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Original Investigation
August 15, 2022

Association of Maternal Antipsychotic Prescription During Pregnancy With Standardized Test Scores of Schoolchildren in Denmark

Author Affiliations
  • 1The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
  • 2Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark
  • 3iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
  • 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  • 5Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
  • 6Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
JAMA Intern Med. 2022;182(10):1035-1043. doi:10.1001/jamainternmed.2022.3388
Key Points

Question  Is there an association between maternal antipsychotic prescription fill during pregnancy and standardized test scores in school-aged children?

Findings  In this register-based cohort study comprising 667 517 schoolchildren in Denmark, maternal antipsychotic prescription filled during pregnancy was not statistically significantly associated with standardized test scores (range, 1-100) in Danish language (adjusted test score difference, 0.5) or in mathematics (adjusted test score difference, 0.4) compared with children whose mothers did not fill prescriptions for antipsychotics during pregnancy.

Meaning  Among Danish school-aged children, maternal antipsychotic prescription during pregnancy did not appear to be associated with children’s standardized test scores.

Abstract

Importance  An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes.

Objective  To examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren.

Design, Setting, and Participants  This register-based cohort study included 667 517 children born in Denmark from January 1, 1997, to December 31, 2009, and who were attending public primary and lower secondary school. All children had completed at least 1 language (Danish) or mathematics test as part of the Danish National School Test Program between 2010 and 2018. Data were analyzed from November 1, 2021, to March 31, 2022.

Exposures  Antipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register.

Main Outcomes and Measures  Differences in standardized test scores (range, 1-100; higher scores indicate better test results) in language and mathematics between children of mothers with and without antipsychotic prescription fills during pregnancy were estimated using linear regression models. Seven sensitivity analyses, including a sibling-controlled analysis, were performed.

Results  Of the 667 517 children included (51.2% males), 1442 (0.2%) children were born to mothers filling an antipsychotic prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antipsychotics was not associated with performance in language (crude mean test score: 50.0 [95% CI, 49.1-50.9] for the exposed children vs 55.4 [95% CI, 55.4-55.5] for the unexposed children; adjusted difference, 0.5 [95% CI, −0.8 to 1.7]) or in mathematics (crude mean test score: 48.1 [95% CI, 47.0-49.3] for the exposed children vs 56.1 [95% CI, 56.1-56.2] for the unexposed children; adjusted difference, 0.4 [95% CI, −1.0 to 1.8]). There was no evidence that results were modified by the timing of filling prescriptions, classes (first-generation and second-generation) of antipsychotics, or the most commonly prescribed antipsychotic monotherapies, including chlorprotixene, flupentixol, olanzapine, zuclopenthixol, quetiapine, perphenazine, and methotrimeprazine. The results remained robust across sensitivity analyses, including sibling-controlled analyses, negative control exposures analyses, and probabilistic bias analyses.

Conclusions and Relevance  In this register-based cohort study, maternal prescription fill for antipsychotics during pregnancy did not appear to be associated with standardized test scores in the offspring. The findings provide further reassuring data on offspring neurodevelopmental outcomes associated with antipsychotic treatment during pregnancy.

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