Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies |
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| Authors: | Lisa R Dolovich Antonio Addis J M Régis Vaillancourt J D Barry Power Gideon Koren Thomas R Einarson |
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| Institution: | aFaculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2, bMotheRisk Programme, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8, cFaculty of Pharmacy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5S 2S2 |
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| 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. Key messages - Pooled data from cohort studies showed no apparent association between fetal exposure to benzodiazepines and the risk for major malformations or oral cleft
- Data from case-control studies showed that risk for major malformations or oral cleft alone was increased
- Until more studies are done, it is prudent to perform level 2 ultrasonography to rule out visible forms of cleft lip
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