Introduction: Acid-suppressive medications (ASMs) may increase the risk of infections, which could contribute to adverse birth outcomes. However, evidence in pregnancy remains limited, particularly regarding differences between ASM classes and duration–response relationships.
Aims: To investigate whether early-pregnancy ASM (i.e., PPIs, H2RAs, or PCAB) use is associated with maternal infection and adverse pregnancy outcomes
Methods: We conducted a population-based cohort study using the Korean healthcare database, including all pregnancies reaching ≥20 weeks’ gestation (2019–2024). Exposure was defined as ASM use with days’ supply overlapping early pregnancy (last menstrual period (LMP) to LMP+140 days). Outcomes were (1) maternal infections (any and serious infections; LMP+141 days until delivery) and (2) adverse birth outcomes (preterm birth and stillbirth). Adjusted relative risks (aRRs) and 95% confidence intervals (CIs) were estimated using log-binomial regression with propensity score fine-stratification weighting. We further conducted subgroup analyses by mediation classes and cumulative ASM use (<14, 14–27, ≥28 days).
Results: Of 898,409 pregnancies, 134,722 (15.0%) were exposed to ASM. ASM use was associated with an increased risk of maternal infections (any infection: aRR 1.17, 95% CI 1.16–1.19; serious infection: 1.34, 1.29–1.40), whereas no increased risk was observed for adverse birth outcomes overall (preterm birth: 0.99, 0.97–1.01; stillbirth: 1.03, 0.95–1.12). These findings were generally consistent across medication classes; notably, a higher risk of serious infection was observed among H2RA users (1.33, 1.27–1.40). However, in the duration–response analysis, ASM use of ≥28 days was associated with significantly increased risks of both preterm birth and stillbirth (1.18, 1.11–1.25 and 1.42, 1.11–1.81, respectively).
Conclusions: ASM use was associated with maternal infection risk and showed a potential duration–response relationship with adverse birth outcomes. These findings highlight the need for careful clinical consideration when prescribing ASMs during pregnancy.
Keywords: acid-suppressive medications, infection, adverse birth outcomes

Introduction: In 2024, the EMA endorsed precautionary measures for valproate use in male patients, citing a potential increased risk of neurodevelopmental disorders (NDDs) in children born to treated fathers during spermatogenesis. However, accumulating evidence — predominantly from European populations — has found no significant association, warranting further corroboration.

Aims: To investigate whether paternal valproate exposure during spermatogenesis is associated with an increased risk of NDDs in children.

Methods: We conducted a cohort study using a nationwide mother-father-child linked dataset (Big-CHENS) of live births in South Korea (2015–2021). Exposure was defined as valproate monotherapy during spermatogenesis, the 90-day period prior to conception. The outcome was any NDD diagnosis, encompassing autism spectrum disorder, ADHD, learning disability, speech/language disorder, intellectual disability, developmental coordination disorder, and behavioral disorder. Three comparator groups were examined: valproate-unexposed fathers from the general population, valproate-unexposed fathers with epilepsy, and an active comparator group (levetiracetam/lamotrigine) with epilepsy. Propensity score-based inverse probability of treatment weighting was applied, and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using weighted Cox regression.

Results: Among 1,835,598 father-child pairs, 10,128 children were exposed to paternal valproate, with 130 NDD events observed (crude HR 1.62, 95% CI 1.35–1.93). After restriction to fathers with epilepsy and granular adjustment of confounders including indication-related factors, no increased risk was observed for valproate-exposed (n=744) versus unexposed (n=3,442) (HR 1.02, 95% CI 0.73–1.42). Results were similarly null against the active comparator (557 vs. 559; HR 1.07, 95% CI 0.74–1.53), and consistent when allowing combination therapy.

Conclusions: Paternal valproate exposure during spermatogenesis was not associated with an increased risk of NDDs in children. The crude excess risk disappeared in both indication-restriction and active-comparator analyses, indicating confounding by indication. Consistent with the growing body of evidence, these findings may support reconsideration of current regulatory precautions.

