After a median follow-up of 11 years, women who gave birth with the assistance of reproductive technology were not at increased risk of cardiovascular disease (CVD) compared to those who did not receive this intervention, a new study shows.
The use of assisted reproductive technologies (ARTs) is steadily increasing, but associated risks for CVD remain largely unknown.
A 2017 meta-analysis yielded weak statistical evidence of a higher risk of stroke among individuals who had used ART (hazard ratio, 1.25; 95% CI, 0.96 – 1.63) but not of cardiac events or diabetes mellitus. However, the small number of events, the heterogeneity between studies, and the short follow-up time did not permit firm conclusions.
The current registry-based study included 2,496,441 women without preexisting CVD who gave birth in Denmark, Finland, Norway, and Sweden. Of these patients, 97,474 (4%) had ART. The ART group was older, and among them, there was a higher prevalence of poor prepregnancy cardiovascular health and polycystic ovary syndrome than among those who did not receive ART.
The main outcome was CVD, defined as ischemic heart disease (including myocardial infarction), cerebrovascular disease (including stroke), cardiomyopathy, heart failure, or venous thrombosis.
Researchers adjusted for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country.
After a median follow up of 11 years, the rate of any CVD was 153 per 100,000 person-years. There was no significant difference in the risk of any CVD among individuals who had used ART compared with those who had not (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91 – 1.02), although there was heterogeneity between countries (AHR for Norway, 0.74; for Sweden, 0.84; for Denmark, 0.98; and for Finland, 1.09).
Several subgroup and sensitivity analyses ― including those that were adjusted for tobacco use, body mass index, educational level, pregnancy complications, and CVD subgroups (ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, deep vein thrombosis) ― showed similar results, although there was a lower risk of myocardial infarction among individuals who had used ART.
Among those who underwent frozen embryo transfer, there was a higher risk of CVD compared to those who had not used ART (AHR, 1.24; 95% CI, 1.02 – 1.51); this, said the authors, might reflect greater severity of the fertility problem, as the couple had usually experienced an unsuccessful fresh embryo transfer attempt before proceeding to frozen embryo transfer.
There was a lower risk of CVD among women who had used intracytoplasmic sperm injection (ICSI) compared to women who had not used ART (AHR, 0.83; 95% CI, 0.74 – 0.94). In vitro fertilization with ICSI typically is used in cases involving a male fertility problem, so this might reflect healthier reproductive status of women, which might help explain their decreased risk of CVD, said the authors.
“These findings may be reassuring to the increasing number of individuals who require assistance from ART to conceive,” the authors write.
In an invited commentary, Stephanie A. Fisher MD, MPH, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, and colleagues say the study “is an important contribution to the literature and highlights key gaps in our understanding at the intersection of reproductive and cardiovascular health,” including understanding the lifetime implications of ART use.
The study was carried out by Maria C. Magnus PhD, Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway, and colleagues. It was published online August 9, 2023, in JAMA Cardiology.
Because women who gave birth after ART were still young (the median age at end of follow-up was 41 years), the researchers could only investigate CVD risk up to middle age. They also could not examine the risk of CVD among women who had undergone ART and remained nulliparous. The authors only had educational level as a measure of socioeconomic status, and there was no information on income and employment, which could have resulted in confounding. They also had no information on the number and time of unsuccessful ART procedures, and they didn’t have a sufficient number of events to evaluate CVD risk in accordance with the number of ART deliveries so as to explore a potential dose-response relationship.
The study received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program. Magnus and Fisher report no relevant conflicts of interest; disclosures of other authors the editorialists are listed in the original articles.
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