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

BMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c6581 (Published 03 December 2010) Cite this as: BMJ 2010;341:c6581
  1. Janneke Jentink, research fellow and lecturer in pharmacoepidemiology1,
  2. Helen Dolk, professor of epidemiology and health services research2,
  3. Maria A Loane, EUROCAT research fellow and lecturer in public health2,
  4. Joan K Morris, professor of medical statistics3,
  5. Diana Wellesley, clinical geneticist4,
  6. Ester Garne, consultant paediatrician and EUROCAT perinatal epidemiologist5,
  7. Lolkje de Jong-van den Berg, professor in pharmacoepidemiology, 1
  8. for the EUROCAT Antiepileptic Study Working Group
  1. 1Department of PharmacoEpidemiology and PharmacoEconomics, Division of Pharmacy, University of Groningen, Netherlands
  2. 2EUROCAT Central Registry, Institute of Nursing Research and School of Nursing, University of Ulster, Antrim, UK
  3. 3Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  4. 4Wessex Clinical Genetics Service, Southampton University Hospitals Trust, Southampton, UK
  5. 5Lillebaelt Hospital, Kolding, Denmark
  1. Correspondence to: L de Jong-van den Berg l.t.w.de.jong-van.den.berg{at}rug.nl
  • Accepted 27 September 2010

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.

Footnotes

  • We thank J Morrow, U Kini, F Vajda, and K Wide for providing us with more detailed information about the cases described in their papers1 3 4 5 and I Barisic for case review.

  • EUROCAT Antiepileptic Study Working Group: Christine Verellen-Dumoulin (Centre de Génétique Humaine IPG), Vera Nelen (Provinciaal Instituut voor Hygiene), Belgium; Ingeborg Barisic (Children’s University Hospital Zagreb, Croatia); Ester Garne (Lillebaelt Hospital, Kolding, Denmark); Babak Khoshnood (Institut National de la Sante et de la Recherche Medicale, INSERM) Bérénice Doray (Registre des Malformations Congenitales D’Alsace), France; Simone Poetzsch (Otto-von-Guericke Universitat Megdeburg), Awi Wiesel (Johannes Gutenberg Universitat, Genurtenregister Mainzer Modell), Germany; Mary O’Mahony (Health Service Executive, Ireland); Anna Pierini (Istituto di Fisiologia Clinica del Consiglio Nazionale delle Ricerche), Francesca Rivieri (Azienda Ospedaliero Universitaria di Ferrara), Italy; Miriam Gatt (Department of Health Information and Research, Malta); Marian Bakker (University Medical Centre Groningen, University of Groningen, Netherlands); Kari Melve (Norwegian Institute of Public Health, Medical Birth Registry of Norway); Anna Latos-Bielenska, Jan P Mejnartowicz (Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu, Poland); Isabel Portillo (Direccion Salud Publica, Departamento Sanidad, Gobierno Vasco, Spain); Marie-Claude Addor (Registre Vaudois des Malformations, Switzerland); David Tucker (Swansea NHS Trust, Congenital Anomaly Register and Information Service for Wales).

  • Contributors: JJ, HD, and LJvB drafted the protocol and paper. LJvB, JJ, and ML coordinated the study. JJ conducted the literature review, conducted validation and coding of drug exposure information, and constructed the tables. ML and JJ compiled the study database. JM conducted the statistical analysis. All authors corrected all versions of the paper. EG, DW, and IB classified malformed cases. EG and IB and all other members of the EUROCAT Antiepileptic Drug Exposure Working Group not mentioned above contributed data to the study from their registry, checked the accuracy of drug exposure information, checked data tables, and commented on the first and final drafts. HD and LJvB are guarantors.

  • Funding: The EUROCAT Central Database is supported in part by the European Public Health Programme, with various sources of public funding for individual registries. Additional funding was obtained from GlaxoSmithKline for a study of lamotrigine, during which the antiepileptic study database was constructed (all authors were involved in this study). GlaxoSmithKline was not involved in the present study.

  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no personal support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required

  • Data sharing: No additional data available.

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