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Pharmacoepidemiology

Association Between Prenatal Exposure to Antipsychotics and Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Preterm Birth, and Small for Gestational Age

Educational Objective
To evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems.

1 Credit CME

JAMA Internal Medicine

Published Online: August 16, 2021

Original Investigation

Article Information and Disclosures

Zixuan Wang, MSc¹;

Adrienne Y. L. Chan, MPH^2,3,4;

David Coghill, MD^5,6;

Patrick Ip, MPH⁷;

Wallis C. Y. Lau, PhD^1,2;

Emily Simonoff, MD⁸;

Ruth Brauer, PhD¹;

Ian C. K. Wong, PhD^1,2,3;

Kenneth K. C. Man, PhD^1,2,3

Author Affiliations

¹Research Department of Practice and Policy, UCL School of Pharmacy, London, England
²Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
³Laboratory of Data Discovery for Health, Hong Kong Science Park, Hong Kong Special Administrative Region, China
⁴Groningen Research Institute of Pharmacy, Unit of PharmacoTherapy, Epidemiology and Economics, University of Groningen, Groningen, the Netherlands
⁵Department of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
⁶Murdoch Children’s Research Institute, Melbourne, Australia
⁷Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
⁸Department of Child and Adolescent Psychiatry, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, England

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Key Points

Question Does prenatal exposure to antipsychotics increase the risk of preterm birth, small for gestational age, attention-deficit/hyperactivity disorder (ADHD), or autism spectrum disorder (ASD)?

Findings In this cohort study of 411 251 mother-child pairs, there was not an increased risk of ADHD, ASD, preterm birth, and small for gestational age with prenatal use of antipsychotics. Maternal psychiatric disorders were associated with a significantly increased risk of ADHD and ASD, but not with preterm birth or small for gestational age in neonates.

Meaning The findings of this study suggest that there is no association between prenatal exposure to antipsychotics and ADHD, ASD, preterm birth, and small for gestational age; however, underlying maternal psychiatric disorders may be associated with the risk of ADHD and ASD in children.

Abstract

Importance The risk of birth and neurodevelopmental complications with prenatal exposure to antipsychotics is unclear.

Objective To evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems.

Design, Setting, and Participants This population-based cohort study included children born between January 2001 and January 2015 with follow-up to December 2019 who were identified by the Hong Kong Clinical Data Analysis and Reporting System. Pregnancies with maternal antidepressant/lithium exposure were removed. Primary analyses compared gestationally exposed and gestationally nonexposed individuals with propensity score fine stratification. Additional analyses included gestationally exposed individuals vs those with past exposure and a sibling-matched analysis to evaluate the effect of confounding by indication.

Exposures Prenatal antipsychotic exposure.

Main Outcomes and Measures Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 standard deviations below the mean for gestational age), and first diagnosis of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children.

Results The cohorts included 333 749 mother-child pairs for ADHD (mean [SD] maternal age at delivery, 31.46 [5.03] years) and 411 251 pairs for ASD, preterm birth, and small for gestational age analyses (mean [SD] maternal age at delivery, 31.56 [5.01] years). There were 13 196 children (3.95%) with a diagnosis of ADHD, 8715 (2.12%) with ASD, 33 891 (8.24%) preterm, and 7009 (1.70%) who were small for gestational age. The weighted hazard ratio (wHR) was 1.16 (95% CI, 0.83-1.61) for ADHD and 1.06 (95% CI, 0.70-1.60) for ASD, while the weighted odds ratio (wOR) was 1.40 (95% CI, 1.13-1.75) for preterm birth and 1.36 (95% CI, 0.86-2.14) for small for gestational age when comparing gestationally exposed with gestationally nonexposed individuals. Additional analyses showed no association when comparing gestationally exposed individuals with those with past exposure (ADHD: wHR, 0.99; 95% CI, 0.60-1.61; ASD: wHR, 1.10; 95% CI, 0.58-2.08; preterm birth: wOR, 0.93; 95% CI, 0.70-1.24; small for gestational age: wOR, 1.21; 95% CI, 0.66-2.20) and in a sibling-matched analysis (ADHD: wHR, 0.41; 95% CI, 0.04-4.93; ASD: wHR, 0.90; 95% CI, 0.40-2.01; preterm birth: wOR, 1.25; 95% CI, 0.85-1.82; small for gestational age: wOR, 0.86, 95% CI, 0.32-2.31).

Conclusions and Relevance In this cohort study, the findings did not suggest that prenatal antipsychotics exposure increased the risk of ADHD, ASD, or small for gestational age. In the primary analysis, there was a small increased risk of preterm birth, but additional analyses comparing gestationally exposed individuals with those with past exposure and comparing gestationally exposed with gestationally nonexposed siblings did not support an increased risk. Given the benefits of treating psychosis during pregnancy, our findings do not support a recommendation for women to discontinue receipt of their regular antipsychotic treatment during pregnancy.

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Article Information

Accepted for Publication: June 11, 2021.

Published Online: August 16, 2021. doi:10.1001/jamainternmed.2021.4571

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wang Z et al. JAMA Internal Medicine.

Corresponding Authors: Kenneth K.C. Man, PhD, Research Department of Practice and Policy, UCL School of Pharmacy, Mezzanine Floor, BMA House, Entrance A, Tavistock Square, London, England WC1H 9JP (kenneth.man@ucl.ac.uk); Ian C. K. Wong, PhD, L2-57, Laboratory Block, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Rd, Pokfulam, 00000 China (wongick@hku.hk).

Author Contributions: Drs Wong and Man 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. Drs Wong and Man were co–senior authors.

Concept and design: Wang, Ip, Simonoff, Brauer, Wong, Man.

Acquisition, analysis, or interpretation of data: Wang, Chan, Coghill, Lau, Simonoff, Wei, Wong, Man.

Drafting of the manuscript: Wang, Simonoff, Man.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang, Chan, Wei, Man.

Obtained funding: Wong, Man.

Administrative, technical, or material support: Man.

Supervision: Ip, Simonoff, Brauer, Wei, Wong, Man.

Conflict of Interest Disclosures: Dr Coghill reported personal fees from Takeda/Shire, Medice, Novartis, and Servier and royalties from Oxford University Press and other Cambridge University Press outside the submitted work. Dr Wong reported research funding from the Hong Kong Research Grants Council, European Commission, and the Laboratory of Data Discovery for Health by the Hong Kong Government InnoHK initiative. Dr Man reported grants from C W Maplethorpe during the conduct of the study as well as grants the National Institute of Health Research, European Commission Framework Horizon 2020, Hong Kong Research Grant Council, Amgen Ltd, and GSK and personal fees from IQVIA outside the submitted work. No other disclosures were reported.

Funding/Support: This study is supported by the CW Maplethorpe Fellowship for KKCM’s Salary at UCL and a grant from the Innovation and Technology Commission of the Hong Kong Special Administration Region Government for Ms Chan’s salary at the University of Hong Kong. Data extraction in Hong Kong is funded by Hong Kong Research Grant Council Collaborative Research Fund number C7009-19G.

Role of the Funder/Sponsor: The funding organizations 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.

Additional Contributions: We thank Lisa Lam, BSc, BA, MJ (University of Hong Kong) and Elizabeth Jamieson, PhD (UCL School of Pharmacy) for help with proofreading the manuscript. They were not compensated for their contributions.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.