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Reproductive medicine
Original research
Nervous system drugs taken by future fathers and birth defects in offspring: a prospective registry-based cohort study
  1. Maarten Wensink1,2,
  2. Ying Lu3,
  3. Lu Tian3,
  4. Tina Kold Jensen4,
  5. Niels Erik Skakkebæk5,
  6. Rune Lindahl-Jacobsen1,2,
  7. Michael Eisenberg6
  1. 1Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark
  2. 2Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Odense C, Denmark
  3. 3Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, USA
  4. 4Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark
  5. 5Department of Growth and Reproduction, Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  6. 6Male Reproductive Medicine and Surgery, Department of Urology, Stanford University School of Medicine, Stanford, California, USA
  1. Correspondence to Dr Maarten Wensink; mwensink{at}health.sdu.dk

Abstract

Objectives To evaluate the association of paternal intake of antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, selective serotonin reuptake inhibitors (SSRIs) and (benzo)diazepines during the development of fertilising sperm with birth defects in offspring.

Design Prospective registry-based cohort study.

Setting Total Danish birth cohort 1997–2016 using Danish national registries.

Participants All 1 201 119 Danish liveborn singletons born 1997–2016 were eligible, 39 803 (3.3%) of whom had at least one major birth defect.

Exposure Offspring were considered exposed if their father had filled at least one prescription in the relevant drug category during development of fertilising sperm (the 3 months prior to conception).

Primary and secondary outcome measures Primary outcome was the diagnosis, in the first year of life, of at least one major birth defect as categorised in the EUROCAT guidelines. Secondary outcome was the diagnosis, in the first year of life, of at least one major birth defect in any of the EUROCAT subcategories. Adjusted ORs (AORs) were calculated, along with their 95% CIs, adjusted for year, education, smoking status and age of the mother, and education, disposable income and age of the father.

Results This study found weak or null associations between birth defects and selected drugs. Specifically, antidepressants (17 827 exposed births) gave 3.5% birth defects (AOR 0.97 (0.89 to 1.05)). Diazepines, oxazepines, thiazepines and oxepines (as antipsychotics, 1633 offspring) gave 4.7% birth defects (AOR 1.22 (0.97 to 1.54)), attenuated to 1.13 when excluding by mothers’ prescriptions. The study was well powered assuming 100% therapy adherence, while assuming 50% therapy adherence, the study remained well powered for the largest groups (SSRIs and antidepressants overall).

Conclusions Antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, SSRIs and benzodiazepine-derived anxiolytics, when taken by the father during development of fertilising sperm, are generally safe with regard to birth defects.

  • epidemiology
  • neurology
  • preventive medicine
  • public health
  • reproductive medicine

Data availability statement

Data may be obtained from a third party and are not publicly available. Data from Statistics Denmark cannot be made publicly available but can be applied for through the usual ways at DST.dk. The grant proposal is summarised here: https://reporter-nih-gov.ezproxy.u-pec.fr/search/C3FoCZUipkCJsZsijQP4LA/project-details/9585127%23details

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2021-053946

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    Data availability statement

    Data may be obtained from a third party and are not publicly available. Data from Statistics Denmark cannot be made publicly available but can be applied for through the usual ways at DST.dk. The grant proposal is summarised here: https://reporter-nih-gov.ezproxy.u-pec.fr/search/C3FoCZUipkCJsZsijQP4LA/project-details/9585127%23details

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    Footnotes

    • Contributors ME, RL-J, NES, YL and TKJ designed the study. MW, YL and LT handled data and statistical analysis. MW wrote the first draft. All authors interpreted the results, revised the manuscript and approved the final version. MW is the guarantor of the article.

    • Funding This study was funded by NIH grant HD096468 (to ME).

    • Disclaimer The funder had no role in the study design, collection, analysis and interpretation of the data and in the writing of the report.

    • Competing interests YL reports grants from Merck, and personal fees from United Health Care, Nektar, and Gilead, outside the submitted work. ME reports advisorships for Sandstone Diagnostics, Dadi, Hannah and Underdog, which are fertility-related companies.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.