Department of Obstetrics and Gynaecology, Queen's University, Kingston Health Sciences Centre, Kingston, ON, Canada.
Department of Medicine, Obstetrics and Gynaecology and Research Institute, McGill University Health Centre, Montreal, QC, Canada.
Hum Reprod. 2022 Aug 25;37(9):2126-2134. doi: 10.1093/humrep/deac129.
STUDY QUESTION: Is the risk of attention-deficit hyperactivity disorder (ADHD) increased in children born to mothers with infertility, or after receipt of fertility treatment, compared to mothers with unassisted conception? SUMMARY ANSWER: Infertility itself may be associated with ADHD in the offspring, which is not amplified by the use of fertility treatment. WHAT IS KNOWN ALREADY: Infertility, and use of fertility treatment, is common. The long-term neurodevelopmental outcome of a child born to a mother with infertility, including the risk of ADHD, remains unclear. STUDY DESIGN, SIZE, DURATION: This population-based cohort study comprised all singleton and multiple hospital births in Ontario, Canada, 2006-2014. Outcomes were assessed up to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Linked administrative datasets were used to capture all hospital births in Ontario, maternal health and pregnancy measures, fertility treatment and child outcomes. Included were all children born at ≥24 weeks gestation between 2006 and 2014, and who were alive at age 4 years. The main exposure was mode of conception, namely (i) unassisted conception (reference group), (ii) infertility without fertility treatment (history of an infertility consultation with a physician within 2 years prior to conception but no fertility treatment), (iii) ovulation induction (OI) or intrauterine insemination (IUI) and (iv) IVF or intracytoplasmic sperm injection (ICSI). The main outcome was a diagnosis of ADHD after age 4 years and assessed up to June 2020. Hazard ratios (HRs) were adjusted for maternal age, income quintile, rurality, immigration status, smoking, obesity, parity, any drug or alcohol use, maternal history of mental illness including ADHD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex. In addition, we performed pre-planned stratified analyses by mode of delivery (vaginal or caesarean delivery), infant sex, multiplicity (singleton or multiple), timing of birth (term or preterm <37 weeks) and neonatal adverse morbidity (absent or present). MAIN RESULTS AND THE ROLE OF CHANCE: The study included 925 488 children born to 663 144 mothers, of whom 805 748 (87%) were from an unassisted conception, 94 206 (10.2%) followed infertility but no fertility treatment, 11 777 (1.3%) followed OI/IUI and 13 757 (1.5%) followed IVF/ICSI. Starting at age 4 years, children were followed for a median (interquartile range) of 6 (4-8) years. ADHD occurred among 7.0% of offspring in the unassisted conception group, 7.5% in the infertility without fertility treatment group, 6.8% in the OI/IUI group and 6.3% in the IVF/ICSI group. The incidence rate (per 1000 person-years) of ADHD was 12.0 among children in the unassisted conception group, 12.8 in the infertility without fertility treatment group, 12.9 in the OI/IUI group and 12.2 in the IVF/ICSI group. Relative to the unassisted conception group, the adjusted HR for ADHD was 1.19 (95% CI 1.16-1.22) in the infertility without fertility treatment group, 1.09 (95% CI 1.01-1.17) in the OI/IUI group and 1.12 (95% CI 1.04-1.20) in the IVF/ICSI group. In the stratified analyses, these patterns of risk for ADHD were largely preserved. An exception was seen in the sex-stratified analyses, wherein females had lower absolute rates of ADHD but relatively higher HRs compared with that seen among males. LIMITATIONS, REASONS FOR CAUTION: Some mothers in the isolated infertility group may have received undocumented OI oral therapy, thereby leading to possible misclassification of their exposure status. Parenting behaviour, schooling and paternal mental health measures were not known, leading to potential residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Infertility, even without treatment, is a modest risk factor for the development of ADHD in childhood. The reason underlying this finding warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This study was made possible with funding from the Canadian Institutes of Health Research, Grant number PJT 165840. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
研究问题:与未经辅助受孕的母亲所生的子女相比,患有不孕症或接受过生育治疗的母亲所生的子女患注意力缺陷多动障碍(ADHD)的风险是否增加?
