Antipsychotic Use During Pregnancy and Risk of Specific Neurodevelopmental Disorders and Learning Difficulties in Children: A Multinational Cohort Study

Abstract

Background: To evaluate whether children prenatally exposed to antipsychotic medication are at increased risk of specific neurodevelopmental disorders and learning difficulties.

Methods: Our population-based cohort study used nationwide register data (2000 to 2020) on pregnant women diagnosed with a psychiatric disorder and their live-born singletons from Denmark, Finland, Iceland, Norway, and Sweden. Cox proportional hazard regression yielded propensity score -weighted hazard ratios (aHRs) and 95% confidence intervals (CIs) for risk of intellectual-, speech or language-, learning- developmental disorders, and a composite outcome of the listed disorders. We defined poor performance as scoring within the lowest quartile on national school tests in mathematics and language arts. We estimated PS-weighted risk ratios (aRRs) using Poisson regression. We analysed data from Denmark separately and pooled results using fixed-effects meta-analysis.

Findings: Among 213 302 children (median follow-up: 6·7 years), 11 626 (5·5%) were exposed to antipsychotics prenatally. Adjusted risk estimates did not suggest an increased risk of neurodevelopmental disorders: aHR of 1·06 (95% CI 0·94–1·20) for the composite outcome, or for poor academic performance: aRR of 1·04 (95% CI 0·91–1·18) in mathematics, and of 1.00 (95% CI 0·87–1·15) in language arts. Results were generally consistent across individual medications, trimesters of exposure, sibling- and sensitivity analyses.

Interpretation : The findings of this large multinational cohort study suggest there is little to no increased risk of child neurodevelopmental disorders or learning difficulties after prenatal exposure to antipsychotics. Our findings can assist clinicians and women managing mental illness during pregnancy.

Funding: : This study was funded by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366) and by the Research Council of Norway through its Centres of Excellence funding scheme (project No. 262700). CB was supported by Australian Government Research Training Program Scholarship. HZ was supported by a UNSW Scientia Program Award during the conduct of the study. This research is also supported by the National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Medicines Intelligence (ID: 1196900).

Declaration of Interest: : CEC, PK, and JR are employees of the Centre for Pharmacoepidemiology at Karolinska Institutet, which receives funding from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies, unrelated to this work. KF and ØK report participation in regulator mandated phase IV studies (PASS) unrelated to the submitted work, funded by pharmaceutical companies (Novo Nordisk, LEO Pharma and Bristol Myers Squibb) and paid to the institution (no personal fees). MG and MKL Leinonen report a grant from the Innovative Medicines Initiative (IMI ConcePTION, grant agreement number 821520) while conducting the study, unrelated to this work. MG and MKL also report that their institution has received funding from pharmaceutical companies to conduct regulator mandated post-marketing drug safety research outside the submitted work. MHB reported fees paid to her institution by valproate market authorization holders for EMA-mandated contract research (PAS studies); speaking and/or consultancy honoraria from Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, AbbVie, Teva, Lilly, and Lundbeck unrelated to the medications in the study. All other authors do not report any competing interests.

Ethical Approval: This research and access to the Nordic data was approved by the National Bioethics Committee, the Data Protection Authority in Iceland, the Directorate of Health, and all other relevant data custodians; the Norwegian Data Inspectorate in Norway and the Regional Ethics Committee for Medical Research of South/East Norway in Oslo, Norway; the Regional Ethical Research Board in Stockholm, Sweden; the Finnish Institute for Health and Welfare and the Social Insurance Institute in Finland (eTable 1). No ethics approval was required in Denmark and Finland.

Keywords: Antipsychotics, pregnancy, Children, neurodevelopmental disorders, Academic Performance, Nordic health registers