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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
PERINATAL EPIDEMIOLOGY
  • 41 Downloads

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.

Keywords

Antiepileptic drugs Preconceptional paternal drugs use Congenital anomalies Nationwide cohort study 

Notes

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.

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.

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)

References

  1. 1.
    Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon C-S, Dykeman J, et al. Prevalence and incidence of epilepsy. A systematic review and meta-analysis of international studies. Neurology. 2017;88(3):296–303.Google Scholar
  2. 2.
    Janz D. Are antiepileptic drugs harmful when given during pregnancy? Ger Med Mon. 1964;9:20–2.Google Scholar
  3. 3.
    Meadow S. Anticonvulsant drugs and congenital abnormalities. The Lancet. 1968;292(7581):1296.Google Scholar
  4. 4.
    Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1–13.Google Scholar
  5. 5.
    Veroniki AA, Cogo E, Rios P, Straus SE, Finkelstein Y, Kealey R, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. 2017;15(1):95.Google Scholar
  6. 6.
    Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975;16(1):1–66.Google Scholar
  7. 7.
    Engeland A, Bramness JG, Daltveit AK, Rønning M, Skurtveit S, Furu K. Prescription drug use among fathers and mothers before and during pregnancy. A population-based cohort study of 106 000 pregnancies in Norway 2004–2006. Br J Clin Pharmacol. 2008;65(5):653–60.Google Scholar
  8. 8.
    Schirm E, Pedersen L, Tobi H, Nielsen GL, Sørensen HT, de van-den Jong Berg L. Drug use among fathers around time of conception: two register based surveys from Denmark and The Netherlands. Pharmacoepidemiol Drug Saf. 2004;13(9):609–13.Google Scholar
  9. 9.
    Abbasi J. The paternal epigenome makes its mark. JAMA. 2017;317(20):2049–51.Google Scholar
  10. 10.
    Day J, Savani S, Krempley BD, Nguyen M, Kitlinska JB. Influence of paternal preconception exposures on their offspring: through epigenetics to phenotype. Am J Stem Cells. 2016;5(1):11.Google Scholar
  11. 11.
    Su XJ, Yuan W, Huang GY, Olsen J, Li J. Paternal age and offspring congenital heart defects: a national cohort study. PLoS ONE. 2015;10(3):e0121030.Google Scholar
  12. 12.
    Cordier S. Evidence for a role of paternal exposures in developmental toxicity. Basic Clin Pharmacol Toxicol. 2008;102(2):176–81.Google Scholar
  13. 13.
    Engeland A, Bjørge T, Daltveit AK, Skurtveit S, Vangen S, Vollset SE, et al. Effects of preconceptional paternal drug exposure on birth outcomes: cohort study of 340 000 pregnancies using Norwegian population-based databases. Br J Clin Pharmacol. 2013;75(4):1134–41.Google Scholar
  14. 14.
    Herzog AG, Drislane FW, Schomer DL, Pennell PB, Bromfield EB, Dworetzky BA, Farina EL, et al. Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy. Neurology. 2006;65(7):1016–20.Google Scholar
  15. 15.
    Xiaotian X, Hengzhong Z, Yao X, Zhipan Z, Daoliang X, Yumei W. Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy. J Clin Neurosci. 2013;20(11):1492.Google Scholar
  16. 16.
    Ceylan M, Yalcin A, Bayraktutan OF, Karabulut I, Sonkaya AR. Effects of levetiracetam monotherapy on sperm parameters and sex hormones: data from newly diagnosed patients with epilepsy. Seizure Eur J Epilepsy. 2016;41:70.Google Scholar
  17. 17.
    Baysal M, Ilgin S, Kilic G, Kilic V, Ucarcan S, Atli O. Reproductive toxicity after levetiracetam administration in male rats: evidence for role of hormonal status and oxidative stress. PLoS ONE. 2017;12(4):e0175990.Google Scholar
  18. 18.
    Ourique GM, Pês TS, Saccol EMH, Finamor IA, Glanzner WG, Baldisserotto B, et al. Resveratrol prevents oxidative damage and loss of sperm motility induced by long-term treatment with valproic acid in Wistar rats. Exp Toxicol Pathol. 2016;68(8):435–43.Google Scholar
  19. 19.
    Lewis SEM, Aitken RJ. DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res. 2005;322(1):33–41.Google Scholar
  20. 20.
    Pedersen CB. The Danish civil registration system. Scand J Public Health. 2011;39(7 suppl):22–5.Google Scholar
  21. 21.
    Knudsen LB, Olsen J. The Danish medical birth registry. Dan Med Bull. 1998;45(3):320–3.Google Scholar
  22. 22.
    Wallach Kildemoes H, Toft Sørensen H, Hallas J. The Danish national prescription registry. Scand J Public Health. 2011;39(7_suppl):38–41.Google Scholar
  23. 23.
    Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health. 2011;39(7_suppl):30–3.Google Scholar
  24. 24.
    Larsen H, Nielsen GL, Bendsen J, Flint C, Olsen J, Sørensen HT. Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries. Scand J Soc Med. 2003;31(1):12–6.Google Scholar
  25. 25.
    Agergaard P, Hebert A, Bjerre J, Sørensen KM, Olesen C, Østergaard JR. Children diagnosed with congenital cardiac malformations at the national university departments of pediatric cardiology: positive predictive values of data in the Danish national patient registry. Clin Epidemiol. 2011;3:61.Google Scholar
  26. 26.
    Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016;11:CD010224.  https://doi.org/10.1002/14651858.cd010224.pub2.Google Scholar
  27. 27.
    Meyer JG. The teratological effects of anticonvulsants and the effects on pregnancy and birth. Eur Neurol. 1973;10(3):179–90.Google Scholar
  28. 28.
    Veiby G, Daltveit AK, Schjølberg S, Stoltenberg C, Øyen AS, Vollset SE, et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia. 2013;54(8):1462.Google Scholar
  29. 29.
    Wald N, Sneddon J, Densem J, Frost C, Stone R. Prevention of neural tube defects: results of the medical research council vitamin study. Lancet. 1992;38(2):131–7.Google Scholar

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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