Introduction

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Benzodiazepines are commonly used for anxiety, insomnia, and epilepsy. Their use is substantial, even by pregnant women. Bergman et al found that 2% of pregnant women in the United States who were receiving Medicaid benefits filled one or more prescriptions for benzodiazepines during pregnancy.¹ As about half of pregnancies in the United States are unplanned,² many women may inadvertently expose the fetus to benzodiazepines during the first trimester. Therefore, women require valid information regarding the risks of benzodiazepine use during pregnancy to avoid exposure to teratogens but also to ensure that they are not denied medication during pregnancy because of unfounded fear of unknown consequences.

Antepartum exposures to benzodiazepines have been associated with teratogenic effects (for instance, facial cleft, skeletal anomalies) in some animal studies ^{3 4} but not others. ^{5 6} Early case-control studies in humans found that maternal benzodiazepine exposure increased the risk of fetal cleft lip and cleft palate. ^{7 8} Subsequent reports implicated benzodiazepines as the cause of major malformations^9-11 and a benzodiazepine syndrome similar to fetal alcohol syndrome. ^{9 12 13} Numerous studies, however, have refuted these findings. ^{1 14-16} These contradictory results have led to considerable controversy surrounding the use of benzodiazepines in pregnancy. We carried out a meta-analysis to examine whether exposure to benzodiazepines during at least the first trimester is associated with increased risk of major malformations or oral cleft.

	Methods

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Data sources
We systematically searched Medline (1966 to December 1997 via Ovid), Embase (1980 to December 1997), Reprotox (a database of reviews on reproductive toxicity topics), references in textbooks on drugs in pregnancy, references of included studies, and review articles. "Benzodiazepine(s)" (exploded as a subject heading or the various preparations put in as textwords) was combined with the following words as subject headings or textwords: fetal diseases, infant, fetal organ maturity, cleft lip, cleft palate, major malformations, and prenatal exposure.

Study selection
Searches were reviewed or completed independently and in duplicate. Cohort or case-control studies in any language considered pertinent were retrieved and included if they examined the relation between human maternal exposure to benzodiazepines in at least the first trimester and major malformations or oral cleft alone and included an unexposed concurrent control group. Major malformations were those described by Heinonen et al, which, among others, include cleft palate and cleft lip.¹⁷ Hereafter "oral cleft" is used for cleft lip or cleft palate, or both. Studies examining only certain subtypes of malformations or studies in patients with epilepsy were included but considered separately from the main analysis. Only studies where exposure occurred during the first trimester were considered as the fetus is most susceptible to teratogens during the period between the 1st and 8th weeks of organogenesis, the lip forms between weeks 4 and 8, and the oral palate forms between weeks 5 and 12. Studies were excluded if they were case series or reports, editorials, reviews, animal studies or used only stillbirths or abortions or the data could not be extracted.

Data extraction
Once the study was included data were extracted and quality assessed independently and in duplicate. Discrepancies were resolved through consensus. Study quality was assessed by using predetermined criteria. These aspects of study quality are provided in the results section as descriptive information.

Data analysis
Studies of different designnamely, cohort and case-control studieswere analysed separately because of differing threats to their internal validity. ^{18 19} Data were analysed by calculating the odds ratio and 95% confidence interval with a random effects model.²⁰ We also calculated ² tests for heterogeneity.²¹ Further sensitivity analyses were performed for case-control studies to assess the impact of recall bias through the use of normal babies compared with malformed babies as controls.

	Results

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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 malformations^37-39 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 ²=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}

View larger version (19K): [in this window] [in a new window]   Fig 1.    Association of major malformations with prenatal exposure to benzodiazepines

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; ²=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; ²=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; ²=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; ²=6.90; P=0.10). ^{10 34 36} Regression analyses for both cohort and case-control studies showed no obvious heterogeneity.

View larger version (16K): [in this window] [in a new window]   Fig 2.    Association of oral cleft with prenatal exposure to benzodiazepines

	Discussion

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Data taken from cohort studies showed no significant association between benzodiazepines taken during the first trimester and either major malformations or malformations of the oral cleft alone. However, data from case-control studies showed a small but significant increased risk for these events. This finding may reflect the substantially higher sensitivity of case-control studies to examine the risk of specific malformations or it may be chance.

The tests of heterogeneity also showed that the cohort studies were not heterogeneous for both major malformation and oral cleft, whereas the case-control studies for oral cleft were heterogeneous, which decreases the reliability of these marginally significant results.

A case series of eight children exposed to benzodiazepines in utero suggested the existence of a benzodiazepine syndrome.⁹ This syndrome was described as dysmorphic features, growth aberrations, and abnormalities of the central nervous system. ^{9 12 13} Our results, however, do not confirm the presence of this syndrome. Even before this report alternative causes for these findings, such as Zellweger syndrome or other genetic abnormalities, have been suggested.⁴²

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.

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.