Labor epidural analgesia and autism spectrum disorder in 3-year-old offspring based on data from the Japan Environment and Children’s Study: a prospective cohort study

To evaluate the association between labor epidural analgesia (LEA) and autism spectrum disorder (ASD) in 3-year-old offspring in Japan. Prospective cohort study utilizing the Japan Environment and Children’s Study, the largest nationwide birth cohort study. A total of 65,742 live singleton offspring were enrolled between January 2011 and March 2014. Offspring born via cesarean delivery or with confirmed chromosomal abnormalities were excluded. Multivariate logistic regression analyses were conducted to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI), accounting for maternal, paternal, and perinatal covariates. Subgroup analyses were performed based on the sex of the offspring. The primary outcome was the diagnosis of ASD at age 3. Among the 65,742 offspring (33,684 boys [51.2%]; mean maternal age, 31.1 [4.9] years), 1,324 (2.0%) were exposed to LEA. ASD was diagnosed in 14 (1.1%) offspring exposed to LEA and 257 (0.4%) not exposed to LEA by age 3. After adjusting for potential confounders, multivariate logistic regression revealed that LEA was associated with an increased risk of ASD (aOR: 2.23; 95% CI: 1.28–3.87). Subgroup analysis indicated that the association was significant in male offspring (aOR: 2.55; 95% CI: 1.40–4.65), but not in female offspring (aOR: 1.41; 95% CI: 0.34–5.91). This study suggests a mild association between LEA and ASD in 3-year-old male offspring. However, the findings should be cautiously interpreted given the limited number of ASD cases in this study. Causal relationships cannot be established since this was an observational study.本研究旨在评估日本地区产妇分娩硬膜外镇痛（labor epidural analgesia, LEA）与3岁子代孤独症谱系障碍（autism spectrum disorder, ASD）之间的关联。本研究依托日本规模最大的全国性出生队列研究——日本环境与儿童研究（Japan Environment and Children’s Study）开展前瞻性队列研究。2011年1月至2014年3月期间，共纳入65742名单胎活产子代。本研究排除了经剖宫产分娩或确诊存在染色体异常的子代。研究采用多因素logistic回归分析，校正母亲、父亲及围产期协变量，估算校正后比值比（adjusted odds ratios, aOR）及95%置信区间（confidence interval, CI）；并依据子代性别开展亚组分析。本研究的主要结局指标为子代3岁时的ASD诊断情况。在纳入的65742名子代中，男性共33684名（占比51.2%）；母亲平均年龄为31.1岁（标准差4.9）。其中1324名（占比2.0%）子代暴露于LEA。至3岁随访节点，暴露于LEA的子代中共有14名（占比1.1%）被确诊为ASD，未暴露组则有257名（占比0.4%）被确诊为ASD。校正潜在混杂因素后，多因素logistic回归分析结果显示，LEA暴露与子代ASD患病风险升高存在显著关联（aOR=2.23；95%CI=1.28~3.87）。亚组分析结果表明，该关联仅在男性子代中具有统计学意义（aOR=2.55；95%CI=1.40~4.65），而在女性子代中未观察到显著关联（aOR=1.41；95%CI=0.34~5.91）。本研究提示，LEA暴露与3岁男性子代的ASD患病风险存在轻度关联。但由于本研究中ASD病例数相对有限，对该研究结果的解读应保持审慎。此外，本研究属于观察性研究，无法确立LEA暴露与ASD之间的因果关系。