Association between infertility and incident onset of systemic autoimmune rheumatic disease after childbirth: a population-based cohort study.

study questionWhat is the association between infertility with or without fertility treatment and incident onset of systemic autoimmune rheumatic disease (SARD) among women who give birth? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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,

methodsThe 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. WIDER IMPLICATIONS OF THE

findingsInfertility 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. TRIAL REGISTRATION NUMBER: N/A.