A nationwide study in Taiwan found that benzodiazepine use during pregnancy was associated with an increased risk of miscarriage – for both long-acting and short-acting benzodiazepines, according to the researchers.
The population-based, case-time-control study of more than 3m pregnancies found that benzodiazepine – a depressant drug often prescribed for anxiety – was linked to a 69% increased risk of miscarriage (95% CI 1.52-1.87), said 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 JAMA Psychiatry.
“The research underscores the need for careful consideration of the risks and benefits when prescribing benzodiazepines to pregnant women,” Hsiao told MedPage Today.
“Healthcare providers should be aware of the potential increased risk of miscarriage and discuss this with patients who rely on the drugs. The decision to prescribe benzodiazepines should involve a thorough evaluation of the potential risks to the foetus and benefits to the mother and her offspring.”
The researchers said their findings tallied with a recent meta-analysis of data from five studies that showed a significant association between benzodiazepine in pregnancy and miscarriage risk (OR 1.86, 95% CI 1.43-2.42), and a UK-based study suggesting that 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 like 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 (one 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, they 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, they said.
Finally, the low prevalence of benzodiazepine use during pregnancy in this study made it challenging to establish exposure thresholds, they reported.
Two European psychiatrists pointed to these limitations, 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 Centre 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, said 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.”
Study details
Benzodiazepine Use During Pregnancy and Risk of Miscarriage
Lin-Chieh Meng, Chih-Wan Lin, Hui-Min Chuang, et al
Published in JAMA Psychiatry on 27 December 2023
Key Points
Question Is benzodiazepine use during pregnancy associated with miscarriage, taking into account both measured and unmeasured confounding factors?
Findings In this case-time-control study, benzodiazepine use during pregnancy was associated with an increased risk of miscarriage, even after accounting for unmeasured confounders, including those related to genetics and the family environment.
Meaning The observation of an increased risk of miscarriage associated with benzodiazepine use during pregnancy suggests that benzodiazepines should only be used after a thorough evaluation of the potential benefits and risks for both the mother and child.
Abstract
Importance
Benzodiazepine use during pregnancy has raised significant concerns due to the potential harmful effects of this drug class on neonates. Studies on the association between benzodiazepine use and the risk of miscarriage are limited.
Objective
To quantify the risk of miscarriage associated with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends.
Design, Setting, and Participants
This was a nationwide, population-based case-time-control study using Taiwan’s National Birth Certificate Application database and the National Health Insurance database. Pregnancies resulting in miscarriage between 2004 and 2018 were included in the case group and were 1:1 matched with exposure time-trend control individuals using disease risk score, considering demographic characteristics and pre-pregnancy comorbidities. Data were analysed from August 2022 to March 2023.
Exposures
Discordant exposures to benzodiazepines during risk period (1-28 days before miscarriage) and 2 reference periods (31-58 days and 181-208 days before the last menstrual period) were compared for each pregnancy.
Main Outcomes and Measures
Miscarriage was defined as any pregnancy loss occurring between the first prenatal care visit (usually 8 weeks) and the 19th completed week of pregnancy.
Results
This study comprised a total of 3 067 122 pregnancies among 1 957 601 women, 136 134 of which (4.4%) resulted in miscarriage. The mean (SD) age of the study population was 30.61 (5.91) years. The use of benzodiazepines during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69; 95% CI, 1.52-1.87), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification. In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 (95% CI, 1.17-1.66) for alprazolam to 2.52 (95% CI, 1.89-3.36) for fludiazepam.
Conclusions and Relevance
This nationwide case-time-control study revealed an increased risk of miscarriage associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and results were unlikely to be due to unmeasured confounding. These findings underscore the necessity for healthcare professionals to meticulously balance the risk-benefit ratio when considering the use of benzodiazepines to treat psychiatric and sleep disorders during pregnancy.
JAMA Psychiatry article – Benzodiazepine Use During Pregnancy and Risk of Miscarriage (Open access)
MedPage Today article – Benzodiazepine Use in Pregnancy Tied to Miscarriage Risk (Open access)
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