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Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study
Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study
Objective: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy.

Design: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications.

Setting: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005.

Participants: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98?075 registrations of malformations covering over 3.8 million births.

Main outcome measures: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes.

Results: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect.

Conclusion: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.
0959-8138
c6581
Jentink, Janneke
3290400b-560f-4bce-9567-0f2b72c6ee2a
Dolk, Helen
cba8a92e-f592-4184-b729-bf852da54e6e
Loane, Maria A.
99115386-eecf-4058-9887-2ce298aa157e
Morris, Joan K.
166e8a8b-5205-4819-b52b-96edfda3e68b
Wellesley, Diana
17cbd6c1-0efb-4df1-ae05-64a44987c9c0
Garne, Ester
1e675ea0-ae2a-42a4-a851-894b4d1abd58
de Jong-van den Berg, Lolkje
6f404fff-c7e2-46cd-a5a4-6dd19e22bb53
EUROCAT Antiepileptic Study Working Group
Jentink, Janneke
3290400b-560f-4bce-9567-0f2b72c6ee2a
Dolk, Helen
cba8a92e-f592-4184-b729-bf852da54e6e
Loane, Maria A.
99115386-eecf-4058-9887-2ce298aa157e
Morris, Joan K.
166e8a8b-5205-4819-b52b-96edfda3e68b
Wellesley, Diana
17cbd6c1-0efb-4df1-ae05-64a44987c9c0
Garne, Ester
1e675ea0-ae2a-42a4-a851-894b4d1abd58
de Jong-van den Berg, Lolkje
6f404fff-c7e2-46cd-a5a4-6dd19e22bb53

Jentink, Janneke, Dolk, Helen, Loane, Maria A., Morris, Joan K., Wellesley, Diana, Garne, Ester and de Jong-van den Berg, Lolkje , EUROCAT Antiepileptic Study Working Group (2010) Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study. BMJ, 341, c6581. (doi:10.1136/bmj.c6581).

Record type: Article

Abstract

Objective: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy.

Design: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications.

Setting: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005.

Participants: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98?075 registrations of malformations covering over 3.8 million births.

Main outcome measures: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes.

Results: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect.

Conclusion: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.

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Published date: 2 December 2010
Organisations: Human Genetics

Identifiers

Local EPrints ID: 169247
URI: http://eprints.soton.ac.uk/id/eprint/169247
ISSN: 0959-8138
PURE UUID: ff4e9270-b171-4efc-bbe9-37bb48639286

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Date deposited: 13 Dec 2010 12:26
Last modified: 14 Mar 2024 02:20

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Contributors

Author: Janneke Jentink
Author: Helen Dolk
Author: Maria A. Loane
Author: Joan K. Morris
Author: Diana Wellesley
Author: Ester Garne
Author: Lolkje de Jong-van den Berg
Corporate Author: EUROCAT Antiepileptic Study Working Group

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