Scime Natalie V, Velez Maria P, Choi May Y, Ray Joel G, Boblitz Alexa, Brown Hilary K
Department of Health and Society, University of Toronto Scarborough, Toronto, ON, Canada.
ICES, Toronto, ON, Canada.
Hum Reprod. 2025 Jan 1;40(1):157-166. doi: 10.1093/humrep/deae253.
What is the association between infertility with or without fertility treatment and incident onset of systemic autoimmune rheumatic disease (SARD) among women who give birth?
Women who experienced infertility but did not use fertility treatment had a higher incidence of SARD up to 9 years after delivery than those who did not experience infertility, even after accounting for their higher rates of preeclampsia, spontaneous preterm birth, and stillbirth.
Infertility is increasingly common and is an under-appreciated risk marker for chronic diseases in women. Despite several studies documenting abnormal immune activity in women with infertility, little is known about the association between infertility and incidence of autoimmune diseases such as SARD which disproportionately develops in reproductive-aged women.
STUDY DESIGN, SIZE, DURATION: This population-based cohort study using linked administrative data for all of ON, Canada, 2012-2021 and included 568 053 singleton births among 465 078 women aged 18-50 years without known pre-existing SARD.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The exposures were: (i) no infertility with unassisted conception (referent [88.0% of the cohort]); (ii) infertility without fertility treatment (9.2%); (iii) infertility with non-invasive fertility treatment (ovulation induction or intrauterine insemination [1.4%]); and (iv) infertility with invasive fertility treatment (IVF or ICSI [1.4%]). SARD was identified by a validated algorithm based on diagnostic codes at two physician visits, one rheumatologist visit, or one hospitalization and measured from the index delivery date, with censoring at death, loss of health insurance, or study end of 31 March 2021. Marginal structural Cox proportional hazards models generated hazard ratios (HR) and 95% CIs representing total effects adjusted for sociodemographic characteristics, comorbidities, and smoking, and controlled direct effects additionally accounting for adverse pregnancy outcomes.
The median (IQR) duration of follow-up was 6.5 (4-9) years. The incidence rate of SARD was 9.3 per 10 000 person-years in women without infertility, 12.5 per 10 000 person-years in those with infertility and no fertility treatment, 10.9 per 10 000 person-years following non-invasive fertility treatment, and 10.9 per 10 000 person-years after invasive fertility treatment. Infertility without treatment was associated with an elevated risk of SARD, even after accounting for adverse pregnancy outcomes (controlled direct effect HR 1.25, 95% CI 1.12-1.40). Neither non-invasive (total effect HR 1.06, 95% CI 0.79-1.42) nor invasive (total effect HR 0.97, 95% CI 0.69-1.36) fertility treatments were associated with SARD.
LIMITATIONS, REASONS FOR CAUTION: Exposure and outcome misclassification is possible as this study used published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. Data on individual-level social and lifestyle factors and underlying causes of infertility were not available and thus were not included in the analysis.
Infertility in the absence of fertility treatment may be an important risk marker for SARD in women who give birth. Greater health provider awareness of SARD symptoms and related gynaecological issues that may be present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years.
STUDY FUNDING/COMPETING INTERESTS(S): This research was funded by the Canadian Institutes of Health Research through a Banting Postdoctoral Fellowship to N.V.S. and Canada Research Chair to H.K.B. (2019-00158) and was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding organizations; no endorsement is intended or should be inferred. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. M.Y.C. has consulted for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada Inc, and Glaxo Smith Kline. All other authors have no conflicts of interest.
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在已生育的女性中，接受或未接受生育治疗的不孕症与系统性自身免疫性风湿性疾病（SARD）的发病之间有何关联？
经历过不孕但未接受生育治疗的女性，在分娩后长达9年的时间里，SARD的发病率高于未经历不孕的女性，即便考虑到她们患先兆子痫、自然早产和死产的比例较高。
不孕症越来越普遍，是女性慢性疾病中一个未得到充分重视的风险指标。尽管有多项研究记录了不孕女性的免疫活动异常，但对于不孕症与自身免疫性疾病（如在育龄女性中不成比例发生的SARD）发病率之间的关联却知之甚少。
研究设计、规模、持续时间：这项基于人群的队列研究使用了2012 - 2021年加拿大安大略省所有的关联行政数据，纳入了465078名年龄在18 - 50岁且无已知既往SARD的女性中的568053例单胎分娩。
参与者/材料、设置、方法：暴露因素包括：（i）无不孕且自然受孕（对照[占队列的88.0%]）；（ii）不孕但未接受生育治疗（9.2%）；（iii）不孕且接受非侵入性生育治疗（促排卵或宫内人工授精[1.4%]）；以及（iv）不孕且接受侵入性生育治疗（体外受精或卵胞浆内单精子注射[1.4%]）。SARD通过一种经过验证的算法，根据两次医生就诊、一次风湿病学家就诊或一次住院时的诊断代码来确定，并从索引分娩日期开始测量，在死亡、失去医疗保险或2021年3月31日研究结束时进行截尾。边际结构Cox比例风险模型生成风险比（HR）和95%置信区间，代表经社会人口学特征、合并症和吸烟调整后的总效应，并通过控制直接效应额外考虑不良妊娠结局。
随访的中位（四分位间距）持续时间为6.5（4 - 9）年。未患不孕症女性的SARD发病率为每10000人年9.3例，不孕但未接受生育治疗的女性为每10000人年12.5例，接受非侵入性生育治疗后的女性为每10000人年10.9例，接受侵入性生育治疗后的女性为每10000人年10.9例。即使考虑到不良妊娠结局，未接受治疗的不孕症与SARD风险升高相关（控制直接效应HR 1.25，95%置信区间1.12 - 1.40）。非侵入性（总效应HR 1.06，95%置信区间0.79 - 1.42）和侵入性（总效应HR 0.97，95%置信区间0.69 - 1.36）生育治疗均与SARD无关。
局限性、谨慎原因：由于本研究使用健康行政数据中已发表的算法，其敏感性和特异性未知或不完善，可能存在暴露和结局的错误分类。关于个体层面的社会和生活方式因素以及不孕的潜在原因的数据不可得，因此未纳入分析。
未接受生育治疗的不孕症可能是已生育女性患SARD的一个重要风险指标。医疗服务提供者提高对SARD症状以及不孕女性可能存在的相关妇科问题的认识，有助于在生育期更早地发现和治疗SARD。
研究资金/利益冲突：本研究由加拿大卫生研究院通过给N.V.S.的班廷博士后奖学金以及给H.K.B.的加拿大研究主席基金（2019 - 00158）资助，并得到ICES的支持，ICES由安大略省卫生部和长期护理部的年度拨款资助。本文所表达的分析、结论、观点和陈述仅为作者的观点，并不反映资助机构的观点；无意也不应推断有任何认可。资助者在研究设计的考虑、数据的收集、分析、解释、报告的撰写或提交文章发表的决定中没有任何作用。M.Y.C.曾为Celltrion、Werfen、Organon、MitogenDx、阿斯利康、加拿大Mallinckrodt公司和葛兰素史克公司提供咨询服务。所有其他作者均无利益冲突。
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