Data analysis was performed from August 2021 to January 2023.

The HRs and corresponding 95% CIs were estimated using Cox proportional hazards regression models. Age of the child was used as the underlying time scale, and we allowed for separate baseline diagnostic rates of psychiatric disorders (stratum) for each country and year of birth to account for country-wise differences in diagnostic practices and calendar period effects. The reference group was children of mothers with epilepsy unexposed to any ASM during the exposure window. We adjusted the HRs for sex of the child, smoking in pregnancy, use of antidepressants (ATC code N06A) in pregnancy, and maternal characteristics assessed at the time of birth (age, parity, highest level of completed education, and psychiatric comorbidity). Missing information on covariates was generally limited (range, 0%-3%), except for maternal smoking status (range, 6%-8%). For maternal smoking, we therefore included a separate missing category and otherwise performed complete case analyses. Proportionality of hazards was assessed visually using log minus log plots.

The cumulative incidence of psychiatric disorders was estimated using a nonparametric approach based on the subdistribution hazards, with death and emigration as competing events.²¹ The cumulative incidence can be interpreted as the risk of being diagnosed with a psychiatric disorder within a given period.

To identify potential heterogeneity across countries, we performed country-wise analyses of any ASM exposure with each of the psychiatric outcomes. Because of the low number of children in many exposure-outcome combinations, the country-specific analyses were not restricted to children of mothers with epilepsy.

Several sensitivity analyses were performed. First, we restricted the population to children of mothers with active epilepsy, defined as a hospital contact with epilepsy or a prescription for antiseizure medication for epilepsy within 1 year before pregnancy and until birth. Second, children of mothers who redeemed only 1 prescription for ASMs during the exposure window were reclassified as unexposed. Third, we applied a minimum age criterion for each psychiatric end point.²²

Results

We identified 38 661 children of mothers with epilepsy (19 852 [51.3%] male and 18 809 [48.7%] female), who were followed up to 22 years of age (mean [SD] age, 7.5 [4.6] years; see eTable 3 in Supplement 1 for length of follow-up by ASM exposure). In total, 16 458 children (42.6%) were prenatally exposed to ASM, and the maternal and pregnancy characteristics of the children are given in Table 1. Prenatal ASM exposure was associated with higher maternal educational attainment and lower levels of maternal smoking and diagnosed psychiatric comorbidity (but slightly higher levels of antidepressant use).

Table 1. Characteristics of Children With and Without Prenatal Exposure to Antiseizure Medication (ASM), Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017).

Characteristic	Children of mothers with epilepsy		Proportion difference (95% CI) (any ASM minus no ASM)
Characteristic	No ASM (n = 22 203)	Any ASM (n = 16 458)	Proportion difference (95% CI) (any ASM minus no ASM)
Country of birth
Denmark	9383 (42.3)	4746 (28.8)	−13.4 (−14.4 to −12.5)
Finland	1225 (5.5)	4656 (28.3)	22.8 (22.0 to 23.5)
Iceland	91 (0.4)	178 (1.1)	0.7 (0.5 to 0.9)
Norway	6097 (27.5)	2950 (17.5)	−9.5 (−10.4 to −8.7)
Sweden	5407 (24.4)	3928 (23.9)	−0.5 (−1.3 to 0.4)
Year of birth
1996-1999	400 (1.8)	1049 (6.4)	4.6 (4.2 to 5.0)
2000-2004	1457 (6.6)	2071 (12.6)	6.0 (5.4 to 6.6)
2005-2009	6481 (29.2)	4788 (29.1)	−0.1 (−1.0 to 0.8)
2010-2014	8550 (38.5)	5519 (33.5)	−5.0 (−5.9 to −4.0)
2015-2017	5315 (23.9)	3031 (18.4)	−5.5 (−6.3 to −4.7)
Sex of child
Male	11 382 (51.3)	8470 (51.5)	0.2 (−0.8 to 1.2)
Female	10 821 (48.7)	7988 (48.5)	−0.2 (−1.2 to 0.8)
Maternal age, y
<20	498 (2.2)	325 (2.0)	−0.3 (−0.6 to 0.0)
20-24	3605 (16.2)	2247 (13.7)	−2.6 (−3.3 to −1.9)
25-29	6945 (31.3)	5114 (31.1)	−0.2 (−1.1 to 0.7)
30-34	6960 (31.3)	5468 (33.2)	1.9 (0.9 to 2.8)
35-39	3482 (15.7)	2739 (16.6)	1.0 (0.2 to 1.7)
40-44	677 (3.0)	545 (3.3)	0.3 (−0.1 to 0.6)
≥45	36 (0.2)	20 (0.1)	0.0 (−0.1 to 0.0)
Missing	0	0	NA
Maternal parity
0	9832 (44.3)	7658 (46.5)	2.2 (1.2 to 3.3)
1	7713 (34.7)	5567 (33.8)	−0.9 (−1.9 to 0.0)
≥2	4605 (20.7)	3138 (19.1)	−1.7 (−2.5 to −0.9)
Missing	53 (0.2)	95 (0.6)	0.3 (0.2 to 0.5)
Maternal educational level
Compulsory	5827 (26.2)	3402 (20.7)	−5.6 (−6.4 to −4.7)
Secondary or preuniversity	9509 (42.8)	7908 (48.0)	5.2 (4.2 to 6.2)
Bachelor’s degree	4231 (19.1)	3205 (19.5)	0.4 (−0.4 to 1.2)
Master’s degree or PhD	2057 (9.3)	1403 (8.5)	−0.7 (−1.3 to −0.2)
Missing	579 (2.6)	540 (3.3)	0.7 (0.3 to 1.0)
Smoking in pregnancy
No	16 823 (75.8)	12 630 (76.7)	1.0 (0.1 to 1.9)
Yes	3931 (17.7)	2590 (15.7)	−2.0 (−2.7 to −1.2)
Missing	1449 (6.5)	1238 (7.5)	1.0 (0.5 to 1.5)
Use of antidepressants in pregnancy	1631 (7.3)	1376 (8.4)	1.0 (0.5 to 1.6)

