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

Methods

Results

Over 1400 studies were considered. Most were not retrieved because two independent reviewers considered that they did not relate to the question under review. Of the studies considered, 74 studies were retrieved and 51 of these were excluded. Studies were excluded because they had no concurrent control group (18), they did not examine major malformations (9), they were carried out on animals (1), benzodiazepines were not studied (1), exposure was not during the first trimester (1), studies were review articles or commentaries (5), data presented were duplicated in an included trial (6), results for benzodiazepines were not reported separately from other agents (5), only a range of results were reported (1), only partial data were provided (2), benzodiazepine exposure was not linked to malformations (1), and the study was not available in North America (1). A complete list of excluded studies is available from the authors. Thirteen studies that examined major malformations, 11 13 14 23^–32 11 studies that examined oral cleft alone, 1 7 10 13 27 30 31 33^–36 and three studies that examined other specific malformations37^–39 were included (some providing information for more than one evaluation). One study unpublished at the time of consideration has since been published.26

Of the 23 included studies, 20 (87%) predefined exposure 1 10 11 13 14 23 25^–28 30^–39 and 22 (96%) predefined the outcome. 1 7 10 11 13 14 23 25^–32 34^–40 Exposure was ascertained mainly through interview with the mother (61% of studies) 7 10 14 25^–30 33 34 36^–38 and outcome was confirmed mainly by using physician examination or records (44% of studies) 11 13 14 25 28 30 32 34 39 40 or malformation registries (30% of studies). 7 10 29 31 35^–37 Equal diagnostic examination between exposed and unexposed groups occurred in all but three studies. 14 25 35 Hartz et al gathered and confirmed information about malformed babies from different sources but did not do so for control babies.14 Czeizel et al sent surveys to up to three controls if initial controls did not respond.35 Laegreid et al used blood samples to confirm benzodiazepine exposure and had blood sample results for 78% of cases but only 66% of controls.25

Various benzodiazepines were used or prescribed, although 48% of the studies (11/23) examined the use of chlordiazepoxide or diazepam only. 10 11 14 23 28 30 32^–34 37 40 Only two studies provided any information regarding the duration of maternal exposure. 25 26 The indications for use were infrequently provided. 11 25 26 41 Sixty one percent (14/23) of studies reported concurrent use of at least some prescription medications. 1 10 11 13 25 26 28^–32 37^–39

Associations with major malformations

Data pooled from seven cohort studies did not show an association between fetal exposure to benzodiazepines during pregnancy and major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1.35; homogeneity χ²=1.74; P=0.62; table 1, figure 1). 11 14 23^–27 Two cohort studies carried out in patients with epilepsy were located. Results of both were not significant. 30 31

Fig 1

Association of major malformations with prenatal exposure to benzodiazepines

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Combination of four case-control studies showed that major malformations were associated with the use of benzodiazepines during pregnancy (3.01; 1.32 to 6.84; χ²=9.87; P=0.008). 13 28 29 32 All included case-control studies that evaluated major malformations used normal babies as controls so subgroup analyses based on types of controls could not be done. Regression analyses for both cohort and case-control studies showed no obvious heterogeneity.

Associations with oral cleft

Data pooled from three cohort studies showed no relation between fetal exposure to benzodiazepines during pregnancy and oral cleft (1.19; 0.34 to 4.15; χ²=0.01; P=0.997; table 2, figure 2). 1 27 33 The analysis of six case-control studies produced a significant odds ratio for oral cleft of 1.79 (1.13 to 2.82; χ²=11.39; P=0.01). 7 10 13 34^–36 Subgroup analysis of the case-control studies with normal babies as controls showed no significant association with oral cleft (1.63; 0.89 to 2.96; χ²=3.81; P=0.15). 7 13 35 Similarly, no significant association was found in analyses of case-control studies with malformed babies as controls (2.03; 0.88 to 4.71; χ²=6.90; P=0.10). 10 34 36 Regression analyses for both cohort and case-control studies showed no obvious heterogeneity.

Fig 2

Association of oral cleft with prenatal exposure to benzodiazepines

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In general, for the analyses of major malformation and oral cleft the risks for case-control studies were grouped at a different end of the distribution than the risks for cohort studies, showing that the relative risks within each study design are of the same magnitude but the absolute differences in risk are of a different order of magnitude between studies (case-control about 10 times greater than cohort). This finding suggests a possible systematic difference between study designs. Funnel plot analyses produced funnel shaped plots, indicating that there was no obvious publication bias.

Two case-control studies examined the association of benzodiazepine use with fetal cardiac malformations. One showed no association between exposure and outcome; the other did. 37 38 One study examined benzodiazepine use with malformations of the central nervous system and did not find any association between exposure and outcome.39

Possible confounding and bias

Concomitant exposure to other medications can result in an overestimation of the risk of benzodiazepines. Fourteen studies, eight of which were case-control, allowed exposure to other potentially teratogenic medications. 1 10 11 13 25 26 28^–32 37^–39 This large number confounds the results. In most studies no information on duration or indication for use of benzodiazepines was provided. Therefore it was difficult to determine if any of the populations included have an increased or decreased risk of major malformations. Studies that evaluated the risk of fetal malformations in women with epilepsy were separated from the main analysis as fetuses born to such women already have an increased risk of major malformations.43 Information is lacking regarding the risk of developing specific malformations.

The use of a normal baby as a control in a case-control study can produce recall bias, as mothers of malformed babies may be more likely to recall exposures than mothers of normal babies. The subgroup analysis that compared benzodiazepine use in mothers of healthy babies as controls compared with mothers of malformed babies as controls produced similar effect sizes, suggesting that recall bias did not have a large effect on study outcome.

The present meta-analysis has several limitations. The number of reports was relatively small and may have limited the power of our analysis. Also, although the overall sample was large, most cases for analyses of both oral cleft and major malformations were derived from only three studies. 1 14 23 With regard to assessment of malformations, the studies used wide ranging definitions for identification of malformations to be considered. When we examined the association of benzodiazepines with cleft lip and cleft palate we had to combine these two malformations as “oral cleft” because many studies combined these malformations as one entity and it was not possible to stratify the data. 1 10 13 36

This study differs from previous reviews. Altshuler et al reported an association between benzodiazepines and oral cleft, but the review included studies that did not have any control groups or studies that did not have concurrent control groups.44 That method of analysis may have seriously increased the strength of association found and the heterogeneity found when studies were combined and thereby produced different results. McElhatton provided a narrative review that succinctly summarised the opposing information, but because the studies presented were not combined systematically or quantitatively the conclusions remain controversial and inconclusive.45

Conclusions

Because women commonly use benzodiazepines and half of all pregnancies are unplanned, counselling of women on the safety of such exposure is clinically important. Pooled data from cohort studies showed no apparent association between benzodiazepine use and the risk for major malformations or oral cleft alone. There was, however, a small but significantly increased risk for oral cleft according to data from the available case-control studies. More case-control studies examining these events are needed especially because the available studies are not homogeneous. Even when the “worst case scenario” is assumed, benzodiazepines do not seem to be major human teratogens, but because some cases of cleft lip can be visualised by fetal ultrasound level 2 ultrasonography should be used to rule out this malformation.