Background

A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown.

Objective

This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding.

Study Design

We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987–2005), Norway (1999–2015), and Sweden (1987–2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6–16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models.

Results

A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10–1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19–1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93–1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96–1.02).

Conclusion

In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder.

中文翻译：

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分娩硬膜外镇痛和随后的后代自闭症谱系障碍和注意力缺陷/多动障碍的风险：一项针对 450 万人及其兄弟姐妹的跨国队列研究

背景

最近的一项研究表明，分娩硬膜外镇痛可能与后代自闭症谱系障碍的发生率增加有关。随后的复制尝试缺乏足够的能力来自信地排除小影响的可能性，并且这种关联的因果性质仍然未知。

客观的

本研究旨在调查在对未测量的家庭混杂因素进行调整后，暴露于硬膜外镇痛与后代自闭症谱系障碍和注意力缺陷/多动障碍的相关程度。

学习规划

我们使用芬兰（1987-2005 年出生的队列）、挪威（1999-2015 年）和瑞典（1987-2011 年）的医学出生登记册（与人口和患者登记相关）确定了 4,498,462 名单身人士及其父母。这些队列从出生起就被追踪，直到他们出现感兴趣的结果、移民、死亡或达到随访结束（平均年龄 13.6-16.8 岁），以先发生者为准。Cox 回归模型用于估计出生时记录的硬膜外镇痛与结果之间特定国家/地区的关联（例如，至少 1 次二级护理诊断为自闭症谱系障碍和注意力缺陷/多动障碍，或至少 1 次处方药物用于治疗）注意力缺陷/多动症的治疗）。通过兄弟姐妹比较，模型根据性别、出生年份、出生顺序和未测量的家庭混杂因素进行了调整。使用逆方差加权固定效应荟萃分析模型对所有 3 个国家的汇总估计值进行了估计。

结果

总共纳入了 4,498,462 人（48.7% 女性），其中 1,091,846 人（24.3%）接受了硬膜外分娩镇痛。其中，1.2% 被诊断患有自闭症谱系障碍，4.0% 被诊断患有注意力缺陷/多动障碍。在人群水平上，汇总估计表明，分娩硬膜外镇痛与后代自闭症谱系障碍的风险增加相关（调整后的风险比，1.12；95％置信区间，1.10-1.14，绝对风险，1.20％对1.07％）和注意力 -缺陷/多动障碍（调整后的风险比，1.20；95% 置信区间，1.19–1.21；绝对风险，3.95% vs 3.32%）。然而，当比较不同程度地接受硬膜外分娩镇痛的同辈兄弟姐妹时，两种情况的相关性均被完全减弱，且置信区间较窄（调整后的风险比[自闭症谱系障碍]，0.98；95% 置信区间，0.93-1.03；调整后的风险比）注意力缺陷/多动障碍比率，0.99；95% 置信区间，0.96–1.02）。

结论

在这项大型跨国研究中，我们发现没有证据支持这样的假设：暴露于硬膜外镇痛会导致后代自闭症谱系障碍或注意力缺陷/多动障碍。