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Risk of autism spectrum disorder in offspring following paternal use of selective serotonin reuptake inhibitors before conception: a population-based cohort study
  1. Fen Yang1,2,
  2. Jianping Chen1,
  3. Mao-Hua Miao1,
  4. Wei Yuan1,
  5. Lin Li1,
  6. Hong Liang1,
  7. Vera Ehrenstein2,
  8. Jiong Li2
  1. 1 Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, China
  2. 2 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
  1. Correspondence to Dr Hong Liang; lucylhcn{at}


Objective The present study aimed to examine the association between paternal selective serotonin reuptake inhibitor (SSRI) use before conception and the risk of autism spectrum disorder (ASD) in offspring.

Design A population-based cohort study.

Methods We conducted a cohort study of 669 922 children born from 1998 to 2008, with follow-up throughout 2013. Based on Danish national registers, we linked information on paternal use of SSRIs, ASD diagnosed in children and a range of potential confounders. The children whose fathers used SSRIs during the last 3 months prior to conception were identified as the exposed. Cox regression model was used to estimate the HR for ASD in children.

Results Compared with unexposed children, the exposed had a 1.62-fold higher risk of ASD (95% CI 1.33 to 1.96) and the risk attenuated after adjusting for potential confounders, especially fathers’ psychiatric conditions (HR=1.43, 95% CI 1.18 to 1.74). When extending the exposure window to 1 year before conception, the increased risk persisted in children of fathers using SSRIs only from the last year until the last 3 months prior to conception (HR=1.54, 95% CI 1.21 to 1.94) but not in children of fathers using SSRIs only during the last 3 months prior to conception (HR=1.17, 95% CI 0.75 to 1.82). We also performed stratified analyses according to paternal history of affective disorders and observed no increased ASD risk among children whose father had affective disorders. Besides, the sibling analysis showed that the ASD risk did not increase among exposed children compared with their unexposed siblings.

Conclusions The mildly increased risk of ASD in the offspring associated with paternal SSRI use before conception may be attributable to paternal underlying psychiatric indications related to SSRI use or other unmeasured confounding factors.

  • mental health
  • adult psychiatry
  • neuropathology

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  • Contributors HL had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. HL, WY and JL conceptualised and designed the study, and MHM and VE helped with its development. FY, LL and JPC conducted the statistical analysis. HL, JPC and FY interpreted the results and FY drafted the initial manuscript. All authors reviewed the manuscript and approved the final version as submitted.

  • Funding The study was supported by the National Natural Science Foundation of China (81428011), the National Key Research and Development Program of China (2016YFC1000505), the European Research Council (ERC-2010-StG-260242-PROGEURO), the Nordic Cancer Union (176673, 186200), the Danish Council for Independent Research (DFF-6110-00019), the Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation.

  • Disclaimer The funding sources 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. The researchers were independent from the funders.

  • Competing interests None declared.

  • Ethics approval The study was based on secondary data. No individuals were approached as a result of the study, nor did we access any other data from the participants. This study was approved by the Danish Data Protection Agency (Document No. 2013-41-2569). All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval by an institutional review board and informed consent are not required for registry-based research in Denmark.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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