Fertility treatment with clomiphene citrate and childhood epilepsy: a nationwide cohort study

Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?

Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood.

Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus.

This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016.

Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression.

A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53).

The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis.

The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment.

Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work.

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