Benzodiazepines Linked to Risk for Spontaneous Abortion

Liam Davenport

April 09, 2019

WARSAW, Poland — Women who begin treatment of anxiety with benzodiazepines during pregnancy have a significantly increased risk for spontaneous abortion compared to their counterparts who do not take these drugs, results of a large-scale study suggest.

Anick Bérard, PhD, from the Faculty of Pharmacy, University of Montreal, Quebec, Canada, and colleagues evaluated more than 27,000 cases of spontaneous abortion and 1.3 million unaffected pregnancies during at 17-year period from an ongoing study.

The investigators found that incident use of benzodiazepines during pregnancy was associated with an 85% increase in the risk of having a clinically detected spontaneous abortion between the 6th and 19th week of pregnancy.

Although the duration of action of the drug did not seem to affect risk, there was an increase in risk with increasing equivalent dose, so that women taking the highest doses had a more than 2.5-fold increased risk for spontaneous abortion.

The findings were presented here at the European Psychiatric Association (EPA) 2019 Congress.

Dose-Response Effect

Bérard said, "Basically, benzodiazepine use seems to be associated with an increase in spontaneous abortion, regardless of type, regardless of duration of action, and there seems to be a dose–response effect."

She explained that this equates to an increase in the absolute rate of spontaneous abortion from around 6% in the background population to around 10%.

"It's a small increase in the risk," Bérard added, "and obviously every time a physician needs to prescribe benzodiazepines, you have to look at the risks and the benefits."

For the study, the investigators gathered data from the ongoing Quebec Pregnancy Cohort, which covers 422,066 pregnancies between January 1998 and December 2015.

The researchers excluded women who had previously taken benzodiazepines and those who underwent induced or planned abortions. They included 27,149 women who experienced clinically detected, spontaneous abortion between the 6th and 19th week of pregnancy (mean, 13 weeks' gestation) during the study period.

Each case patient was then matched with up to five randomly selected women who had not experienced spontaneous abortion, yielding a control group of 134,305 women.

The results showed that women who experienced spontaneous abortion were significantly more likely to have used benzodiazepines for the first time during pregnancy than other women, at 1.4% vs 0.6% (odds ratio adjusted for comedication use and indication, 1.85).

Women who experienced spontaneous abortion were also more likely than control women to be aged 35 years or older at gestation and to have been diagnosed with mood and anxiety disorders or insomnia in the 12 months prior to pregnancy.

When the researchers more closely analyzed benzodiazepine exposure, they found that, with respect to the risk for spontaneous abortion, associations were similar for short-acting benzodiazepines and for long-acting drugs (adjusted odds ratios, 1.81 and 1.73, respectively). Short-acting drugs were defined as those having a duration of action of up to 24 hours.

However, there appeared to be a dose–response effect with respect to mean daily diazepam equivalent dose of benzodiazepines across the cohort.

For women whose mean equivalent dose was 1–5 mg/day, the adjusted odds ratio for spontaneous abortion was 1.73. The odds rose to 1.96 for women who took an equivalent dose of 6–20 mg/day and to 2.55 for women who took more than 20 mg/day.

Moreover, certain benzodiazepines, such as diazepam (multiple brands), temazepam (multiple brands), bromazepam (multiple brands), alprazolam (multiple brands), and clonazepam (Klonapine, Roche), appeared to be more strongly associated with spontaneous abortions than other benzodiazepines.

Bérard cautioned against overinterpreting these results, however, because confounding may have occurred if the number of patients who were exposed to some drugs was small.

Think Twice

Commenting on the findings for Medscape Medical News, Farzaneh Saeedzadeh-Sardahaee, MD, Norwegian University of Science and Technology, Trondheim, Norway, who chaired the poster session, said that in her practice, she sees women who become very anxious because they have become pregnant, whether the pregnancy is wanted or unwanted, and there aren't any other short-term treatments that work.

"If you ask me as a clinician, I would think twice before giving them any benzodiazepines, and I would ask them what they want to do with the pregnancy. Obviously, if they don't want to keep the baby, it's a completely different scenario, and many of them don't want the baby. But if they do want it, then I would be very cautious — I think anyone would be very cautious."

Saeedzadeh-Sardahaee added that more severe cases are "more problematic, because you have to do something, and then maybe you could use other medications that would indirectly reduce the anxiety."

However, one problem is that some medications take time to work.

Saeedzadeh-Sardahaee said, "Benzodiazepines can give you a window, if you absolutely have to" use them.

"You can use another medication as an adjunct, and then use benzodiazepines short term, at the lowest possible dose. Once you have titrated the dose of, for example, the antidepressant that is supposedly going to combat the anxiety, you can get rid of the benzodiazepines," she said.

However, she added that "it is easily said, but it is not really easily done."

The study was funded by the Canada Foundation for Innovation, Fonds de recherche Santé Québec, and Réseau Québécois de recherche sur les medicaments. Bérard is a consultant for plaintiffs in litigation involving antidepressants.

European Psychiatric Association (EPA) 2019 Congress: Poster EPA19-0071. Presented April 7, 2019.

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