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Use of benzodiazepine agents in early pregnancy was associated with increased risk of spontaneous abortion, according to a nested case-control study.

Women who started using benzodiazepines in pregnancy were at an increased risk for miscarriage from the sixth through 19th gestational week compared to unexposed women (adjusted odds ratio 1.85, 95% CI 1.61-2.12), after controlling for pre-pregnancy maternal mood and anxiety disorders, reported Anick Bérard, PhD, of the Centre Hospitalier Universitaire Sainte-Justine in Montreal, Canada, and colleagues.

Increasing diazepam-equivalent doses strengthened the association between benzodiazepine exposure and spontaneous abortion, with women who received the highest dose (>20 mg) at the highest risk for miscarriage (aOR 2.55, 95% CI 1.08-6.01, P<0.01), although this was evaluated in just 10 cases, they wrote in .

"Anxiety and mood disorders need to be treated during pregnancy," Bérard told 番茄社区 in an email. "Given the high prevalence of anxiety and mood disorders during pregnancy, physicians need to evaluate the benefits and risks of using benzodiazepines given that alternative nonpharmacologic treatments exist."

Benzodiazepines have been shown to and are classified as an , indicating the potential benefits of these drugs may warrant their use, despite positive evidence of human fetal risk, Bérard said.

For this study, she and her team collected data from the of all pregnant women within the Quebec Public Prescription Drug Insurance Plan from 1998 to 2015. Women from the ages of 15 to 45 who were continuously enrolled one year prior to their last menstrual period and throughout their pregnancy were included. Excluded were those exposed to teratogens within the first trimester or women with untreated seizures, a history of epilepsy, prior use of benzodiazepines, or planned abortions.

Spontaneous abortions were defined as occurring from the sixth gestational week through the 19th completed week and benzodiazepine exposure was classified as filling at least one prescription from the last menstrual period to the miscarriage diagnosis.

In total, 6.1% of 442,066 pregnancies ended in spontaneous abortions. Case pregnancies were a mean age of around 24. These cases were matched to up to five controls for a total of 134,305 control pregnancies.

Compared to the matched control group, women who experienced pregnancy loss were significantly more likely to be older and on welfare, Bérard reported.

The authors also found that compared to controls, case pregnancies were also more likely to have hypertension or asthma, have diagnoses of drug, tobacco, and alcohol dependence, hospitalization or emergency department visits, or concomitant antidepressants or antipsychotics exposures.

There were 375 cases who were exposed to benzodiazepines in early pregnancy compared with 788 controls. The most commonly prescribed agents were lorazepam (44.8%) and clonazepam (23.4%), the authors noted. Diazepam was linked with the highest risk of spontaneous abortion (aOR 3.43, 95% CI 1.42-8.32, P=0.006).

Short-acting (half-life ≤24 hours) benzodiazepines were associated with an increased risk of spontaneous abortion (aOR 1.81, 95% CI 1.55-2.12) compared to controls, as were long-acting (>24 hours) benzodiazepines (aOR 1.73, 95% CI 1.31-2.28), the authors noted.

This upped the risk for spontaneous pregnancy from 6.1% to 11.3% for short-acting benzodiazepine use and from 6.1% to 10.6% for long-acting use, Bérard said.

She also noted that just three agents were not associated with a significantly higher risk of spontaneous abortion, including flurazepam hydrochloride, triazolam, and combined antipsychotics, though these still upped the risk.

The authors noted that tobacco and alcohol dependence, as well as the number of women prescribed folic acid, were used as proxies for missing data on smoking, alcohol, and folic acid intake. The study was also limited because researchers did not have data on assisted reproduction and only included women in the QPC cohort. Spontaneous abortions occurring before 6 weeks and after 20 weeks were also not included. Lastly, the analysis of individual benzodiazepine agents had a lower statistical power than the overall analysis due to smaller sample sizes.

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