Master student School of pharmacy, National Defense Medical Center, Taiwan (Republic of China)
Background: To date, the actual relationship between benzodiazepine receptor agonist (BZRA) exposure and the incidence of neurodevelopmental disorders (NDs) in offspring was still inconclusive.
Objectives: This cohort study aimed to evaluate the association between maternal BZRA exposure and NDs in offspring. Different dose levels of BZRA and different trimester exposures were also investigated.
Methods: This study used data from Taiwan Birth Certificate Application and National Health Insurance Research Database. We initially included pregnant mothers aged ≥20 years old (2004~2012) and excluded multiple births and stillbirths. 212,741 mother receiving BZRA were defined as BZRA users and 1,397,399 mother who did not receive any BZRA were identified as non-users. The children who had been diagnosed with NDs, including intellectual disability (ID), reading disorder (RD), speech and language disorder (SLD), motor function disorder (MFD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) during the follow-up period (until 2018) were identified as NDs cases. We used Cox proportional hazard model with robust variance estimation to calculate the hazard ratios (HRs) of NDs for children with maternal exposure of BZRAs and IPTW was performed to balance the confounders between groups. We further investigated the connection between different BZRA dose levels, different trimester exposures, and NDs risk in children.
Results: Overall, the risk of NDs for BZRA users was higher compared with non-users. The weighted HR was 1.08 (95% confidence interval [CI]: 1.06-1.09, p< 0.001). The BZRA users had 1.11, 1.08, 1.09, 1.11, and 1.09-fold significantly higher risk in ID, RD, SLD, MFD, and ADHD, respectively, than non-users. Moreover, the NDs risk was greater in high dose levels. This study observed that high dose BZRA users had 1.21- (95% CI: 1.18-1.24), 1.35- (95% CI: 1.26-1.46), and 1.26- (95% CI: 1.22-1.30) fold risk for NDs, ID, and ADHD, respectively, than non-users. Additionally, BZRA exposure in mid-late pregnancy also shows a significantly elevated risk of NDs. In BZRA users, the weighted HR of overall NDs was 1.12 (95% CI: 1.10-1.15) in 2nd trimester and 1.10 (95% CI: 1.07-1.14) in 3rd trimester in comparison with non-users. Maternal BZRA exposure in 2nd and 3rd trimesters both show 1.18-fold risk of ADHD compare with non-users.
Conclusions: This is the first study demonstrate the relationship between maternal BZRAs exposure and increased risk of NDs, including ID, RD, SLD, MFD, and ADHD. In addition, maternal BZRA exposure in mid-late pregnancy and high cumulative dose of BZRAs may have poor impact on offspring’s neurodevelopment.
.jpg "Yi Lin Chiang, MS (she) photo")