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Prenatal exposure to valproate monotherapy was associated with a 1.80-fold (95% CI, 1.60-2.03) increased risk of the combined psychiatric end point compared with no prenatal ASM exposure (Table 2). None of the other monotherapies was associated with a significantly increased risk of the combined psychiatric end point, but associations were found for polytherapy with valproate (aHR, 1.85; 95% CI, 1.56-2.18) and polytherapy without valproate (aHR, 1.32; 95% CI, 1.15-1.51) (Table 2).

Table 2. Incidence Rates, Hazard Ratios, and Cumulative Incidence at 10 and 18 Years of Age of the Combined Psychiatric End Point in Children Exposed and Unexposed to ASM During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017).

Exposure	No. of children	No. of children with psychiatric disorder	Incidence rate per 10 000 person-years (95% CI)	aHR (95% CI)		Cumulative incidence, % (95% CI)
Exposure	No. of children	No. of children with psychiatric disorder	Incidence rate per 10 000 person-years (95% CI)	Basic^a	Full^b	Age 10 y	Age 18 y
No ASM	22 203	1892	132.9 (127.1-139.0)	1 [Reference]	1 [Reference]	13.9 (13.2-14.6)	31.3 (28.9-33.6)
Any ASM^c	16 458	2201	178.9 (171.6-186.5)	1.12 (1.05-1.20)	1.17 (1.09-1.25)	17.4 (16.6-18.2)	30.8 (29.2-32.3)
Monotherapies
Valproate	1952	515	304.6 (279.4-332.1)	1.71 (1.52-1.92)	1.80 (1.60-2.03)	27.2 (24.9-29.4)	42.1 (38.2-45.8)
Lamotrigine	5288	389	117.0 (105.9-129.2)	0.87 (0.78-0.97)	0.91 (0.82-1.02)	12.4 (11.1-13.8)	24.1 (19.7-28.7)
Levetiracetam	1061	59	130.7 (101.3-168.7)	1.14 (0.87-1.48)	1.30 (0.99-1.71)	17.6 (12.2-23.8)	NA
Carbamazepine	2665	391	156.4 (141.7-172.7)	0.94 (0.83-1.07)	1.06 (0.93-1.22)	15.0 (13.4-16.7)	27.3 (24.5-30.1)
Oxcarbazepine	1460	197	144.2 (125.4-165.9)	0.78 (0.65-0.92)	0.85 (0.71-1.02)	12.3 (10.4-14.4)	27.1 (23.1-31.2)
Topiramate	290	34	182.0 (130.1-254.8)	1.31 (0.92-1.85)	1.34 (0.94-1.90)	20.4 (14.0-27.7)	NA
Clonazepam	339	64	189.0 (147.9-241.4)	1.26 (0.97-1.64)	1.08 (0.83-1.42)	15.8 (11.7-20.5)	35.1 (26.2-44.1)
Pregabalin	120	8	164.1 (82.1-328.1)	1.61 (0.80-3.26)	1.06 (0.52-2.16)	NA	NA
Gabapentin	138	16	190.6 (116.8-311.1)	1.48 (0.90-2.42)	1.30 (0.78-2.18)	NA	NA
Polytherapies
Without valproate	2092	295	205.1 (183.0-229.9)	1.33 (1.17-1.51)	1.32^d (1.15-1.51)	21.0 (18.6-23.5)	31.7 (27.5-36.0)
With valproate	822	202	311.9 (271.7-358.0)	1.86 (1.58-2.19)	1.85 (1.56-2.18)^d	28.7 (25.0-32.5)	NA^e

