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

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Fertility treatment with clomiphene citrate and childhood epilepsy : a nationwide cohort study. / Kettner, L O; Matthiesen, N B; Ramlau-Hansen, C H; Kesmodel, U S; Henriksen, T B.

I: Human Reproduction, Bind 36, Nr. 9, deab110, 09.2021, s. 2567-2575.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{bda394d1cf534853bb98e9556b5bf109,
title = "Fertility treatment with clomiphene citrate and childhood epilepsy: a nationwide cohort study",
abstract = "STUDY QUESTION: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?SUMMARY ANSWER: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood.WHAT IS KNOWN ALREADY: 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.STUDY DESIGN, SIZE, DURATION: 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.PARTICIPANTS/MATERIALS, SETTING, METHODS: 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.MAIN RESULTS AND THE ROLE OF CHANCE: 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).LIMITATIONS, REASONS FOR CAUTION: 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.WIDER IMPLICATIONS OF THE FINDINGS: 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.STUDY FUNDING/COMPETING INTEREST(S): 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.TRIAL REGISTRATION NUMBER: N/A.",
keywords = "clomiphene citrate, epilepsy, fertility treatment, intrauterine insemination, ovulation induction",
author = "Kettner, {L O} and Matthiesen, {N B} and Ramlau-Hansen, {C H} and Kesmodel, {U S} and Henriksen, {T B}",
note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
year = "2021",
month = sep,
doi = "10.1093/humrep/deab110",
language = "English",
volume = "36",
pages = "2567--2575",
journal = "Human Reproduction",
issn = "0268-1161",
publisher = "Oxford Academic",
number = "9",

}

RIS

TY - JOUR

T1 - Fertility treatment with clomiphene citrate and childhood epilepsy

T2 - a nationwide cohort study

AU - Kettner, L O

AU - Matthiesen, N B

AU - Ramlau-Hansen, C H

AU - Kesmodel, U S

AU - Henriksen, T B

N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2021/9

Y1 - 2021/9

N2 - STUDY QUESTION: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?SUMMARY ANSWER: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood.WHAT IS KNOWN ALREADY: 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.STUDY DESIGN, SIZE, DURATION: 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.PARTICIPANTS/MATERIALS, SETTING, METHODS: 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.MAIN RESULTS AND THE ROLE OF CHANCE: 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).LIMITATIONS, REASONS FOR CAUTION: 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.WIDER IMPLICATIONS OF THE FINDINGS: 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.STUDY FUNDING/COMPETING INTEREST(S): 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.TRIAL REGISTRATION NUMBER: N/A.

AB - STUDY QUESTION: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?SUMMARY ANSWER: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood.WHAT IS KNOWN ALREADY: 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.STUDY DESIGN, SIZE, DURATION: 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.PARTICIPANTS/MATERIALS, SETTING, METHODS: 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.MAIN RESULTS AND THE ROLE OF CHANCE: 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).LIMITATIONS, REASONS FOR CAUTION: 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.WIDER IMPLICATIONS OF THE FINDINGS: 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.STUDY FUNDING/COMPETING INTEREST(S): 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.TRIAL REGISTRATION NUMBER: N/A.

KW - clomiphene citrate

KW - epilepsy

KW - fertility treatment

KW - intrauterine insemination

KW - ovulation induction

U2 - 10.1093/humrep/deab110

DO - 10.1093/humrep/deab110

M3 - Journal article

C2 - 34128056

VL - 36

SP - 2567

EP - 2575

JO - Human Reproduction

JF - Human Reproduction

SN - 0268-1161

IS - 9

M1 - deab110

ER -