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Fertility Treatment and Childhood Epilepsy: A Nationwide Cohort Study

Kettner, Laura Ozer; Kesmodel, Ulrik Schiøler; Ramlau-Hansen, Cecilia Høst; Bay, Bjørn; Ritz, Beate; Matthiesen, Niels Bjerregaard; Henriksen, Tine Brink

doi: 10.1097/EDE.0000000000000618
Perinatal Epidemiology

Background: Fertility treatment includes hormonal stimulation of the woman and in vitro manipulation of gametes and embryos that may influence prenatal brain development. We aimed to investigate the association between fertility treatment and childhood epilepsy, including specific types of treatment and indications, as well as subtypes of epilepsy.

Methods: In this nationwide birth cohort study, we included all pregnancies in Denmark resulting in live-born singletons, 1995–2003. Children conceived by fertility treatment and children developing epilepsy (until 2013) were identified from Danish national registers.

Results: A total of 565,116 pregnancies were included; 8,071 children (1.4%) developed epilepsy. Children conceived after ovulation induction or intrauterine insemination had a slightly higher risk of childhood epilepsy (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.00, 1.31). The association was more pronounced for the subtypes idiopathic generalized and focal epilepsy. Regarding the specific hormonal treatments, only clomiphene citrate was associated with an increased risk of childhood epilepsy, also in a sibling analysis (HR: 2.07; 95% CI: 1.05, 4.08). In vitro fertilization or intracytoplasmic sperm injection was not associated with an overall increased risk of childhood epilepsy but with idiopathic generalized epilepsy (HR: 1.43; 95% CI: 0.99, 2.05). No clear associations were seen regarding other treatment types or indications.

Conclusions: Children conceived by ovulation induction or intrauterine insemination with clomiphene citrate may be at slightly increased risk of childhood epilepsy. Furthermore, children conceived by in vitro fertilization or intracytoplasmic sperm injection may be at slightly increased risk of idiopathic generalized epilepsy.

From the aPerinatal Epidemiology Research Unit and Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; bThe Fertility Clinic, Department of Obstetrics and Gynecology, Herlev University Hospital, Herlev, Denmark; cDepartment of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; dThe Fertility Clinic, Department of Obstetrics and Gynecology, Aarhus University, Regions Hospital Horsens, Denmark; and eDepartment of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA.

Submitted 11 May 2016; accepted 4 January 2017.

Financial supported by Aarhus University; the Aase and Ejnar Danielsen Foundation; the A.P. Møller Foundation for the Advancement of Medical Science; the Danish Doctors’ Insurance Association sponsored by SEB Pension; the Niels Bohr Foundation; the Torben and Alice Frimodt Foundation; Carl and Ellen Hertz’s Grant; Managing Director Jacob Madsen and Olga Madsen’s Foundation; the Foundation of 1870; the Oticon Foundation; the Lundbeck Foundation, and Professor Torben Iversen’s Travel Grant.

Ulrik Schiøler Kesmodel previously performed teaching sessions for Merck Serono and Ferring. The other authors declare no conflict of interest.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com).

Correspondence: Laura Ozer Kettner, Perinatal Epidemiology Research Unit and Department of Pediatrics, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200 Aarhus N, Denmark. E-mail: Laura@kettner.nu.

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