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Abbreviations: aHR, adjusted hazard ratio; ASM, antiseizure medication; NA, not analyzed because of low numbers or insufficient follow-up time.

^{^a}

Adjusted for year of birth, sex of the child, and country of birth.

^{^b}

Additionally adjusted for maternal age, parity, educational level, smoking in pregnancy, use of antidepressants in pregnancy, and maternal psychiatric comorbidity.

^{^c}

Numbers in monotherapy and polytherapy do not add up to any ASM exposure because the following monotherapies are not included because of low numbers: eslicarbazepine, lacosamide, acetazolamide, phenobarbital, and phenytoin.

^{^d}

The aHR for the risk of the combined psychiatric end point for polytherapy with valproate vs polytherapy without valproate was 1.39 (95% CI, 1.15-1.69).

^{^e}

Estimated based on available data up to 17 years of age (40.4%; 95% CI, 35.3%-45.5%).

Figure 1 shows the cumulative risk of psychiatric disorders across childhood and adolescence (see point estimates with 95% CIs for ages 10 and 18 years in Table 2). Children of mothers with epilepsy unexposed to ASM had a 31.3% (95% CI, 28.9%-33.6%) risk of being diagnosed with a psychiatric disorder by 18 years of age, whereas the corresponding risk was 42.1% (95% CI, 38.2%-45.8%) for valproate monotherapy exposure and 40.4% (95% CI, 35.3%-45.5%) for valproate polytherapy exposure (could only be estimated up to 17 years).

Children with prenatal valproate exposure had an increased risk of a range of early-onset disorders (Figure 2 and Figure 3), including intellectual disability (aHR, 2.70; 95% CI, 1.94-3.74), ASD (aHR, 2.45; 95% CI, 1.84-3.26), other developmental disorders (aHR, 2.76; 95% CI, 2.27-3.36), ADHD (aHR, 1.41; 95% CI, 1.10-1.81), and attachment disorder (aHR, 1.91; 95% CI, 1.15-3.18). In contrast, prenatal valproate exposure was not associated with increased risk of later-onset psychiatric disorders, such as anxiety, mood, substance use, or schizophrenia spectrum disorders. Analyses of lamotrigine and oxcarbazepine consistently identified no increased risk across the entire spectrum of psychiatric disorders studied, as did analyses of carbamazepine, with the exception of the risk of tic disorder (aHR, 1.76; 95% CI, 1.07-2.89). Analyses of levetiracetam were hampered by limited follow-up (mean [SD], 4.4 [3.1] years), but prenatal levetiracetam exposure was associated with higher rates of anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and ADHD (aHR, 1.78; 95% CI, 1.03-3.07). The number of children with prenatal exposure to topiramate was relatively low (n = 290; mean [SD] follow-up, 7.0 [3.7] years), but they had an increased risk of ADHD (aHR, 2.38; 95% CI, 1.40-4.06) and potentially of intellectual disability (aHR, 2.23; 95% CI, 0.90-5.50) and ASD (aHR, 1.93; 95% CI, 0.95-3.94).

