Long-term risk of cardiovascular disease after assisted reproductive technology and infertility: A cohort study

The use of Assisted Reproductive Technology (ART) is increasing worldwide. These treatments involve ovarian stimulation to enable multiple follicle recruitment, hence inducing supraphysiological estrogen levels. While most long-term follow-up of women undergoing ART has concerned cancer incidence, the long-term safety regarding cardiovascular and metabolic diseases remains under-explored. This study was performed to assess the risk of acute myocardial infarction, cerebral ischemic conditions, intracranial hemorrhage, type 2 diabetes mellitus, heart failure, aortic aneurysm or dissection, and chronic kidney disease in women that conceived with ART, and to investigate the role of the underlying infertility and its risk factors.

Swedish national registers allowed us to follow a nationwide cohort of 380,756 women from their first birth between 1992 and 2002 until the end of 2023. The safety of ART was evaluated by comparing women with infertility who conceived with and without ART, while adjusting for baseline differences in age, body mass index, country of origin, socioeconomic factors, pre-existing comorbidity, smoking and year. The role of infertility was additionally explored by comparing all women with and without infertility adjusting for age, as well as the aforementioned baseline characteristics. Cumulative risks were plotted using inverse-probability weighted Kaplan-Meier curves. To facilitate the comparison of groups, we also estimated risk differences and ratios at 10-, 20-, and 30 years of follow-up. Use of ART was not associated with cardiovascular disease except for an excess risk of cerebral ischemic conditions, with a 30-year risk ratio of 1.44 (95% Confidence Interval (CI) [1.09,1.90]). With the exception of cerebral ischemic conditions, intracranial hemorrhage, aortic dissection, and chronic kidney disease, women with a history of infertility exhibited consistently higher risk of all outcomes, and adjustment for differences in baseline characteristics explained some but not all of these elevated risks. Even though the study period was restricted with respect to the earliest years of ART implementation, the number of exposed was still low and risks calculated with limited precision, particularly at the beginning and at the end of the follow-up due to very few events and decreasing numbers at risk, respectively.

With the exception of ischemic cerebral conditions, the findings provide reassurance regarding the long-term cardiometabolic safety of ART use, while adding to the growing literature suggesting that infertility can act as a marker of women's cardiovascular and metabolic disease.