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

  • Fen Yang
  • Wei Yuan
  • Hong Liang
  • Xiuxia Song
  • Yongfu Yu
  • Bizu Gelaye
  • Maohua MiaoEmail author
  • Jiong Li


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.


Antiepileptic drugs Preconceptional paternal drugs use Congenital anomalies Nationwide cohort study 


Author 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.


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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10654_2019_509_MOESM1_ESM.pdf (384 kb)
Supplementary material 1 (PDF 383 kb)


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood ResearchFudan UniversityShanghaiChina
  2. 2.Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark
  3. 3.Department of Epidemiology, Fielding School of Public HealthUniversity of California, Los Angeles (UCLA)Los AngelesUSA
  4. 4.Department of EpidemiologyHarvard T. H. Chan School of Public HealthBostonUSA
  5. 5.MOE-Shanghai Key Laboratory of Children’s Environmental HealthXin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina

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