The cumulative incidence of specific psychiatric disorders at 15 years of age by ASM exposure is shown in Table 3 (corresponding estimates at ages 10 and 18 years are provided in eTables 4 and 5 in Supplement 1). The most common disorders in children of mothers with epilepsy prenatally exposed to valproate monotherapy was other developmental disorders (including developmental disorders of speech, scholastic skills, and motor function). The cumulative incidence at 15 years was 18.2% (95% CI, 16.1%-20.3%), which was substantially higher than in children of mothers with epilepsy unexposed to ASM (4.7%; 95% CI, 4.1%-5.4%). Other disorders with elevated absolute risks in children with prenatal valproate monotherapy exposure included ADHD (9.6%; 95% CI, 7.8%-11.7%), ASD (6.8%; 95% CI, 5.4%-8.5%), and intellectual disability (5.2%; 95% CI, 4.1%-6.5%). Country-specific analyses of associations between prenatal ASM exposure and each psychiatric end point are provided in eTable 6 in Supplement 1. These analyses showed that absolute rates of psychiatric disorders varied among the 5 countries, but there was little variation in the relative risk measures (ie, the HRs ranged from 1.7 to 2.3 for the combined psychiatric end point in children with vs without prenatal ASM exposure).

Table 3. Cumulative Incidence of Psychiatric Disorders at Age 15 Years in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017)^a.

Psychiatric disorder	ASM		Monotherapies					Polytherapies
Psychiatric disorder	No (n = 22 203)	Any (n = 16 458)	Valproate (n = 1952)	Lamotrigine (n = 5288)	Carbamazepine (n = 2665)	Oxcarbazepine (n = 1460)	Clonazepam (n = 339)	Without valproate (n = 2092)	With valproate (n = 822)
Substance use	0.0 (0.0-0.1)	0.2 (0.1-0.4)	NA	NA	NA	NA	NA	NA	NA
Schizophrenia spectrum	0.7 (0.4-1.2)	0.5 (0.3-0.8)	NA	NA	NA	NA	NA	NA	NA
Mood	1.5 (1.0-2.2)	2.4 (1.9-3.1)	1.7 (0.9-2.9)	NA	3.0 (2.0-4.4)	3.5 (2.1-5.6)	NA	NA	NA
Anxiety	8.6 (7.6-9.8)	8.4 (7.6-9.3)	8.3 (6.5-10.4)	8.9 (6.5-11.6)	7.5 (6.0-9.3)	6.1 (4.2-8.4)	8.1 (4.5-13.1)	9.2 (6.9-11.9)	13.8 (10.2-17.9)
Eating	0.5 (0.3-0.8)	0.5 (0.3-0.7)	NA	NA	NA	NA	NA	NA	NA
Personality	0.3 (0.1-0.7)	0.3 (0.2-0.5)	NA	NA	NA	NA	NA	NA	NA
Intellectual disability	2.3 (1.9-2.8)	3.1 (2.7-3.5)	5.2 (4.1-6.5)	2.1 (1.2-3.4)	NA	2.5 (1.5-3.8)	NA	3.8 (2.4-5.5)	6.4 (4.4-9.0)
ASD	4.0 (3.4-4.7)	4.2 (3.7-4.8)	6.8 (5.4-8.5)	4.2 (2.8-6.1)	2.4 (1.7-3.2)	2.9 (1.9-4.2)	NA	4.3 (3.0-5.9)	7.7 (5.4-10.6)
Other developmental disorder	4.7 (4.1-5.4)	8.6 (8.0-9.3)	18.2 (16.1-20.3)	NA	7.2 (6.0-8.5)	5.8 (4.5-7.4)	NA	10.2 (8.3-12.4)	19.9 (16.3-23.7)
ADHD	7.9 (7.1-8.8)	7.5 (6.8-8.2)	9.6 (7.8-11.7)	5.9 (4.5-7.6)	5.7 (4.5-7.1)	6.4 (4.8-8.3)	9.7 (5.8-14.7)	8.3 (6.3-10.6)	8.2 (5.8-11.1)
ODD/CD	1.9 (1.5-2.4)	1.6 (1.3-2.0)	NA	NA	NA	2.4 (1.4-3.7)	NA
Attachment disorder	1.3 (1.0-1.7)	1.5 (1.2-1.8)	1.9 (1.2-2.9)	NA	NA	NA	NA	NA	NA
Tic disorder	1.7 (1.3-2.1)	1.6 (1.3-1.9)	1.6 (1.0-2.5)	NA	1.8 (1.2-2.6)	NA	NA
Any psychiatric disorder	22.8 (21.5-24.2)	25.0 (23.9-26.1)	34.8 (31.9-37.6)	19.7 (17.0-22.6)	22.3 (20.1-24.6)	20.2 (17.3-23.3)	22.5 (17.1-28.5)	27.8 (24.4-31.3)	38.5 (33.7-43.3)

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Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CD, conduct disorder; NA, not analyzed and estimated for combinations with fewer than 20 exposed cases or with insufficient follow-up (children with prenatal exposure to levetiracetam, topiramate, gabapentin, and pregabalin are consequently not included); ODD, oppositional defiant disorder.