Keywords: Valproate, Neurodevelopmental Disorders, Paternal Exposure

Introduction: Paracetamol is the first-line analgesic globally during pregnancy. Observational studies have reported associations between prenatal paracetamol exposure and increased risks of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring, raising concern. However, these findings may be confounded by unmeasured familial factors.

Aims: To assess the association between prenatal paracetamol exposure and risks of ASD and ADHD in offspring using a sibling-matched study design to control for familial confounding.

Methods: This population-based cohort study (2001-2023, Hong Kong) used deidentified electronic health records within a triangulation framework. From 708,020 mother-child pairs (43.3% exposed), sibling-matched cohorts were constructed of children from families with discordant prenatal paracetamol exposure and sufficient follow-up (≥2 years for ASD and ≥5 years for ADHD). Exposure was identified from electronic dispensing records. Outcomes were incident diagnoses of ASD (ICD-9-CM 299) or ADHD (ICD-9-CM 314), or a prescription for ADHD-specific medication.

Results: The final cohorts comprised 124,333 children for ASD analysis (mean age 9.3 years; 50.3% male) and 97,285 for ADHD analysis (mean age 7.6 years; 50.2% male). In sibling-matched analyses, prenatal paracetamol exposure was not associated with the risk of ASD (aHR, 1.00; 95% CI, 0.91-1.11) or ADHD (aHR, 1.01; 95% CI, 0.93-1.08). Null associations were consistent across exposure timing, cumulative dose, and usage patterns. However, positive associations were observed in conventional cohort analyses, and importantly, also in negative control analyses of prepregnancy exposure for ASD (HR, 1.12; 95% CI, 1.08-1.17) and ADHD (HR, 1.24; 95% CI, 1.20-1.28).

Conclusions: This sibling-matched analysis found no evidence of an association between prenatal paracetamol exposure and the risk of ASD or ADHD in offspring. The positive signals observed in conventional studies are likely attributable to residual familial confounding. These findings provide important reassurance regarding the safety of indicated paracetamol use during pregnancy.

Keywords: Prenatal paracetamol exposure; Autism; Sibling-matched design

Introduction: Prenatal opioid exposure may affect child health, yet evidence on its long-term impact on hospital admissions remains limited by unmeasured confounding, small samples, and short follow-up periods.
Aims: We aimed to investigate the association between prenatal opioid exposure and the risk of hospital admission in children.
Methods: A population-based birth cohort in South Korea was established by linking mothers and children using National Health Insurance Service data (January 2009–December 2023). Propensity score (PS)-matched and sibling comparison cohorts were constructed, and dose-dependent and time-attenuation analyses were performed. All 5,249,439 individuals with eligible children born between 2010 and 2017 were included (2,236,167 mothers and 3,013,262 children), with follow-up of up to 14 years. Prenatal opioid exposure was defined as two or more maternal prescriptions within any trimester to exclude single-use prescriptions. Analyses were also stratified by opioid type. The primary outcome was adjusted incidence rate ratio (aIRR) of hospital admissions, including infections, non-infectious respiratory, gastrointestinal, oral cavity, genitourinary conditions, and injuries/external causes.
Results: Of 2,928,186 pregnancies, 2,809,515 and 118,671 infants were unexposed and exposed to prenatal opioids, respectively. Hospital admission rates in exposed children were 29% higher in the PS-matched cohort (aIRR, 1.29 [95% CI, 1.29–1.30]). The association was attenuated in the sibling comparison cohort, indicating potential shared familial influences, but remained significant (aIRR, 1.08 [95% CI, 1.07–1.09]). A dose-dependent relationship was observed (low-dose: aIRR, 1.19 [95% CI, 1.18–1.19]; high-dose: aIRR, 1.39 [95% CI, 1.39–1.40]). Significantly elevated rates were observed across all examined morbidity categories. These effects diminished with age but remained evident up to five years of age.
Conclusions: In this nationwide birth cohort study, maternal opioid prescription during pregnancy was significantly associated with increased risk of hospital admissions in the offspring across various causes of morbidities, with a dose-dependent pattern.
Keywords: maternal opioid prescriptions, prenatal opioid exposure, hospital admissions