总结答案:不孕症本身可能与后代的 ADHD 有关,而使用生育治疗并不会放大这种风险。
已知情况:不孕症和生育治疗的使用很常见。患有不孕症的母亲所生的孩子的长期神经发育结果,包括 ADHD 的风险,仍不清楚。
研究设计、规模、持续时间:这是一项基于人群的队列研究,纳入了 2006 年至 2014 年期间安大略省所有的单胎和多胎医院分娩,结局评估截至 2020 年 6 月。
参与者/材料、设置、方法:使用链接的行政数据集捕获了安大略省所有的医院分娩、产妇健康和妊娠措施、生育治疗和儿童结局。纳入标准为:妊娠 24 周以上且在 4 岁时存活的所有儿童。主要暴露因素为受孕方式,即(i)未经辅助受孕(参照组)、(ii)不孕但未接受生育治疗(在受孕前 2 年内曾与医生咨询过不孕,但未接受生育治疗)、(iii)促排卵(OI)或宫腔内人工授精(IUI)、(iv)体外受精(IVF)或胞浆内单精子注射(ICSI)。主要结局为 4 岁后诊断为 ADHD,并在 2020 年 6 月之前进行评估。调整了母亲年龄、收入五分位数、农村/城市程度、移民状况、吸烟、肥胖、产次、任何药物或酒精使用、母亲精神疾病史包括 ADHD、孕前糖尿病或慢性高血压以及婴儿性别等因素的危害比(HRs)。此外,我们还根据分娩方式(阴道分娩或剖宫产)、婴儿性别、倍数(单胎或多胎)、分娩时间(足月或早产 <37 周)和新生儿不良发病率(无或有)进行了预先计划的分层分析。
主要结果和机会的作用:该研究纳入了 925488 名由 663144 名母亲所生的儿童,其中 805748 名(87%)来自未经辅助受孕的母亲,94206 名(10.2%)遵循不孕症但未接受生育治疗,11777 名(1.3%)遵循 OI/IUI,13757 名(1.5%)遵循 IVF/ICSI。从 4 岁开始,对儿童进行了中位数(四分位距)为 6 年(4-8 年)的随访。未辅助受孕组的 ADHD 发生率为 7.0%,不孕但未接受生育治疗组为 7.5%,OI/IUI 组为 6.8%,IVF/ICSI 组为 6.3%。未辅助受孕组 ADHD 的发病率为每 1000 人年 12.0,不孕但未接受生育治疗组为 12.8,OI/IUI 组为 12.9,IVF/ICSI 组为 12.2。与未经辅助受孕组相比,不孕但未接受生育治疗组的 ADHD 调整后 HR 为 1.19(95%CI 1.16-1.22),OI/IUI 组为 1.09(95%CI 1.01-1.17),IVF/ICSI 组为 1.12(95%CI 1.04-1.20)。在分层分析中,这些 ADHD 的风险模式基本保持不变。唯一的例外是性别分层分析,其中女性的 ADHD 绝对发病率较低,但与男性相比,HR 相对较高。
局限性、谨慎的原因:孤立性不孕组中的一些母亲可能接受了未记录的 OI 口服治疗,从而可能导致其暴露状况的错误分类。不知道育儿行为、教育和父亲的心理健康措施,这可能导致潜在的残余混杂。
研究结果的更广泛意义:不孕症,即使没有治疗,也是儿童期 ADHD 发展的一个适度危险因素。这一发现的原因值得进一步研究。
研究资助/利益冲突:这项研究得到了加拿大卫生研究院的资助,资助号为 PJT 165840。作者没有报告任何利益冲突。
临床试验注册号:无。
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