^{^a}

The age of 15 years was chosen for balance, on one hand providing estimates for adolescent-onset disorders and on the other hand ensuring sufficient follow-up data for as many ASMs as possible. Estimates at ages 10 and 18 years are provided in eTables 3 and 4 in Supplement 1.

Restricting the population to 25 139 children of mothers with active epilepsy, of whom 15 378 (61.2%) were prenatally exposed to ASM, did not substantially change associations with the combined psychiatric end point, with the exception of the association with topiramate, which was stronger (aHR, 1.60; 95% CI, 1.11-2.29), and the association with levetiracetam (aHR, 1.38; 95% CI, 1.03-1.84), which reached statistical significance (eTable 7 in Supplement 1). Requiring at least 2 redeemed prescriptions did not meaningfully change the associations with each of the 9 ASM monotherapies (eTable 8 in Supplement 1), but the association with levetiracetam reached statistical significance (aHR, 1.35; 95% CI, 1.02-1.79). Finally, only negligible changes in associations were observed when a lower age limit was applied for each of the 13 psychiatric disorders (eTable 9 in Supplement 1).

Discussion

In this large population-based cohort with up to 22 years of follow-up, we estimated the absolute and relative risk of a broad spectrum of psychiatric disorders in childhood and adolescence associated with prenatal ASM exposure among children of mothers with epilepsy. Our findings strengthen the evidence for the warning against the use of valproate in pregnancy, support concerns about the use of topiramate, and raise some concern about levetiracetam. For pregnant women with epilepsy, the results reassuringly indicate that prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine are associated with little or no long-term behavioral or developmental problems in their children.

Children with prenatal valproate exposure faced an absolute risk of being diagnosed with a psychiatric disorder that exceeded 40% by the age of 18 years, mainly driven by a marked excess of neurodevelopmental disorders. These findings strengthen previous evidence of the association between prenatal valproate exposure and risk of ASD,^{6,7,8,9,10,23} ADHD,^7,11,12 cognitive impairment,^{9,10,13,14,15,16,17,18} and developmental delay.^18,24,25 Our study is the first, to our knowledge, to report associations between prenatal valproate exposure with other psychiatric and behavioral disorders. We observed no increased risk of psychiatric disorders occurring mainly later in life (eg, schizophrenia or mood disorders). However, we found an increased risk of attachment disorder in children with prenatal valproate exposure, which has not been reported before. The potential mechanism is unclear, but insecure attachment has been reported to be more prevalent in children with neurodevelopmental disorders,²⁶ which could explain the finding. It is also possible that women using valproate in pregnancy have more severe epilepsy and psychiatric comorbidity, which may in turn affect mother-child attachment during the child’s upbringing.

Previous studies^27,28 suggest that topiramate has a teratogenic potential; however, evidence regarding the risk of adverse behavioral outcomes is limited. Interestingly, we observed an increased risk of ADHD with prenatal topiramate exposure, which extends the potential behavioral risks identified in a recent SCAN-AED study¹⁰ based on the same cohort of children. In that study,¹⁰ 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).^6,29 Findings from the 2 SCAN-AED studies contrast a few prior studies reporting no reductions in child cognitive abilities³⁰ and no increased risk of neurodevelopmental disorders associated with prenatal topiramate exposure⁹ but align with a few others.^31,32,33 More evidence is therefore needed, but our findings strengthen the increasing concerns about the use of topiramate in pregnancy.