Introduction: Dyslipidemia is increasingly common among women of reproductive age, yet lipid-lowering options become limited once pregnancy is recognized. Ezetimibe lowers cholesterol through intestinal absorption rather than endogenous cholesterol synthesis, suggesting a fetal risk profile that may differ from statins. However, evidence regarding ezetimibe exposure during early pregnancy remains scarce.
Aims: To evaluate the association between ezetimibe exposure during early pregnancy and spontaneous abortion (SAB) among women with dyslipidemia.
Methods: We conducted a nationwide cohort study using the Korean National Health Information database (2013–2023). Women aged 15–49 years with diagnosis of dyslipidemia and prior use of ezetimibe or statin within 180 days before the estimated last menstrual period (LMP) were included. Ezetimibe exposure was defined as a prescription overlapping the period from LMP through gestational week 6. The outcome was SAB between 7 and 20 gestational weeks. Risk ratios (RRs) were estimated using log-binomial regression weighted by propensity score overlap weights for maternal and clinical covariates and inverse probability of censoring weights for induced abortion. Given common statin co-prescribing, sensitivity analysis compared concurrent ezetimibe-statin exposure with statin exposure alone using the same window as ezetimibe exposure.
Results: Among 19,021 pregnancies with prior dyslipidemia, 2,121 (11.2%) were ezetimibe-exposed and 16,900 (88.8%) were unexposed, mean age 36.4 vs. 35.5 years. Concomitant statin use during the exposure assessment period was 98.1% in ezetimibe-exposed and 37.3% in unexposed. Ezetimibe exposure was not associated with increased SAB risk (crude RR 0.93 [95% CI 0.90–0.96], weighted RR 0.92 [95% CI 0.87–0.99]). Results were consistent in sensitivity analysis (weighted RR 0.92 [0.85–1.00]).
Conclusions: Ezetimibe exposure early in pregnancy was not associated with increased risk of SAB in women with dyslipidemia. These findings provide population-based evidence on the safety of early-pregnancy ezetimibe exposure, although further studies are needed to confirm these results.
Keywords: ezetimibe, spontaneous abortion, perinatal pharmacoepidemiology

Introduction: Benzodiazepines may increase the risk of miscarriage owing to their potential effects on fetal development. Most previous studies have assessed benzodiazepines as a drug class, with limited evidence regarding their dose, half-life categories, or individual agents. In addition, benzodiazepine use patterns vary by region.
Purpose: To evaluate the association between benzodiazepine exposure during early pregnancy and the risk of miscarriage, with a focus on dose-response, half-life, and individual agents.
Methods: This nested case-control study was conducted using a large Japanese administrative database. Cases were defined as pregnancies ending in miscarriage between 2005 and 2023. Controls were randomly selected through risk-set sampling with replacement and matched in a 3:1 ratio. Conditional logistic regression, adjusted for confounders, was used to assess the associations.
Results: Overall, 44,118 cases were matched with 132,317 controls, with a mean age of 33.2 years. The prevalence of benzodiazepine exposure was 1.7% and 1.2% among cases and controls, respectively. Etizolam (0.3%) had the highest prevalence, followed by alprazolam (0.3%) and brotizolam (0.2%) in both groups. Adjusted odds ratio (OR) for benzodiazepine exposure during early pregnancy was 1.241 (95% confidence interval: 1.136–1.357). Adjusted ORs for high-dose (1.212 [1.050–1.400]) and medium-dose (1.189 [1.037–1.363]) exposure were numerically higher than that for low-dose exposure (1.111 [0.934–1.322]). Adjusted OR for long-acting benzodiazepines (1.308 [1.124–1.522]) was numerically higher than those for intermediate- (1.132 [0.999–1.284]) and short-acting (1.157 [1.030–1.300]) agents. Adjusted ORs for etizolam, alprazolam, and brotizolam were 0.929 (0.782–1.103), 0.853 (0.707–1.030), and 1.454 (1.180–1.791), respectively.
Conclusions: Benzodiazepine exposure during early pregnancy was modestly associated with an increased risk of miscarriage. Although associations tended to be stronger with higher dose levels and longer half-life categories, estimates across subgroups lacked precision and should be interpreted with caution.
Keywords: anxiety; benzodiazepine; miscarriage