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Original Investigation
December 2018

Association of Autism Spectrum Disorder With Prenatal Exposure to Medication Affecting Neurotransmitter Systems

Author Affiliations
  • 1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
  • 2Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York
  • 3Department of Community Mental Health, University of Haifa, Haifa, Israel
  • 4Meuhedet Health Services, Tel Aviv, Israel
  • 5Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York
  • 6Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 7Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
  • 8Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 9Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 10Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
JAMA Psychiatry. 2018;75(12):1217-1224. doi:10.1001/jamapsychiatry.2018.2728
Key Points

Question  Do prenatal exposures to medication affecting neurotransmitter systems increase the risk of autism spectrum disorders?

Findings  This population-based case-control cohort study of 95 978 individuals from the population of a single health maintenance organization assessed the effects of prenatal exposure to medications that affect major neurotransmitter systems. Most of the associations were substantially modified when accounting for maternal characteristics.

Meaning  Higher estimates of autism spectrum disorder risk among the offspring of mothers taking certain medications during pregnancy are most likely not owing to pharmacologic effects of those drugs.

Abstract

Importance  Prenatal exposure to certain medications has been hypothesized to influence the risk of autism spectrum disorders (ASD). However, the underlying effects on the neurotransmitter systems have not been comprehensively assessed.

Objective  To investigate the association of early-life interference with different neurotransmitter systems by prenatal medication exposure on the risk of ASD in offspring.

Design, Setting, and Participants  This case-control study included children born from January 1, 1997, through December 31, 2007, and followed up for ASD until January 26, 2015, within a single Israeli health maintenance organization. Using publicly available data, 55 groups of medications affecting neurotransmitter systems and prescribed to pregnant women in this sample were identified. Children prenatally exposed to medications were compared with nonexposed children. Data were analyzed from March 1, 2017, through June 20, 2018.

Main Outcome and Measures  Hazard ratios (HRs) and 95% CIs of ASD risk associated with exposure to medication groups using Cox proportional hazards regression, adjusted for the relevant confounders (eg, birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year before pregnancy).

Results  The analytic sample consisted of 96 249 individuals (1405 cases; 94 844 controls; mean [SD] age at the end of follow-up, 11.6 [3.1] years; 48.8% female), including 1405 with ASD and 94 844 controls. Of 34 groups of medications, 5 showed nominally statistically significant association with ASD in fully adjusted models. Evidence of confounding effects of the number of maternal diagnoses on the association between offspring exposure to medication and ASD was found. Adjusting for this factor, lower estimates of ASD risk among children exposed to cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55-0.95; P = .02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P = .04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P = .045), or α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P = .04) were observed. Exposure to antagonists of neuronal nicotinic acetylcholine receptor α was associated with higher estimates of ASD risk (HR, 12.94; 95% CI, 1.35-124.25; P = .03).

Conclusions and Relevance  Most of the medications affecting neurotransmitter systems in this sample had no association with the estimates of ASD risk. Replication and/or validation using experimental techniques are required.

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