For lamotrigine, carbamazepine (with 1 exception), oxcarbazepine, clonazepam, pregabalin, and gabapentin, we found no association between prenatal exposure and psychiatric disorders. Evidence of cognitive and behavioral outcomes following prenatal exposure to these ASMs is most comprehensive for lamotrigine and carbamazepine,³⁴ and findings from cohorts of children born to mothers with epilepsy largely, but not entirely,^23,24,35 align with our findings. Important prospective clinical investigations from the UK and US (the Neurodevelopmental Effects of Antiepileptic Drugs^13,14 study and its extension Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs¹⁵) and data from European¹⁶ and US-based²⁵ registries of pregnant women taking ASM have provided robust evidence regarding the comparative safety of lamotrigine and carbamazepine compared with valproate in terms of their neurodevelopmental effects. For oxcarbazepine, our findings are consistent with the existing, yet limited, evidence.³⁴

Limitations

This study has several potential limitations. First, we present a vast number of analyses and did not adjust for multiple comparisons, which increases the risk of type 1 errors. Results should therefore be considered explorative. Second, given the large number of specific exposure-outcome combinations, it was not feasible to undertake in-depth analyses of, for example, exposure timing or dose. However, our results may serve to generate specific hypotheses for future research. Third, important country-wise differences existed in terms of data availability. For instance, the length of look-back in the registers to identify maternal epilepsy varied, with only 1 year before pregnancy in Iceland and Finland compared to up to 20 years in Denmark. Hence, the proportion of mothers with active epilepsy and in need of ASM treatment in pregnancy differed among countries, but sensitivity analyses in children of mothers with active epilepsy reassuringly aligned with the overall conclusions. Diagnostic rates of psychiatric disorders also varied among countries, possibly indicating differences in diagnostic practice or registration. However, we accounted for this in our statistical models, and country-specific analyses indicated that the relative risk measures varied less than absolute measures, suggesting that diagnostic differences were nondifferential in relation to prenatal ASM exposure. Fourth, residual confounding by maternal lifestyle (eg, body mass index and alcohol consumption) and psychiatric disease is possible. Lifestyle information is generally not well captured in the registers, but through the adjustment for correlated characteristics, such as maternal educational attainment and smoking, we have likely somewhat accounted for this. Information on maternal psychiatric disorders was only available from specialized health care, but we adjusted for antidepressant use in pregnancy, thereby capturing women pharmacologically treated in primary care or by private specialists only. Fifth, pregnant women who redeemed prescriptions for ASM were assumed to ingest the medication, and although high levels of adherence have been reported,³⁶ some misclassification is possible. However, analyses restricting the exposure definition to at least 2 prescriptions (where such misclassification was reduced) were in line with the main findings. Furthermore, the quality of the data in the national prescription registers is considered to be high because of the reimbursement structure in the health care systems,³⁷ which provides a strong economic incentive for recording all dispensed drugs and ensures high sensitivity in capturing drug exposures. Sixth, despite the sizeable population and lengthy follow-up, our data were insufficient to evaluate several less frequently used ASMs, including zonisamide, lacosamide, phenobarbital, and phenytoin, and we could not fully evaluate therapies such as levetiracetam and topiramate. Seventh, generalizability may depend on contextual factors, such as access to psychiatric care, diagnostic threshold norms, and differences in clinical practice (eg, in terms of types and dosing of ASM).

Conclusions

Findings from this large multinational cohort study strengthen the evidence for the warning against the use of valproate in pregnancy, support concerns about the use of topiramate, raise preliminary indication for caution with use of levetiracetam, and provide reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders. Long-term follow-up data are still needed for less frequently used ASMs to fully evaluate potential behavioral risks associated with prenatal exposure.

Supplement 1.

eTable 1. Information Available in SCAN-AED From Each Country to Determine Maternal Epilepsy Status

eTable 2. List of ICD-10 codes and Corresponding Disorders Included in the 13 Subgroups of Psychiatric Disorders

eTable 3. Average Length of Follow-up by ASM Exposure Groups

eTable 4. Cumulative Incidence of Psychiatric Disorders at Age 10 Years in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in Five Nordic Countries (1996-2017)

eTable 5. Cumulative Incidence of Psychiatric Disorders at Age 18 Years in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in Five Nordic Countries (1996-2017)

eTable 6. Country-Specific Incidence Rates, Hazard Ratios, and Cumulative Incidence of Specific Psychiatric Disorders in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on Children Born in Five Nordic Countries (1996-2017)

