Infertility affects approximately one in eight reproductive-aged couples globally, with 1% of births annually in North America attributed to fertility treatments. Fertility treatments have an immediate short-term goal—achieving pregnancy—but potential unintended toxicity is a major concern for women who receive reproductive assistance. Long-term data about health effects, however, are lacking. In a recent study from JACC, Jacob A. Udell, MD, MPH, and colleagues investigated the possibility that fertility therapy could contribute to subsequent cardiovascular disease following successful pregnancy.

Udell et al. analyzed data from the General Reproductive Assistance and Vascular Illness Downstream (GRAVID) study, which included nearly 1.2 million women. Of these, 6,979 gave birth following fertility therapy. These women were more likely to be older, have a higher income, and have a higher number of prenatal visits; there was also a higher prevalence of certain cardiovascular risk factors among this group (older age, hypertension, hyperlipidemia, and diabetes). Also, as the authors expected, women who gave birth following fertility therapy more commonly had a history of pelvic inflammatory disease, endometriosis, and cancer.

Short-term outcomes (including development of gestational diabetes, pre-eclampsia, and serious placental complications) were more likely to occur in women treated with fertility therapy. After a median of 9.7 years of follow-up, however, these women actually had fewer cardiovascular events than controls (103 vs. 117 events per 100,000 person-years; adjusted HR = 0.55); this association remained true in a subgroup analysis of women aged ≥30 years. The risks for individual components of the composite primary outcome can be found in TABLE 1.

Overall, use of fertility therapy was associated with an increase in short-term pregnancy complications, but, in the long term, these women had about half the risk of death or major adverse cardiovascular events compared to controls. “A better understanding of the long-term risks associated with fertility therapy might help inform decision making around reproductive technology and motivate cardiovascular risk reduction,” the authors suggested.

They also noted that further re-evaluation of patients for emergence of cardiovascular events at a later age will be important, given the relative young age and brief duration of follow-up in this report, especially, they wrote, “given societal trends for women to delay pregnancy until older age with a higher likelihood of baseline heart disease.”

The authors offered a few potential explanations for this decreased risk, including:

• Women who have fertility challenges are prone towards healthier behavior following successful delivery
• Fertility therapy offers an unknown pleiotropic biologic protective mechanism
• Women with distinctly adverse lifestyles do not generally seek fertility treatment

“We know pregnancy is a ‘stress test’ for later cardiovascular and metabolic disease,” Jolien W. Roos-Hesselink, MD, PhD, and Mark R. Johnson, MD, PhD, wrote in an accompanying editorial. “Indeed, complications arising during pregnancy may actually be the first presentation of a subclinical disease.” For example, the occurrence of pre-eclampsia is a strong predictor for hypertension and subsequent cardiovascular events—perhaps by unmasking subclinical endothelial dysfunction. “Of course longer duration of follow-up is warranted and the discussion is not yet closed, but the findings in this study are reassuring for women who need fertility treatment.”

References

Roos-Hesselink JW, Johnson MR. J Am Coll Cardiol. 2013 July 19. [Epub ahead of print]
Udell JA, Lu H, Redelmeier DA. J Am Coll Cardiol. 2013 July 19. [Epub ahead of print]