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Here is a simple question with strong clinical implications. Do benzodiazepines cause major congenital malformations with first-trimester exposure? In a new study, the findings are relatively clear besides an important additional result. Let’s take a look at this paper, which presented a straightforward question and an honest answer.
Dr. Sophie Grigoriadis and 12 colleagues, mostly from the University of Toronto, dredged through the literature on benzodiazepine exposure in pregnancy and identified 24,000 potentially relevant papers, selecting 56 for close examination. Eight of these papers met their criteria for inclusion because they described outcomes with sufficient rigor to consider on the order of 5,000 exposed pregnancies and 2 million unexposed pregnancies as a comparison group. For groups that size, we can imagine there are going to be malformations, roughly 200 in the exposed group and 64,000 out of 2 million in the unexposed pregnancies.
The odds ratio for major congenital malformations, namely how much did benzodiazepines contribute to an additional risk, was 1.1. A 1.0 would mean no contribution whatsoever. So, 1.1 is small. It is not statistically significant. The p-value was 0.07, and the confidence intervals ran from 0.99 to 1.3. It is close, but maybe there is still a little room to worry about. The authors conclude, “We found no significant risk for congenital malformation.” However, here is the important twist which the authors indicate has not been previously reported: Three of those 8 studies examined data on pregnancies with exposure to both benzodiazepines and antidepressants. In the women thus exposed, the rate of major congenital malformations was increased relative to no exposure. The odds ratio was 1.4, but the p-value was 0.008.
Does this mean we should start hunting for women who are on both an antidepressant and a benzodiazepine in our practice or our consulting work in primary care? In reviewing the risks with these women, should they become pregnant? Perhaps not. This is the first report of this possible connection of benzodiazepines plus antidepressants and malformations. The authors did this study in the first place because benzodiazepine exposure alone had been shown in some studies to pose a risk, and in other studies, there was no significant increase.
Behind all of these numbers lies a risk that is much harder to quantify—namely, the risk to a developing child of mom’s untreated symptoms, like anxiety, depression, mood, and energy cycling. That is the key comparison. So, what is the risk if we do not use these medications at all? We are not getting a look at that in this meta-analysis. So, at minimum, we might say that a woman who is taking a benzodiazepine and an antidepressant should be getting an excellent response to that combination to justify their continuation if pregnancy is potentially being considered or it is a possibility.
In summary, we can thank the authors here for a considerable effort in winnowing vast literature to give us this meta-analysis of 8 studies with 2 conclusions. First, no statistically increased risk from benzodiazepines alone. And second, a new finding of risk from the combination of benzodiazepines and antidepressants.
Abstract
Benzodiazepine Use During Pregnancy Alone or in Combination With an Antidepressant and Congenital Malformations: Systematic Review and Meta-Analysis
Sophie Grigoriadis, Lisa Graves, Miki Peer, Lana Mamisashvili, Cindy-Lee Dennis, Simone N Vigod, Meir Steiner, Cara Brown, Amy Cheung, Hiltrud Dawson, Neil Rector, Melanie Guenette, Margaret Richter
Objective: To summarize the effects of antenatal benzodiazepine exposure as monotherapy and in combination with antidepressants on the risk of congenital malformations.
Data sources: MEDLINE, PsycINFO, CINAHL, Embase, and the Cochrane Library were searched from inception to June 30, 2018, using controlled vocabulary and keywords (eg, prenatal, benzodiazepines, malformation).
Study selection: English-language cohort studies with prospectively collected data on the risk of malformations in benzodiazepine-exposed and -unexposed offspring were evaluated. 23,909 records were screened, 56 studies were assessed for eligibility, and 8 studies were included.
Data extraction: Quality was assessed by 2 independent reviewers and data extracted. Random-effects models were used for outcomes (≥ 3 studies). Subanalyses examined effect of potential moderators including study quality and timing of exposure, among others.
Results: Prenatal benzodiazepine use was not associated with an increased risk of congenital malformations (odds ratio [OR] = 1.13; 95% CI, 0.99 to 1.30, 8 studies, n = 222/5,195 exposed and 64,335/2,082,467 unexposed), including with first trimester exposure specifically (OR = 1.08; 95% CI, 0.93 to 1.25, P = .33; 5 studies, n = 181/4,331 exposed and 64,308/2,081,463 unexposed). There was no significant association with cardiac malformation following exposure (OR = 1.27; 95% CI, 0.98 to 1.65, P = .07; 4 studies, n = 61/4,414 exposed and 19,260/2,033,402 unexposed). However, concurrent use of benzodiazepine and antidepressants during pregnancy was associated with a significantly increased risk of congenital malformations (OR = 1.40; 95% CI, 1.09 to 1.80, P = .008; 3 studies).
Conclusions: Benzodiazepine exposure during pregnancy does not appear to be associated with congenital malformations or with cardiac malformations specifically. There may be an increased risk of congenital malformations when benzodiazepines are used in conjunction with antidepressants, suggesting that caution with this combination is warranted.
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Reference
Grigoriadis, S., Graves, L., Peer, M., Mamisashvili, L., Dennis, C., Vigod, S. N., Steiner, M., Brown, C., Cheung, A., Dawson, H., Rector, N., Guenette, M., & Richter, M. (2019). Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations. The Journal of Clinical Psychiatry, 80(4).
