Fertility Therapy Failure Tied to Increased Risk of Heart Problems

By Marilynn Larkin, Reuters Health

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NEW YORK (Reuters Health) – Fertility treatment failure is associated with an increased risk of cardiovascular disease over the long term, researchers in Canada say.

“Infertility may indicate an underlying predisposition toward premature cardiovascular disease, yet little is known about potential long-term cardiovascular events following fertility therapy,” they suggest in a paper online March 13 in CMAJ.

Dr. Jacob Udell, a scientist at the Institute for Clinical Evaluative Sciences in Toronto, and colleagues studied medical records of more than 28,000 women (mean age, 35) who received fertility treatments between 1993 and 2011. Half the women received at least 3 treatments.

Overall, 67% did not become pregnant.

Over a median 8.4 years of followup, 2,686 cardiovascular events were identified. The annual rate was 19% higher among those who did not become pregnant compared with those who did (1.08 versus 0.91 per 100 patient years; p<0.001).

Treatment failure was most common among those who were older, were living in lower income neighborhoods, used less health care and had experienced fewer miscarriages or stillbirths. Hypercholesterolemia (p<0.001), smoking (p=0.02), asthma (p=0.02), neoplasms (p<0.001) and depression (p=0.03) also were more common among those who did not conceive.

By contrast, diabetes and hypertension were less common among women who did not get pregnant compared with those who did (p<0.001).

The cardiovascular event rate increase was explained mostly by increases in the heart failure rate (adjusted relative rate ratio, 2.25) and cerebrovascular events (aRRR, 1.25), with an aRRR of 1.08 for venothromboembolic events.

Figure: In vitro fertilization procedure. Robert G. Edwards received the Nobel Prize
in 2010 for the development of this technique. (Image by Solis Invicti)

“Our findings certainly should not be cause for alarm,” Dr. Udell told Reuters Health. “Although we found a 19% relative increase in heart and stroke disease, especially heart failure, the absolute risk was modest, equal to about four additional events per 1000 women over 10 years of follow up among those who did not deliver a child.”

Nevertheless,” he said by email, “we think this is an opportunity for doctors to listen to women, including potentially their experiences with infertility years earlier, and factor that in when estimating future risk and recommending lifestyle changes or other preventive treatment.”

“There's a whole host of reasons why fertility therapy might not work that could also impact future risk of heart disease,” Dr. Udell continued. “Mechanistically, one theory is that fertility therapy acts as a potential ‘stress test’ and may uncover those who are destined for medical troubles.”

“An alternative explanation is that repeated cycles of these powerful medications may lead to premature heart disease,” he said. “The biggest limitation of our study is that we don't know exactly which drugs, and what doses, and what degree of monitoring were received by these women.”

“Another limitation is that the average woman was in her late 40s at the end of our study, so there may be more issues to come in the years ahead. We plan to focus on both of these issues in future research studies,” he concluded.

Cardiologists were intrigued by the findings.

Dr. David Ferman, a member of the Spectrum Health Cardiac Obstetric Perinatal Enterprise, called the findings “striking” and said the study provides a “significant basis” for future work that “may reveal targets for treatment, risk stratification and prevention.”

Of note, he told Reuters Health by email, “the baseline characteristics of the two groups reveal some significant differences in cardiovascular risk factors, even prior to fertility therapy . . . Specific details on the fertility therapy regimens were not available to discern treatment-related differences, nor were there specific details on medical therapy and severity of cardiovascular risk factors.”

“Infertility is a complex condition with incompletely understood pathophysiology,” Dr. Ferman said. “However, cardiovascular comorbidities and risk factors are also complex and heterogeneous. Could it be that the patients for whom fertility treatment failed had predisposing cardiovascular factors that interact with fertility? How much of the difference in cardiovascular events is actually treatment-related?”

Dr. Steven Burstein, director of the Cardiac Catheterization Laboratory at Good Samaritan Hospital in Los Angeles, California, told Reuters Health the findings “are interesting and unanticipated.”

“The reasons for the increase in vascular events are unclear and it’s hard to conceive that the cardiovascular events are simply associated with short-term hormonal manipulation,” he said by email. “Other unidentified factors must play a role, exacerbated by the inability to conceive after fertility therapy. An assessment of other risk factors would be important, and their treatment, an imperative.”

Dr. Nicole Weinberg, a cardiologist at Providence Saint John’s Health Center in Santa Monica, California, called the study “very provocative.”

“We know from the women's heart disease guidelines that preeclampsia, gestational diabetes and pregnancy-induced hypertension are risk factors for cardiovascular disease,” she told Reuters Health by email. “This likely falls in line with the concept that our vasculature affects our heart similarly as it affects other organs, including our uterus.”

Click here for more information. SOURCE: CMAJ 2017.

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