ACCEL | Infertility affects approximately one in eight reproductive-age couples globally, and for decades has often been treated with fertility therapy. The focus of such therapy is on achieving pregnancy and not long-term health, yet unintended toxicity can occur. One concern is that fertility therapy might lead to downstream cardiovascular events due to increased risks of maternal metabolic syndromes (e.g., gestational diabetes mellitus and hypertension), direct endothelial dysfunction, and prothrombotic effects from ovarian hyperstimulation with hyperestrogenemia.

Take-aways Because fertility medications may lead to endothelial injury with long-term adverse consequences for the mother, investigators conducted a large population-based cohort analysis to determine whether fertility therapy might contribute to subsequent cardiovascular disease. Successful fertility therapy was not associated with an increased risk of cardiovascular disease later in life and had lower risk-adjusted all-cause mortality, thromboembolic events, and subsequent depression, alcoholism, and self-harm. These results should allay any concern that successful fertility therapy increases the short-term (10-year) risk of cardiovascular disease later in life.

Nevertheless, long-term data are lacking on the health effects associated with fertility therapy for women who have a successful pregnancy, in part because of a lack of uniform reporting of adverse outcomes after fertility therapy and legislation sometimes prohibiting health data linkage.

Jacob A. Udell, MD, and colleagues studied whether fertility therapy might contribute to subsequent cardiovascular risk by performing a population-based cohort analysis of 1,186,753 women who gave birth in Ontario, Canada, between 1993 and 2010, of whom 6,979 gave birth after fertility therapy.¹

The investigators observed a 5-fold increase in the use of fertility therapy over the last 2 decades, particularly among older women. The use of fertility therapy was associated with an increase in several short-term pregnancy complications, yet women who delivered after fertility therapy had about half the risk of long-term death or major adverse cardiovascular events compared to controls. Specifically, after 9.7 years of median follow-up, the rate of the primary outcome—a composite of death or hospitalization for a major adverse cardiovascular event including nonfatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, or heart failure—was lower among women who had received fertility treatment than controls (103 events vs. 117 events per 100,000 person-years), with an adjusted hazard ratio of 0.55. The decreased risk of long-term adverse events associated with fertility therapy was consistent across age and socioeconomic groups.

Explaining the Effects Seen

Not only was fertility treatment associated with a reduction in death and thromboembolic disease, but it also seemed to protect against the development of risk factors for cardiovascular disease. Given that the population receiving fertility treatment at baseline had more cardiovascular risk factors, it would seem unlikely that they were a particularly healthy group.

The authors suggested three possible explanations for the results, with one being that women who have had successful fertility treatment opt for a healthier lifestyle than women who conceived without fertility treatment. There is also the possibility that the treatment has some beneficial effect. Or, it's possible that women who have unhealthy lifestyles do not choose to have fertility treatment.

Fertility treatment is unlikely to have some intrinsic health-promoting effect, suggesting that the adoption of a healthy lifestyle may be the most likely.

Jolien W. Roos-Hesselink, MD, PhD, and Mark R. Johnson, MD, PhD, wrote in an accompanying commentary that while a longer duration of follow-up is warranted and the discussion is not yet closed, the findings are reassuring for women who need fertility treatment.² Overall, however, they noted that it should be remembered that the population needing fertility treatment is at increased risk of cardiovascular and metabolic disease. Further, the data can only be applied to women who conceived and had a live birth. The outcome for women whose treatment was unsuccessful may be very different and should be investigated.

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References

1. Udell JA, Lu H, Redelmeier DA. J Am Coll Cardiol. 2013;62:1704-12.
2. Roos-Hesselink JW, Johnson MR. J Am Coll Cardiol. 2013;62:1713-4.

To listen to an interview with Jacob A. Udell, MD, about cardiovascular risk of fertility therapy, visit youtube.cswnews.org. The interview was conducted by Anthony N. DeMaria, MD.

Keywords: Metabolic Syndrome, Fertility, Thromboembolism, Life Style, Follow-Up Studies, Ischemic Attack, Transient, Cardiovascular Diseases, Live Birth, Risk Factors, Pregnancy, CardioSource WorldNews, ACC Publications

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