Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada.
ICES, Toronto, Ontario, Canada.
JAMA Netw Open. 2023 Nov 1;6(11):e2343954. doi: 10.1001/jamanetworkopen.2023.43954.
Previous studies on the risk of childhood autism spectrum disorder (ASD) following fertility treatment did not account for the infertility itself or the mediating effect of obstetrical and neonatal factors.
To assess the association between infertility and its treatments on the risk of ASD and the mediating effect of selected adverse pregnancy outcomes on that association.
DESIGN, SETTING, AND PARTICIPANTS: This was a population-based cohort study in Ontario, Canada. Participants were all singleton and multifetal live births at 24 or more weeks' gestation from 2006 to 2018. Data were analyzed from October 2022 to October 2023.
The exposure was mode of conception, namely, (1) unassisted conception, (2) infertility without fertility treatment (ie, subfertility), (3) ovulation induction (OI) or intrauterine insemination (IUI), or (4) in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
The study outcome was a diagnosis of ASD at age 18 months or older. Cox regression models generated hazard ratios (HR) adjusted for maternal and infant characteristics. Mediation analysis further accounted for the separate effect of (1) preeclampsia, (2) cesarean birth, (3) multifetal pregnancy, (4) preterm birth at less than 37 weeks, and (5) severe neonatal morbidity.
A total of 1 370 152 children (703 407 male [51.3%]) were included: 1 185 024 (86.5%) with unassisted conception, 141 180 (10.3%) with parental subfertility, 20 429 (1.5%) following OI or IUI, and 23 519 (1.7%) following IVF or ICSI. Individuals with subfertility or fertility treatment were older and resided in higher-income areas; the mean (SD) age of each group was as follows: 30.1 (5.2) years in the unassisted conception group, 33.3 (4.7) years in the subfertility group, 33.1 (4.4) years in the OI or IUI group, and 35.8 (4.9) years in the IVF or ICSI group. The incidence rate of ASD was 1.93 per 1000 person-years among children in the unassisted conception group. Relative to the latter, the adjusted HR for ASD was 1.20 (95% CI, 1.15-1.25) in the subfertility group, 1.21 (95% CI, 1.09-1.34) following OI or IUI, and 1.16 (95% CI, 1.04-1.28) after IVF or ICSI. Obstetrical and neonatal factors appeared to mediate a sizeable proportion of the aforementioned association between mode of conception and ASD risk. For example, following IVF or ICSI, the proportion mediated by cesarean birth was 29%, multifetal pregnancy was 78%, preterm birth was 50%, and severe neonatal morbidity was 25%.
In this cohort study, a slightly higher risk of ASD was observed in children born to individuals with infertility, which appears partly mediated by certain obstetrical and neonatal factors. To optimize child neurodevelopment, strategies should further explore these other factors in individuals with infertility, even among those not receiving fertility treatment.
先前关于生育治疗后儿童自闭症谱系障碍（ASD）风险的研究没有考虑到不孕本身或产科和新生儿因素的中介作用。
评估不孕及其治疗对 ASD 风险的关联，以及选定不良妊娠结局对该关联的中介作用。
设计、地点和参与者：这是一项在加拿大安大略省进行的基于人群的队列研究。参与者均为 24 周或以上妊娠的单胎和多胎活产儿，时间为 2006 年至 2018 年。数据于 2022 年 10 月至 2023 年 10 月进行分析。
暴露因素为受孕方式，具体包括（1）未经辅助受孕、（2）不孕但未接受生育治疗（即生育力低下）、（3）促排卵（OI）或宫腔内人工授精（IUI）、或（4）体外受精（IVF）或卵胞浆内单精子注射（ICSI）。
研究结果为 18 个月或以上被诊断为 ASD。Cox 回归模型生成了经产妇和婴儿特征调整后的危险比（HR）。中介分析进一步考虑了（1）子痫前期、（2）剖宫产、（3）多胎妊娠、（4）早产（<37 周）和（5）严重新生儿发病率等因素的单独影响。
共纳入 1370152 名儿童（703407 名男性[51.3%]）：1185024 名（86.5%）未经辅助受孕，141180 名（10.3%）为父母生育力低下，20429 名（1.5%）接受 OI 或 IUI，23519 名（1.7%）接受 IVF 或 ICSI。生育力低下或接受生育治疗的个体年龄较大，居住在高收入地区；每组的平均（SD）年龄如下：未经辅助受孕组为 30.1（5.2）岁，生育力低下组为 33.3（4.7）岁，OI 或 IUI 组为 33.1（4.4）岁，IVF 或 ICSI 组为 35.8（4.9）岁。未经辅助受孕组 ASD 的发病率为每 1000 人年 1.93 例。与后者相比，生育力低下组 ASD 的调整 HR 为 1.20（95%CI，1.15-1.25），OI 或 IUI 组为 1.21（95%CI，1.09-1.34），IVF 或 ICSI 组为 1.16（95%CI，1.04-1.28）。产科和新生儿因素似乎在受孕方式与 ASD 风险之间的关联中起到了相当大的中介作用。例如，在接受 IVF 或 ICSI 后，剖宫产的中介比例为 29%，多胎妊娠的中介比例为 78%，早产的中介比例为 50%，严重新生儿发病率的中介比例为 25%。
在这项队列研究中，不孕个体所生儿童的 ASD 风险略高，这似乎部分由某些产科和新生儿因素介导。为了优化儿童神经发育，策略应进一步探讨这些不孕个体的其他因素，即使他们没有接受生育治疗。
