Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies

• Published in: BMJ Vol. 317; no. 7162; pp. 839 - 843
• Main Authors: Dolovich, Lisa R, Addis, Antonio, Vaillancourt, J M Régis, Power, J D Barry, Koren, Gideon, Einarson, Thomas R
• Format: Journal Article
• Language: English
• Published: London British Medical Journal Publishing Group 26.09.1998; British Medical Association; BMJ Publishing Group LTD; BMJ Publishing Group; British Medical Journal
• Edition: International edition
• Subjects: Abnormalities, Drug-Induced - etiology; Azepines; Benzodiazepines; Benzodiazepines - adverse effects; Biological and medical sciences; Birth defects; Case control studies; Cleft lip; Cleft Lip - chemically induced; Cleft Palate - chemically induced; Cohort Studies; Epilepsy; Female; First trimester of pregnancy; Humans; Infants; Maternal Exposure; Medical sciences; Meta analysis; Neuropharmacology; Pharmacology. Drug treatments; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Studies; Human; Statistical analysis; Cleft lip; First trimester; Case control study; Female genital diseases; Metaanalysis; Pregnancy; Tranquillizer; Association; Malformation; Cohort study; Risk factor; Benzodiazepine derivatives; Complication; Female
• ISSN: 0959-8138; 0959-8146; 1468-5833; 1756-1833
• DOI: 10.1136/bmj.317.7162.839

Abstract Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. Design Meta-analysis. Setting: Studies from 1966 to present. Subjects: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. Interventions:Data extraction and quality assessment were done independently and in duplicate. Main outcome measures: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. Results:Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1.35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). Conclusions:Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.