Benzodiazepine use during an IVF cycle and its impacts on miscarriage and other pregnancy outcomes.

Abstract

Study question: How does benzodiazepine use during an IVF cycle affect pregnancy outcomes?

Summary answer: Benzodiazepine use was neither positively nor adversely associated with IVF pregnancy outcomes overall.

What is known already: Benzodiazepine use during oocyte retrieval, primarily with midazolam, and diazepam use at the time of embryo transfer (ET) have been reported to yield comparable procedural success rates to those of non-users, respectively. However, these studies focus on exposure at a single time point, necessitating a more comprehensive investigation of benzodiazepine use across the entire IVF treatment period.

Study design size duration: A retrospective cohort study was conducted using Korea's Health Insurance Review and Assessment (HIRA) database between October 2017 and June 2024. A total of 99 484 women with a first completed IVF cycle were included.

Participants/materials setting methods: Benzodiazepine users were defined as individuals who had at least one prescription during an IVF cycle (from the last menstrual period to ET) (user group, n = 28 649). Non-users were defined as those who had no benzodiazepine prescriptions within 365 days prior to ET to minimize exposure misclassification (non-user group, n = 61 433). The outcomes of interest were four IVF outcomes: clinical pregnancy rate, miscarriage rate, live birth rate, and preterm birth rate. To compare the two groups, propensity score overlap weighting was applied to adjust for potential imbalances in confounders. Relative risks (RRs) with 95% CIs were estimated using Poisson regression in the overlap-weighted at-risk population cohort for each outcome.

Main results and the role of chance: Compared with non-users, benzodiazepine users had a lower prevalence of prior live birth and a higher prevalence of anxiety disorders, along with greater use of antidepressants before adjustment. The absolute event rates of each outcome were as follows: (i) clinical pregnancy rate: 36.0% of users versus 35.7% of non-users, (ii) miscarriage rate: 14.9% versus 15.2%, (iii) live birth rate: 99.3% versus 99.3%, (iv) preterm birth rate: 13.3% versus 11.6%. Most IVF outcomes were comparable between groups, though a marginally increased risk of preterm birth was observed among users (clinical pregnancy: adjusted RR 1.02 [95% CI 1.00 to 1.05]; miscarriage: 0.99 [0.91 to 1.08]; live birth: 1.00 [1.00 to 1.00]; preterm birth: 1.10 [0.99 to 1.21]). However, stratified analyses by cumulative dose showed no dose-response relationship (≤1.2 mg and >2 mg, respectively-preterm birth: 1.09 [0.99 to 1.21] and 1.01 [0.87 to 1.17]). Additionally, the point estimate was closer to the null among users prescribed both injectable and oral agents during the cycle (preterm birth: 1.04 [0.86 to 1.26]). The robustness of the main findings was supported by analyses accounting for benzodiazepine exposure during pregnancy and by multiple sensitivity analyses.

Limitations reasons for caution: Despite rigorous statistical adjustment, residual confounding by unmeasured factors and potential exposure misclassification due to discrepancies between prescription timing and actual medication use cannot be completely ruled out.

Wider implications of the findings: This large population-based study found no association between benzodiazepine use throughout the IVF cycle and pregnancy outcomes. Although a small increase in preterm birth risk was observed, there was no evidence of a dose-response relationship or additional risk among patients with exposure to both oral and injectable formulations during the exposure assessment period. However, further studies are needed to evaluate the potential association.

Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2026-25474077); This research was supported by a grant (RS-2026-25511535) from Ministry of Food and Drug Safety in 2026.

Disclosures: J-YS received grants from the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the National Research Foundation of Korea, and pharmaceutical companies, including LG Chem, GSK, Pfizer, Handok, JnJ, and SK Bioscience, outside the submitted work.

Trial registration number: N/A.