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

BMJ 1998;317:839-843 ( 26 September )

Papers

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

Lisa R Dolovich, PharmD candidate, ^a Antonio Addis, research fellow, ^b J M Régis Vaillancourt, PharmD candidate, ^a J D Barry Power, PharmD candidate, ^a Gideon Koren, director of MotheRisk and clinical pharmacology, ^b Thomas R Einarson, professor of social and administrative pharmacy. ^c

^a Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2, ^b MotheRisk Programme, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8, ^c Faculty of Pharmacy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5S 2S2

Correspondence to: Dr Koren

Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of majormalformations 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 malformationsor oral cleft alone, measured as odds ratios and 95% confidenceintervals 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 oralcleft (1.19; 0.34 to 4.15). Analysis of case-control studies showedan association between exposure to benzodiazepines and developmentof 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 therisk of major malformations or oral cleft. On the basis of pooleddata from case-control studies, however, there was a significantincreased risk for major malformations or oral cleft alone. Untilmore research is reported, level 2 ultrasonography should be usedto 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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Rapid Responses:

Read all Rapid Responses

What is meant by 'ruling out?': Ed Walker
bmj.com, 28 Sep 1998 [Full text]
Is meta-analysis of observational studies useful?: Christopher Cates
bmj.com, 29 Sep 1998 [Full text]
Quality of primary studies should affect the inferences made from meta-analyses: Khlaid S Khan
bmj.com, 30 Oct 1998 [Full text]
Impact of recall bias in meta-analysis of benzodiazepine use in pregnancy: Samuel Erny, et al.
bmj.com, 9 Jan 1999 [Full text]