Cardiovascular Disease Risks With Fertility Treatment: What We Know

Although the use of fertility therapy has steadily increased in the past few decades, research findings pertaining to related long-term cardiovascular outcomes are scarce and conflicting.

For example, a population-based Swedish study reported higher rates of hypertension (hazard ratio [HR], 1.27; 95% CI, 1.13-1.41), and a trend toward higher stroke incidence (HR, 1.27; 95% CI, 0.96-1.68) in women who received fertility therapy vs women who did not, while no such associations were observed in a Canadian population-based study.^1,2

A Need for Vigilance

Up to 4% of pregnancies are currently attributed to in vitro fertilization (IVF) and intrauterine insemination (IUI), and these rates are expected to continue to increase.³ “The use of fertility therapy is bound to keep rising as our population chooses to delay parenthood,” noted Natalie Dayan MD, MSc, FRCPC and Jacob Udell, MD, MPH, FRCPC. “Thus, we will probably see more and more age-related infertility, and we need to ensure the short-term and longer-term safety of high-dose hormonal treatments that characterize fertility therapy,” they told Cardiology Advisor.

Dr Dayan is an assistant professor of medicine at McGill University and director of McGill University Health Centre (MUHC) Obstetrical Medicine and a clinician scientist at MUHC Research Institute, Centre for Outcomes Research and Evaluation (CORE). Dr Udell is a cardiologist and clinician scientist at Women’s College Hospital and the Peter Munk Cardiac Centre of the University Health Network and an assistant professor of medicine at the University of Toronto in Canada.

As for potential mechanisms underlying a connection between cardiovascular disease (CVD) and fertility therapy, including IVF and IUI, it has been proposed that “repeated cycles of ovarian hyperstimulation and associated hyperestrogenemia contribute to a prothrombotic state and may also cause endothelial injury by affecting the renin-angiotensin system,” according to a new paper published in the Journal of the American College of Cardiology , in which Drs Dayan and Udell were two of the investigators.⁴ In addition, the CV stress associated with pregnancy at older ages could also contribute to CVD.

Latest Findings and Challenges

Drs Dayan and Udell and colleagues conducted a review and meta-analysis that revealed a lack of research on the topic and significant heterogeneity in the limited studies that have examined it.⁴ Their analysis included 6 observational studies involving 41,910 women with a history of fertility therapy and 1,400,202 women with no such history. Their results demonstrated no increase in the risk for cardiac events (pooled HR, 0.91; 95% CI, 0.67-1.25; I² = 36.6%) or diabetes (pooled HR, 0.93; 95% CI, 0.87-1.001; I² = 0%), although they did observe a trend toward elevated stroke risk (pooled HR, 1.25; 95% CI, 0.96-1.63; I² = 0%).

“In general, the overall takeaway from the study is that conclusions regarding the CV safety of fertility therapy are not definitive, and concerns regarding long-term CV risks remain,” said Ki Park, MD, a clinical assistant professor of medicine in interventional cardiology at the University of Florida in Gainesville, who coauthored a related editorial published in the Journal of the American College of Cardiology.⁵

Dr Park told Cardiology Advisor that there are many confounding variables to consider when exploring links between CV risk and fertility therapy: “The most prominent potential confounder is the condition that led to infertility in the first place — whatever is driving impaired fertility, such as hormonal dysfunction or vascular dysfunction, may also be responsible for the increase in CV risk in the long run.” The design of most studies in this area thus far does not allow for the control of confounding variables.

Randomized trials are optimal for minimizing confounding factors, but since researchers cannot randomly assign women to fertility therapy vs no fertility therapy, it is “challenging to know whether the types of women who require fertility therapy are at risk for cardiovascular disease by virtue of the underlying infertility itself,” Drs Dayan and Udell explained.

One way to reduce some of these confounding factors is to compare infertile women who received fertility therapy with women who did not, as in one of the studies reviewed. Many studies, however, lack data on infertile populations.

The investigators suggested that future studies use a statistical method called propensity score analysis to make this comparison while adjusting for confounding variables such as age and cause of infertility. Another helpful method is to compare women who received fertility therapy but did not become pregnant (severe infertility) with women who received fertility therapy and did become pregnant (nonsevere infertility). Dr Udell and colleagues used this approach in a recent study of 28,442 women who had received fertility therapy, of whom 32.9% subsequently gave birth.⁶ Their findings revealed an annual rate of CV events that was 19% higher in women who did not give birth vs women who did (1.08 vs 0.91 per 100 patient-years; 95% CI, 13% to 30%; P <.001).⁶

Next Steps

The primary need for future research is to build a registry of relevant data that can be used for more detailed analysis, Dr Park noted. Another research need, according to Drs Dayan and Udell, is “prospective long-term longitudinal follow-up of populations of women who seek fertility treatments — whether they receive them or not. Any subsequent pregnancies as well as nonpregnancy health outcomes should be measured repeatedly over time, and women who receive fertility therapy can be compared [with] women who do not.” In addition, women who receive more than 1 course of treatment can be compared with women who received a single course or no treatment.

The researchers explained that the main takeaway of their review is that this area deserves further study, and they hope it underscores the importance of investigating the health effects of fertility therapy. “As of now we have found no clear signal suggesting long-term harm with respect to [CVD], but we lack sufficient data to definitively declare its safety — or harm, especially regarding stroke,” they concluded. “What we do know is that pregnancy-related complications such as preeclampsia and preterm birth are associated with premature [CVD]. We do not yet know if fertility therapy is another woman-specific risk factor for heart disease.”

References

1. Westerlund E, Brandt L, Hovatta O, Wallén H, Ekbom A, Henriksson P. Incidence of hypertension, stroke, coronary heart disease, and diabetes in women who have delivered after in vitro fertilization: a population-based cohort study from Sweden. Fertil Steril. 2014;102(4):1096-1102.
2. Udell JA, Lu H, Redelmeier DA. Long-term cardiovascular risk in women prescribed fertility therapy. J Am Coll Cardiol. 2013;62(18):1704-1712.
3. Talaulikar VS, Arulkumaran S. Reproductive outcomes after assisted conception. Obstet Gynecol Surv. 2012;67(9):566-583.
4. Dayan N, Filion KB, Okano M, et al. Cardiovascular risk following fertility therapy: systematic review and meta-analysis. J Am Coll Cardiol. 2017;70(10):1203-1213.
5. Pepine CJ, Park K. Fertility therapy and long-term cardiovascular risk: raising more questions than answers? J Am Coll Cardiol. 2017;70(10):1214-125.
6. Udell JA, Lu H, Redelmeier DA. Failure of fertility therapy and subsequent adverse cardiovascular events. CMAJ. 2017;189(10):E391-7.