Women with incident exposure to short- and long-acting benzodiazepines and all specific benzodiazepine agents during early pregnancy were more likely to suffer spontaneous abortion (SA) than women not exposed to the drugs, rising to more than three times the risk with diazepam, according to new research* from Canada published in JAMA Psychiatry. The study authors urged doctors to evaluate carefully the risk/benefit ratio of prescribing benzodiazepines in early pregnancy for common problems such as insomnia, anxiety, and mood disorders, given that alternative nonpharmacologic treatments exist.
The research team, from Montreal, Quebec, pointed out that we already know that benzodiazepine use in early pregnancy is associated with SA, but there have been no studies so far into the association between specific benzodiazepine agent exposure and the risk of SA. So, they conducted a nested case—control study to quantify the risk of SA associated with gestational benzodiazepine incident use by drug class, duration of action, and specific benzodiazepine agent.
They analysed 18 years’ data from 1 January 1998 for all 442,066 pregnancies covered by the Quebec Prescription Drug Insurance Plan. They randomly matched each case of SA (defined as pregnancy loss between the beginning of the sixth week of gestation and the 19th completed week of gestation) with up to five controls. They defined benzodiazepine exposure as at least one filled prescription between the first day of the last menstrual period and the index date (the calendar date of the SA diagnosis), and then categorised exposure by overall use, long- or short-acting benzodiazepine, and specific benzodiazepine agents.
The researchers reported that of all 27,149 pregnancies that ended in SA, 375 (1.4%) were among women exposed to benzodiazepines in early pregnancy compared with 788 (0.6%) of the 134,305 matched control pregnancies (crude odds ratio, OR 2.39). They then adjusted for potential confounders, including maternal mood and anxiety disorders before pregnancy. Compared with non-use, benzodiazepine exposure in early pregnancy was associated with a significantly increased risk of SA (adjusted odds ratio, AOR 1.85). The excess risk was similar among pregnancies exposed to short-acting (284 exposed cases; adjusted OR 1.81) and long-acting (98 exposed cases; AOR 1.73) benzodiazepines during early pregnancy.
Their analysis showed that risks of SA for individual drugs (AOR) were: alprazolam 2.02; bromazepam 2.34; clonazepam 1.77; diazepam 3.43; flurazepam hydrochloride 1.13 – not statistically significant; lorazepam 1.75; oxazepam 1.48; temazepam 2.74; triazolam 1.14 – not significant. The strength of the association between benzodiazepines and SA increased along with diazepam-equivalent daily dose.
They concluded: “An increased risk of SA was observed among early pregnancies with incident exposure to short and long-acting benzodiazepines and all specific benzodiazepine agents during early pregnancy. Insomnia, anxiety, and mood disorders are prevalent during pregnancy; clinicians should carefully evaluate the risk/benefit ratio of prescribing benzodiazepines in early pregnancy since alternative nonpharmacologic treatments exist.”
*Sheehy O, Zhao J, Bérard A. Association between incident exposure to benzodiazepines in early pregnancy and risk of spontaneous abortion. JAMA Psychiatry. Published online 15 May 2019. doi:10.1001/jamapsychiatry.2019.0963