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Preconceptional paternal antiepileptic drugs use and risk of congenital anomalies in offspring: a nationwide cohort study

  • PERINATAL EPIDEMIOLOGY
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Abstract

Recent studies have shown that certain pharmacological agents used by fathers before conception may increase the risk of adverse neonatal outcomes in offspring. However, little is known about the effect of paternal use of antiepileptic drugs (AEDs) on congenital anomalies in children. Based on Danish national registers, we conducted a cohort study of 733, 282 singletons born from 1997 to 2008, with follow-up throughout 2013. The children whose fathers used AEDs during the 3 months before conception were categorized as the exposed. Logistic regression model was used to examine association between paternal AEDs use before conception and the risk of congenital anomalies in offspring. Compared with unexposed children, the exposed had a 23% increased risk of congenital anomalies (odds ratios (OR) 1.23, 95% confidence interval [CI] 1.10–1.37) after adjusting for potential confounders. When extending the exposure window to 1 year before conception to the end of pregnancy, except for those using AEDs during 3 months before conception (the susceptible period of exposure), the increased risks were also observed in children whose fathers were former users (i.e., those using AEDs only from 1 year to 3 months before conception) (OR 1.29, 95%CI 1.03–1.61) and later users (i.e., those using AEDs only during pregnancy) (OR 1.35, 95%CI 1.12–1.65). This study suggested that the mildly increased risk of congenital anomalies in the offspring associated with paternal AEDs use before conception may be attributable to the underlying indications related to AEDs use.

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Funding

This work was supported by the National key research and development program of China [2016YFC1000505], Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation [CX2017-06], the Shanghai Sailing Program [17YF1416100], the National Natural Science Foundation of China [21628701, 81530086], the Nordic Cancer Union [176673, 186200, R217-A13234-18-S65], the Danish Council for Independent Research [DFF-6110-00019B], Karen Elise Jensens Fond [2016], and Novo Nordisk Fonden (NNF18OC0052029). No funder had any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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Authors and Affiliations

  1. NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, #779 Lao Hu Min Road, Shanghai, 200032, China

    Fen Yang, Wei Yuan, Hong Liang, Xiuxia Song & Maohua Miao

  2. Department of Clinical Epidemiology, Aarhus University Hospital, 8200, Aarhus, Denmark

    Fen Yang, Yongfu Yu & Jiong Li

  3. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Yongfu Yu

  4. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA

    Bizu Gelaye

  5. MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiong Li

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  1. Fen Yang
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  2. Wei Yuan
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  3. Hong Liang
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  7. Maohua Miao
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  8. Jiong Li
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Contributions

FY contributed to the study design, data analysis and interpretation, and drafting of the manuscript. MHM contributed to the conception and study design, interpretation of the results, and revising of the manuscript, and XXS helped with its development. JL retrieved the data. WY, HL, YFY, BG and JL contributed to the interpretation of the results and revising of the manuscript. All authors commented on drafts and read and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. JL is the guarantor.

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Correspondence to Maohua Miao.

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Yang, F., Yuan, W., Liang, H. et al. Preconceptional paternal antiepileptic drugs use and risk of congenital anomalies in offspring: a nationwide cohort study. Eur J Epidemiol 34, 651–660 (2019). https://doi.org/10.1007/s10654-019-00509-2

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  • DOI: https://doi.org/10.1007/s10654-019-00509-2

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