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Defective placentation syndromes and autism spectrum disorder in the offspring: population-based cohort and sibling-controlled studies

  • PSYCHIATRIC EPIDEMIOLOGY
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Abstract

Defective placentation underlies diverse syndromic manifestations that could affect brain development including: (1) placental abruption, (2) term preeclampsia with a small-for-gestational age (SGA) infant, (3) preterm preeclampsia, and (4) spontaneous preterm birth. We investigated the relations between these defective placentation syndromes and the incidence of Autism Spectrum Disorder (ASD) in offspring. We conducted a population-based cohort study of 1,645,455 non-malformed singleton infants born in Sweden 2000–2016 who were followed for up to 17 years using national registers. We compared ASD rates for children prenatally exposed and unexposed to defective placentation syndromes with use of adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression. We also conducted sibling-controlled analyses among 1,092,132 full siblings. The association of the syndromes with ASD independent of preterm birth was estimated in mediation analyses. There were 23,810 cases of ASD. In both general cohort and sibling analyses, adjusted HRs (95% CI) of ASD were increased in children of mothers with term preeclampsia combined with SGA [1.5 (1.3, 1.9) and 1.9 (1.1, 3.3), respectively], preterm preeclampsia < 34 weeks [1.8 (1.4, 2.2) and 4.2 (2.1, 8.5), respectively], and spontaneous very or extremely preterm birth (≤ 31 weeks) [2.6 (2.2, 3.0) and 2.4 (1.5, 3.8), respectively]. Placental abruption was associated with increased HR of ASD in general cohort analysis only. The association between preeclampsia and ASD was not fully explained by preterm birth. In conclusion, syndromes linked to defective placentation are associated with increased incidence of ASD in the offspring.

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Acknowledgements

The study was supported by the National Institutes of Health (R21 MH120824), the Swedish Research Council for Health, Working Life and Welfare (2014-0073 and 2017-00134), and the Karolinska Institutet (Unrestricted Distinguished Professor Award 2368/10-221 to SC).

Funding

The study was supported by the National Institutes of Health (R21 MH120824), the Swedish Research Council for Health, Working Life and Welfare (2014–0073 and 2017–00134), and the Karolinska Institutet (Unrestricted Distinguished Professor Award 2368/10–221 to SC).

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Authors and Affiliations

  1. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Eduardo Villamor

  2. Department of Epidemiology, Mailman School of Public Health, New York State Psychiatric Institute, Columbia University, New York, NY, USA

    Ezra S. Susser

  3. Clinical Epidemiology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden

    Sven Cnattingius

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  1. Eduardo Villamor
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  2. Ezra S. Susser
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  3. Sven Cnattingius
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All authors contributed to the study conception and design. EV performed the analyses and wrote the first draft of the manuscript. SC obtained the data. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Eduardo Villamor.

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The authors have no relevant financial or non-financial interests to disclose submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. None of the authors has conflicts of interest to disclose.

Ethical approval

This study was approved by the Regional Ethical Review Board in Stockholm, Sweden (No. 2018/5:2). In accordance with their decision, data linkage was allowed without informed consent from participants involved in the study. All individuals’ information was anonymized and de-identified prior to analysis.

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Villamor, E., Susser, E.S. & Cnattingius, S. Defective placentation syndromes and autism spectrum disorder in the offspring: population-based cohort and sibling-controlled studies. Eur J Epidemiol 37, 827–836 (2022). https://doi.org/10.1007/s10654-022-00884-3

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