Assisted reproductive technology (ART) is increasingly used worldwide and involves ovarian stimulation that produces supraphysiological hormone levels. While short-term complications such as venous thromboembolism after ART have been documented, the long-term effects of ART exposure on cardiovascular and metabolic disease remain understudied. The authors aimed to assess whether conceiving with ART is associated with long-term risks for a range of cardiometabolic outcomes, and to disentangle the role of ART from that of the underlying infertility and its risk factors.
The study used Swedish national register linkages to assemble a nationwide cohort of 380,756 women who had their first birth between 1992 and 2002 and followed them through the end of 2023. The registers provided information on births, diagnoses, and sociodemographic and clinical covariates. The principal analytic comparison evaluated safety of ART by comparing women with infertility who conceived with ART to women with infertility who conceived without ART, while adjusting for baseline differences including age, body mass index (BMI), country of origin, socioeconomic factors, pre-existing comorbidity, smoking and calendar year.
A secondary comparison assessed the role of infertility itself by comparing women with and without a recorded history of infertility, with adjustment for the same baseline characteristics. The cohort was restricted to births that resulted in live births; the authors noted that data on women who underwent treatment without a live birth were not available in the registers used.
Pre-specified outcomes included acute myocardial infarction, cerebral ischemic conditions, intracranial hemorrhage, type 2 diabetes mellitus, heart failure, aortic aneurysm or dissection, and chronic kidney disease. Cumulative risks were plotted using inverse-probability weighted Kaplan–Meier curves. To present comparative measures over time, the investigators estimated risk differences and risk ratios at 10, 20, and 30 years of follow-up.
Comparisons between groups were adjusted for measured baseline covariates to account for confounding, and standardized differences were used to evaluate balance. The authors provided confidence intervals for risk ratios to reflect precision of estimates.
The cohort comprised 380,756 women with first births from 1992–2002 and follow-up through 2023.
Use of ART was not associated with increased risk for most long-term cardiovascular or metabolic outcomes examined.
An exception was observed for cerebral ischemic conditions: ART was associated with a higher long-term risk, with a 30-year risk ratio reported as 1.44 (95% CI 1.09–1.90).
When comparing women with and without a history of infertility, women with infertility exhibited consistently higher risks for most outcomes (with some exceptions, including intracranial hemorrhage, aortic dissection and chronic kidney disease).
After 30 years of follow-up and adjustment for baseline characteristics, women with infertility had approximately 36% higher risk of acute myocardial infarction, 34% higher risk of type 2 diabetes mellitus, and 24% higher risk of heart failure relative to women without infertility.
Adjustment for measured baseline covariates reduced but did not fully explain the elevated risks observed for women with infertility.
The findings largely offer reassurance that conception with ART is not associated with increased long-term risk of most studied cardiovascular and metabolic conditions. The observed excess risk of cerebral ischemic conditions following ART warrants further investigation to confirm the finding, identify potential mechanisms, and determine whether specific ART protocols or patient subgroups are at higher risk.
Separately, the consistent association between a history of infertility and increased long-term cardiometabolic risk supports the view that infertility can serve as a marker for later cardiovascular and metabolic disease in women. Clinicians may consider this evidence when assessing long-term preventive care needs for women with a history of infertility.
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In this large, register-based Swedish cohort followed for up to 30 years after first birth, conception with ART was not associated with increased long-term risk for most cardiovascular and metabolic outcomes assessed, but was associated with an elevated risk of cerebral ischemic conditions. A history of infertility itself was consistently associated with higher long-term cardiometabolic risk, even after adjustment for measured baseline factors. The authors emphasize the need for further research to confirm the ischemic stroke finding, to explore mechanisms linking infertility to later cardiometabolic disease, and to evaluate risks among women who undergo ART but do not achieve a live birth.