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Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study

Published online by Cambridge University Press:  26 March 2021

Arad Kodesh ,
Stephen Z. Levine ,
Vahe Khachadourian ,
Rayees Rahman ,
Avner Schlessinger ,
Paul F. O'Reilly ,
Jakob Grove ,
Diana Schendel ,
Joseph D. Buxbaum  and
Lisa Croen
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Arad Kodesh
Affiliation:
Department of Community Mental Health, University of Haifa, Haifa, Israel Meuhedet Health Services, Tel Aviv, Israel
Stephen Z. Levine
Affiliation:
Department of Community Mental Health, University of Haifa, Haifa, Israel
Vahe Khachadourian
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Rayees Rahman
Affiliation:
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Avner Schlessinger
Affiliation:
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Paul F. O'Reilly
Affiliation:
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Jakob Grove
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark Department of Biomedicine – Human Genetics, Aarhus University, Aarhus, Denmark Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
Diana Schendel
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark Section for Epidemiology, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
Joseph D. Buxbaum
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Lisa Croen
Affiliation:
Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
Abraham Reichenberg
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Sven Sandin
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Magdalena Janecka*
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Biomedicine – Human Genetics, Aarhus University, Aarhus, Denmark Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
*
Author for correspondence: Magdalena Janecka, E-mail: magdalena.janecka@mssm.edu
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Abstract

Background

Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring.

Methods

This exploratory case–cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period).

Results

The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92–3.90), p = 2.43 × 10−8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38–2.57), p = 7.06 × 10−5] and psychiatric [depressive disorder; HR = 2.11 (1.32–3.35), p = 1.70 × 10−3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54–0.71), p = 1.80 × 10−11].

Conclusions

Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Keywords

Autismdiagnosis-widematernal healthprenatal effects
Type
Original Article
Information
Psychological Medicine , Volume 52 , Issue 16 , December 2022 , pp. 4076 - 4084
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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