Benzodiazepine Use Linked to Increased Risk of Miscarriage

Taking benzodiazepines during pregnancy is associated with an increased risk of miscarriage, according to a new study.¹

To treat anxiety and insomnia during pregnancy, some women are prescribed benzodiazepines, which contain anxiolytic and hypnotic properties. About 1.7% of pregnant women are prescribed this medication during the first trimester.

Benzodiazepine has a potential role in cell proliferation and differentiation processes. Because of this, the drug could possibly cause fetal developmental abnormalities leading to miscarriage.

Studies from the 1970s provided evidence benzodiazepine exposure in the first trimester can increase the risk of infants being born with facial clefts, cardiac malfunctions, and other malformations.² However, later studies did not find a significant increase in malfunctions when taking benzodiazepine during pregnancy. Moreover, benzodiazepine use has been associated with decreased infant birth weight and increased risk of ectopic pregnancy.^3,4

A previous nested case-control study similarly explored the risk of miscarriage when confounding for underlying diseases and sociodemographic factors.¹ Here, the investigators found women who took benzodiazepines during pregnancy had an 85% higher risk of miscarriage. The study did not confound for other factors like severity of anxiety, insomnia, comorbidities, economic status, lifestyle, and genetic factors.

A new case-time-control design study, led by Lin-Chieh Meng, MS, from the Graduate Institute of Clinical Pharmacy at National Taiwan University, sought to evaluate the risk of miscarriage associated with benzodiazepine use during pregnancy while examining measured and unmeasured confounding factors.

“In this nationwide case-time-control study of approximately 3 million pregnancies, we found that benzodiazepine use during pregnancy was associated with an approximately 70% increased risk of miscarriage,” the investigators wrote.

The investigators pointed out that several of other studies found taking benzodiazepines during pregnancy was not associated with an increased risk of adverse pregnancy outcomes. Yet the same did not apply for the new study, finding an increased risk for miscarriage.

Meng and colleagues pulled data from 2 sources: the National Health Insurance database from 2002 – 2019 and the National Birth Certificate Application database from 2004 – 2018. The National Health Insurance database provided health insurance claims for visits, procedures, and prescriptions for the majority (> 99%) of the population in Taiwan. This database identified pregnancies resulting in a miscarriage. Meanwhile, the National Birth Certificate Application database provided data on all live births and stillbirths with gestational age of > 20 weeks or birth weight > 500 g.

The study examined 3,067,122 pregnancies among 1,957,601 women, with a mean age of 30.61 years. Of these women, 136,134 (4.4%) had miscarriages. The investigators matched women with miscarriages with time-trend control individuals; in total, there were 134,864 pairs, comparable in terms of age, comorbidities, medication use, and health care use.

The investigators used a case-time-control study design containing 2 self-adjusted analyses: a case-crossover analysis and an exposure time-trend control crossover analysis. A case-crossover analysis allows investigators to control time-invariant factors like underlying disease severity and genetic factors. The team used an exposure time-trend control alongside the case-time control design to avoid biases.

“By design, our case-time-control study eliminates the biasing effect of unmeasured confounding factors in situations where exposure varies over time,” the investigators wrote.

The investigators used 28-day periods for exposure assessment, as the risk period was defined as 1 – 28 days before the index date. Miscarriage was considered any pregnancy loss occurring between the first prenatal care visit (around week 8 of gestation) and the 19th completed week or pregnancy. The team did not include women who had a miscarriage before the first prenatal care visit or after 20 weeks of gestation since they were considered to have stillbirths.

Women exposed received ≥ 1 prescription of benzodiazepine during the risk or reference period (either 31 – 58 or 181 – 208 days before the last menstrual period). The investigators examined short-acting (half-life ≤ 24 hours), or long-acting (half-life > 24 hours) benzodiazepines. The team also evaluated exposure to commonly used prescriptions like alprazolam, diazepam, lorazepam, oxazolam, and fludiazepam.

For women who had miscarriages, 1502 were exposed to benzodiazepines during the risk period only, and 2806 were exposed during the reference period only. Meanwhile, for time-trend control individuals, 753 were exposure during the risk period, and 2386 were exposed during the reference periods.

After adjusting for the odds ratio, the investigators found exposure to benzodiazepines was linked to an increased risk of miscarriage (odds ratio [OR], 1.69; 95% CI, 1.52 – 1.87). Also, both long-acting benzodiazepines demonstrated an increased risk of miscarriage with case-time-control’s odds ratio of 1.67 (95% CI, 1.44 – 1.93) and 1.66 (95% CI, 1.47 – 1.87), respectively.

The subgroup analyses also showed an increased risk of miscarriage linked to a commonly used benzodiazepine. For example, alprazolam had a case-time-control odds ratio of 1.39 (95% CI, 1.17 – 1.66), and fludiazepam had a case-time-control odds ratio of 2.52 (95% CI, 1.89 – 3.36). Even with the sensitivity analyses—when the exposure assessment period was redefined to 56 days—the team found benzodiazepine was associated with a significant increased risk of miscarriage. Though, in the negative control analyses, the investigators found no increased risk for miscarriage associated with benzodiazepine use.

The investigators noted several limitations in the study, such as exposure classification only relying on filled prescriptions, individuals inaccurately reporting a voluntary abortion as involuntary, not examining other confounding factors, and benzodiazepine withdrawal potentially affecting fetal development. Ultimately, the investigators believe that clinicians should be cautious when prescribing benzodiazepines during early pregnancy.

“The findings of this study also provide evidence to guide clinicians in making informed decisions regarding the treatment of psychiatric and sleep disorders in pregnant women,” the investigators wrote. “Prescribing benzodiazepines should only be considered following a comprehensive evaluation of the potential benefits and risks for both the mother and the child.”

^References

1. ^{Meng LC, Lin CW, Chuang HM, Chen LK, Hsiao FY. Benzodiazepine Use During Pregnancy and Risk of Miscarriage. JAMA Psychiatry. Published online December 27, 2023. doi:10.1001/jamapsychiatry.2023.4912}
2. ^{McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol. 1994;8(6):461-475. doi:10.1016/0890-6238(94)90029-9}
3. ^{Rosenfeld, S. Benzodiazepine Use Decreases Infant Birth Weight. HCPLive. June 23, 2020. https://www.hcplive.com/view/benzodiazepine-use-decreases-infant-birth-weight. Accessed December 30, 2023.}
4. ^{Rosenfeld, S. Benzodiazepine Use Increases Risk of Ectopic Pregnancy. HCPLive. June 3, 2020. https://www.hcplive.com/view/benzodiazepine-use-increases-risk-ectopic-pregnancy. Accessed December 30, 2023.}