目的:评估使用辅助生殖技术进行受孕是否与儿童印记障碍有关,以及与不孕症相关的父母因素的影响。
方法:一项全国性的基于注册的队列研究。
方法:1997-2017年期间瑞典所有出生的单胎(N=2084127),随访至2018年12月31日。
方法:在辅助生殖技术中实施的特定方法的使用主要结果指标:国际疾病分类第10版用于识别三个不同的印记障碍组:Prader-Willi/Silver-Russell综合征,Beckwith-Wiedemann综合征,和中央性早熟。采用Cox模型结合逆概率治疗权重估计加权风险比(wHR),置信区间(CI)为95%,考虑多个混杂因素。
结果:共有1044名儿童被诊断出患有相关疾病,其中52个是用辅助生殖技术构思的。与所有其他儿童相比,接受ART的儿童被诊断出患有任何研究的印记障碍的总体风险升高(HR1.84,95%CI:1.38-2.45)。在调整了父母的背景因素后,关联部分减弱(wHR1.50,95%CI:0.97-2.32),但在加权比较中也仅限于已知不孕症夫妇的子女(wHR1.52,95%CI:1.05-2.21).对于Prader-Willi/Silver-Russell综合征和Beckwith-Wiedemann综合征的特定诊断,与已知不孕症夫妇的孩子相比,使用辅助生殖技术受孕的儿童表现出微小的超额风险,无法与null区分开(wHR1.56[95%CI:0.93-2.62]和1.80[95%CI:0.99-3.28],分别)。进一步的亚组分析显示,联合使用细胞质内单精子注射和冷冻保存胚胎与Prader-Willi/Silver-Russell综合征(wHR4.60,95%CI:1.72-12.28)和Beckwith-Wiedemann综合征(wHR6.69,95%CI:2.09-21.45)的风险较高。使用辅助生殖技术受孕的儿童的中央性早熟病例数量太少(N=3),无法做出任何有意义的推断。
结论:细胞质内精子注射和冷冻保存胚胎的联合使用与儿童Prader-Willi/Silver-Russell综合征和Beckwith-Wiedemann综合征的风险较小有关,独立于与生育相关的父母因素。
OBJECTIVE: To assess whether the use of assisted reproductive technology (ART) therapy for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility.
METHODS: A nationwide register-based cohort study.
METHODS: Swedish national registers and nationwide quality IVF register.
METHODS: All liveborn singletons in Sweden (N = 2,084,127) between 1997 and 2017 with follow-up to December 31, 2018.
METHODS: The use of specific methods implemented in ART.
METHODS: The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS), as well as central precocious puberty. The Cox model combined with inverse probability treatment weights was used to estimate the weighted hazard ratio (wHR) with a 95% confidence interval (CI), accounting for multiple confounders.
RESULTS: A total of 1,044 children were diagnosed with the disorders of interest, and 52 of them were conceived using ART therapy. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived using ART therapy compared with all other children (HR, 1.84; 95% CI, 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR, 1.50; 95% CI, 0.97-2.32), but remained in the weighted comparison restricted to children of couples with known infertility (wHR, 1.52; 95% CI, 1.05-2.21). For the specific diagnoses of PWS/SRS, and BWS compared with children of couples with known infertility, children conceived with ART therapy showed a small excess risk, which could not be distinguished from the null (wHR, 1.56; 95% CI, 0.93-2.62 and 1.80; 95% CI, 0.99-3.28, respectively). Further subgroup analysis showed that the combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with a higher risk of both PWS/SRS (wHR, 4.60; 95% CI, 1.72-12.28) and BWS (wHR, 6.69; 95% CI, 2.09-21.45). The number of central precocious puberty cases in children conceived using ART therapy was too small (N = 3) to make any meaningful inference.
CONCLUSIONS: The combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of PWS/SRS, and BWS in children, independent of parental factors related to infertility.