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Benzodiazepine use during pregnancy was associated with an increased risk of miscarriage, according to a nationwide study in Taiwan.

The population-based, case-time-control study of more than 3 million pregnancies found that benzodiazepine use was linked with a 69% increased risk of miscarriage (95% CI 1.52-1.87), according to Fei-Yuan Hsiao, PhD, of National Taiwan University in Taipei, and colleagues.

The increased risk was present for both long-acting (OR 1.67, 95% CI 1.44-1.93) and short-acting (OR 1.66, 95% CI 1.47-1.87) benzodiazepines, they reported in .

"The research underscores the need for careful consideration of the risks and benefits when prescribing benzodiazepines to pregnant women," Hsiao told MedPage Today in an email.

"Healthcare providers should be aware of the potential increased risk of miscarriage and discuss this with patients who rely on benzodiazepines," Hsiao added. "The decision to prescribe benzodiazepines should involve a thorough evaluation of the potential risks to the fetus and benefits to the mother and their offspring."

The researchers said their findings were consistent with a of data from five studies that showed a significant association between benzodiazepine use during pregnancy and miscarriage risk (OR 1.86, 95% CI 1.43-2.42), and a that showed benzodiazepine use in early pregnancy carried a 60% higher risk of miscarriage.

Still, those studies had limitations, so Hsiao and colleagues conducted the first analysis that used a case-time-control design to account for time-invariant confounders such as genetic and sociodemographic factors. "By design, our case-time-control study eliminates the biasing effect of unmeasured confounding factors in situations where exposure varies over time," they wrote.

They used Taiwan's National Birth Certificate Application database and its National Health Insurance database to identify pregnancies that resulted in miscarriage from 2004 to 2018. Cases were matched with controls based on exposure time-trends and disease risk scores.

Of the 3,067,122 pregnancies among 1,957,601 women (mean age 30.61 years), 136,134 (4.4%) resulted in miscarriage.

Benzodiazepine use was defined as receiving at least one prescription during a risk period (1 to 28 days before miscarriage) or two reference periods (31 to 58 days and 181 to 208 days before the last menstrual period).

In addition to the main findings, Hsiao and colleagues revealed the increased risk of miscarriage was consistent across a range of subgroup and sensitivity analyses.

In subgroup analyses, risk varied by the type of benzodiazepine, with the highest risk seen for fludiazepam (OR 2.52, 95% CI 1.89-3.36) and lowest for alprazolam (OR 1.39, 95% CI 1.17-1.66). Other commonly used benzodiazepines were also associated with a higher risk of miscarriage, including diazepam (OR 1.69, 95% CI 1.31-2.19), lorazepam (OR 1.42, 95% CI 1.13-1.79), and oxazolam (OR 1.54, 95% CI 1.27-1.86).

These analyses also showed a dose-response association, ranging from OR 1.61 (95% CI 1.43-1.82) for low-dose exposure to OR 1.86 (95% CI 1.53-2.25) with high-dose exposure.

"It suggests that if benzodiazepines are used, it should be at the lowest effective dose," Hsiao said.

In sensitivity analyses, risks of miscarriage were attenuated but still significantly increased, the researchers noted.

Given the study design, the results are "unlikely to be due to unmeasured confounding," the researchers said, but they noted some limitations. For instance, the study relied on filled prescriptions, which might not accurately reflect true benzodiazepine use among the patient population.

There was also the potential for misclassification of pregnancy outcomes. And even though the case-time-control design helped mitigate some confounding factors, there was still potential for some residual confounders in the study, the researchers said.

Finally, the low prevalence of benzodiazepine use during pregnancy in this study made it challenging to establish exposure thresholds, they reported.

Indeed, two European psychiatrists were , with one noting that the results have a "large risk of confounding by indication, i.e., patients with mental health problems receiving more benzodiazepines."

"Of course, we should always be prudent during pregnancy with any medication use," added Christiaan Vinkers, MD, PhD, of Amsterdam University Medical Center in the Netherlands. "However, anxiety and severe insomnia undoubtedly also have detrimental effects on the mother and unborn child."

Simon Wessely, MD, MSc, of King's College London in England, added that while the study was well conducted and used a large number of patients, "The big question is, is this cause-and-effect? And the problem is, we can't tell."

"There may be plenty of reasons why someone is being prescribed benzodiazepines and is also at higher risk of miscarriage," Wessely added. "They did the best they could to control for these, and the association remained, but it's always an issue in this kind of study. The main lesson is that for lots of reasons we should continue all efforts to reduce the prescriptions of benzodiazepines anyway, especially for anything more than a very short period."

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