eTable 7. Incidence Rates, Hazard Ratios (HR) and Cumulative Incidence at Age 10 and 18 Year of the Combined Psychiatric Endpoint in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 25 139 Children of Mothers With Active Epilepsy in Five Nordic Countries (1996-2017)

eTable 8. Incidence Rates, Hazard Ratios (HR) and Cumulative Incidence at Age 10 and 18 Year of the Combined Psychiatric Endpoint in Children Exposed (at Least Two Prescriptions) and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in Five Nordic Countries (1996-2017)

eTable 9. Age-Restricted Analysis of Specific Psychiatric Disorders in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on Children Born in Five Nordic Countries (1996-2017

eFigure. Flowchart of the study population

Click here for additional data file.^{(435.5KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(14.4KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Information Available in SCAN-AED From Each Country to Determine Maternal Epilepsy Status

eTable 2. List of ICD-10 codes and Corresponding Disorders Included in the 13 Subgroups of Psychiatric Disorders

eTable 3. Average Length of Follow-up by ASM Exposure Groups

eFigure. Flowchart of the study population

Click here for additional data file.^{(435.5KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(14.4KB, pdf)}

[noi230018r1] 1.Cohen JM, Cesta CE, Furu K, et al. Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006-2016: a study in the five Nordic countries, United States, and Australia. Pharmacoepidemiol Drug Saf. 2020;29(8):913-922. doi: 10.1002/pds.5035 [DOI] [PubMed] [Google Scholar]

[noi230018r2] 2.Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics. 2016;13(4):811-820. doi: 10.1007/s13311-016-0464-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi230018r3] 3.Kurko T, Saastamoinen LK, Tuulio-Henriksson A, et al. Trends in the long-term use of benzodiazepine anxiolytics and hypnotics: a national register study for 2006 to 2014. Pharmacoepidemiol Drug Saf. 2018;27(6):674-682. doi: 10.1002/pds.4551 [DOI] [PubMed] [Google Scholar]

[noi230018r4] 4.Medicines and Healthcare Products Regulatory Agency. Antiepileptic Drugs: Review of Safety of Use During Pregnancy. Medicines and Healthcare Products Regulatory Agency; 2021. Accessed March 4, 2023. https://www.gov.uk/government/publications/public-assesment-report-of-antiepileptic-drugs-review-of-safety-of-use-during-pregnancy/antiepileptic-drugs-review-of-safety-of-use-during-pregnancy

[noi230018r5] 5.Jentink J, Loane MA, Dolk H, et al. ; EUROCAT Antiepileptic Study Working Group . Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185-2193. doi: 10.1056/NEJMoa0907328 [DOI] [PubMed] [Google Scholar]

[noi230018r6] 6.Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-1703. doi: 10.1001/jama.2013.2270 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

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

Julie Werenberg Dreier, PhD

Marte-Helene Bjørk, PhD

Silje Alvestad, PhD

Mika Gissler, PhD

Jannicke Igland, PhD

Maarit K Leinonen, PhD

Yuelian Sun, PhD

Helga Zoega, PhD

Jacqueline M Cohen, PhD

Kari Furu, PhD

Torbjörn Tomson, PhD

Jakob Christensen, DrMedSci

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Design, Setting, and Population

Maternal Use of ASM in Pregnancy

Child Psychiatric Disorders

Statistical Analysis

Results

Table 1. Characteristics of Children With and Without Prenatal Exposure to Antiseizure Medication (ASM), Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017).

Table 2. Incidence Rates, Hazard Ratios, and Cumulative Incidence at 10 and 18 Years of Age of the Combined Psychiatric End Point in Children Exposed and Unexposed to ASM During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017).

Figure 1. Cumulative Incidence of the Combined Psychiatric End Point According to Prenatal Antiseizure Medication (ASM) Exposure.

Figure 2. Hazard Ratios (HRs) of Psychiatric Disorders According to Maternal Antiseizure Medication (ASM) Use in Pregnancy for Valproate, Lamotrigine, Levetiracetam, and Carbamazepine Monotherapies.

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.

Table 3. Cumulative Incidence of Psychiatric Disorders at Age 15 Years in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017)a.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 3. Cumulative Incidence of Psychiatric Disorders at Age 15 Years in Children Exposed and Unexposed to Antiseizure Medication (ASM) During Pregnancy, Based on 38 661 Children of Mothers With Epilepsy in 5 Nordic Countries (1996-2017)^a.