Department of Gynaecology and Obstetrics, Nordsjaellands Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
J Child Psychol Psychiatry. 2019 Feb;60(2):151-159. doi: 10.1111/jcpp.12961. Epub 2018 Aug 23.
Increasing attention deficit hyperactivity disorder (ADHD) incidence has been proposed to be caused by factors influencing microbiota in early life. We investigated the potential causality between ADHD and two surrogate markers for changes in children's microbiota: birth delivery mode and early childhood antibiotic use.
This population-based, prospective cohort study linked nationwide registers of data for native Danish singleton live births in Denmark from 1997 to 2010. Exposure variables were delivery mode and antibiotic use during the first 2 years of life. The main outcome measure was ADHD diagnosis or redeemed ADHD medication prescriptions. For statistical analysis, we used both advanced sibling models and a more traditional approach.
We included 671,592 children, followed from their second birthday in the period 1999-2014 for 7,300,522 person-years. ADHD was diagnosed in 17,971. In total, 17.5% were born by cesarean delivery, and 72% received antibiotic treatment within their first 2 years of life. In the adjusted between-within sibling survival model, mode of delivery or antibiotics had no effect on ADHD when compared with vaginal delivery or no antibiotic treatment as hazard ratios were 1.09 (95% confidence interval 0.97-1.24) for intrapartum cesarean, 1.03 (0.91-1.16) for prelabor cesarean, 0.98 (0.90-1.07) for penicillin, and 0.99 (0.92-1.06) for broader spectrum antibiotics. In a sibling-stratified Cox regression, intrapartum cesarean was associated with increased ADHD risk, but other exposures were not. In a descriptive, nonstratified Cox model, we found increased risk for ADHD for all exposures.
Detailed family confounder control using the superior between-within model indicates that cesarean delivery or use of antibiotics during the first 2 years of life does not increase ADHD risk. Therefore, our study suggests that changes in children's microbiota related to cesarean delivery or antibiotic use, do not cause ADHD.
越来越多的注意力缺陷多动障碍 (ADHD) 发病率被认为是由影响生命早期微生物群的因素引起的。我们研究了 ADHD 与儿童微生物群变化的两个替代标志物之间的潜在因果关系：分娩方式和儿童早期抗生素的使用。
本研究是一项基于人群的前瞻性队列研究，将丹麦全国的出生登记数据与丹麦 1997 年至 2010 年的本地单胎活产儿相关联。暴露变量为分娩方式和出生后前 2 年的抗生素使用情况。主要结局测量指标为 ADHD 诊断或开具 ADHD 药物处方。对于统计分析，我们同时使用了先进的同胞模型和传统方法。
我们纳入了 671592 名儿童，从他们的两岁生日开始，在 1999 年至 2014 年期间进行了 7300522 人年的随访。共诊断出 17971 例 ADHD。共有 17.5%的儿童为剖宫产分娩，72%的儿童在出生后的前 2 年内接受了抗生素治疗。在调整后的同胞生存模型中，与阴道分娩或未接受抗生素治疗相比，分娩方式或抗生素使用并未增加 ADHD 的风险，风险比分别为 1.09（95%置信区间 0.97-1.24），择期剖宫产为 1.03（0.91-1.16），青霉素为 0.98（0.90-1.07），广谱抗生素为 0.99（0.92-1.06）。在同胞分层 Cox 回归中，择期剖宫产与 ADHD 风险增加相关，但其他暴露因素无此相关性。在描述性、非分层 Cox 模型中，我们发现所有暴露因素均增加了 ADHD 的风险。
使用优越的同胞内模型进行详细的家庭混杂因素控制表明，剖宫产分娩或出生后前 2 年内使用抗生素不会增加 ADHD 的风险。因此，我们的研究表明，与剖宫产分娩或抗生素使用相关的儿童微生物群变化不会导致 ADHD。
