Adolescents Conceived by ART Show Increased Vascular Aging

Premature vascular aging, previously observed in youths conceived through assisted reproductive technologies (ART), persists at 5-year follow-up, showing progression to arterial hypertension in adolescence and young adulthood despite the absence of conventional cardiovascular risk factors, a new study shows.

"We found that ART-induced premature vascular aging persisted over a 5-year period in apparently healthy adolescents and young adults without any detectable classical cardiovascular risk factors and progressed to increased arterial BP [blood pressure] and BPV [BP variability], as assessed by 24-h ABMP [ambulatory blood pressure monitoring]," the authors conclude. "These data underscore the potential of ART to increase cardiovascular risk in this rapidly growing group."

The findings raise flags for potential cardiovascular problems later in life, senior author Emrush Rexhaj, MD, from the Department of Cardiology and Biomedical Research at the University Hospital Bern, Switzerland, told theheart.org | Medscape Cardiology.

"It is well established that arterial blood pressure in adolescents/young adults tracks for arterial blood pressure later in life," Rexhaj said.

"Arterial blood pressure in the ART participants was significantly higher than in control participants," he noted. Therefore, "it can be expected that this difference in blood pressure between ART and controls will further increase during lifetime, and in turn increase the prevalence of established arterial hypertension in ART."

Their findings are published in the September issue of the Journal of the American College of Cardiology.

Generalized Vascular Dysfunction

In a 2012 study, on which Rexhaj was a coauthor, 65 ART-conceived children with an average age of 12 years were compared with 57 control children who were conceived naturally. Those conceived through ART were found to have generalized vascular dysfunction that "does not appear to be related to parental factors but to the ART procedure itself," the researchers concluded.

The new study follows up on the groups 5 years later, reporting on 54 participants from the ART-conceived group (mean age, 16.5 years) and 43 age- and sex-matched controls (mean age, 17.4 years).

At follow-up, those conceived by ART continued to show premature vascular aging, with flow-mediated dilation of the brachial artery approximately 25% smaller (P < .001). The ART-conceived participants also had increased carotid-femoral pulse-wave velocity (P = .03) and carotid-intima-media thickness (P < .01).

Ambulatory blood pressure monitoring values were also significantly higher in those conceived by ART than in controls, in measures of systolic (119.8 ± 9.1 mm Hg vs 115.7 ± 7.0 mm Hg; P = .03), as well as diastolic blood pressure (71.4 ± 6.1 mm Hg vs 69.1 ± 4.2 mm Hg; P = .02).

In addition, 24-hour blood pressure variability, an important independent predictor of cardiovascular risk, was notably higher in ART-conceived participants than in controls (P = .001 for systolic; P = .03 for diastolic; mean blood pressure variability, P = .02 for ART vs controls).

Meanwhile, as many as eight of the ART participants met ambulatory blood pressure monitoring criteria for arterial hypertension (>130/80 mm Hg and/or >95th percentile), compared with just one of the controls (P = .041).

With the study's exclusion criteria ruling out many potential confounders that are known to be common with ART, such as premature birth, the results may in fact under-represent the cardiovascular risk, Rexhaj said.

"ART markedly increases the risk for the complications (such as low birth weight and premature birth). Thus, compared to the general ART population, ours is a low-cardiovascular-risk ART population and may underestimate this risk," he said.

In addition to premature birth, exclusion criteria included low birth weight, which is known to potentially play a role in vascular function later in life, and preeclampsia.

Mean gestational age, pregnancy or perinatal complications, and other factors (including body mass index [BMI] and lipid, creatinine or electrolyte plasma concentrations) did not differ between the groups.

High-sensitivity C-reactive protein levels were normal and similar in the groups, as were maternal factors such as BMI, smoking status, and general cardiovascular risk profiles.

Of the ART-conceived participants, 43 had involved fresh embryos that were transferred immediately, and the remaining 11 zygotes had been kept frozen at the two-pronuclear stage for transfer at a later time point, the authors noted.

Five control participants and three conceived with ART were taking noncardiac medication during the time of the study.

Genetic Mechanisms Considered

In an earlier study of mice, Rexhaj and his colleagues identified specific alterations of genes that are key to cardiovascular regulation in the ART-conceived mice, suggesting a possible mechanism for the abnormalities.

"It is very likely that similar mechanisms cause ART-induced alterations of the cardiovascular phenotype in humans which are related to ART per se and not to other factors, such as sterility, hormonal stimulation, of the ovulation, et cetera," Rexhaj said.

The participants in the current study are believed to represent the oldest group to date of ART-conceived children to undergo advanced cardiovascular analysis, he noted.

"To the best of my knowledge, no other study has performed extensive state-of-the-art assessments of the cardiovascular phenotype of ART people older than ours," Rexhaj said.

More than six million people have been conceived through ART, and with higher arterial blood pressure in adolescence known to be linked to higher levels later in life, patients and clinicians alike should be aware of the risk, Rexhaj said.

"This population at risk should be mindful of their lifestyle habits, [such as] overweight, sedentary lifestyle, smoking," he suggested.

"In addition, we suggest performing an ambulatory blood pressure measurement at age between 16 and 20 in this population."

Other notable studies suggesting cardiovascular risks in children conceived through ART include research showing ART-induced intrauterine cardiac remodeling that can persist 3 years after birth.

And in another study, teenagers conceived with ART showed an increased susceptibility to developing insulin resistance.

Long-term Effects

The new findings add to the evidence of potential effects of ART, said Judette Louis, MD, MPH, an associate professor at the University of Southern Florida College of Medicine Obstetrics & Gynecology, Tampa. There has been increasing interest in the long-term effects of in vitro fertilization, she noted in an interview.

"There have been a number of studies reporting cardiovascular disease in the offspring," Louis noted. "What this adds is evidence that changes seen in childhood persist into adolescence and young adult life."

The study has some important caveats, particularly in the sample size, she noted.

"This is a small study, and the endpoints are intermediary. They are looking at markers of vascular aging and not actual cardiovascular events," Louis said. "To really determine how much of a problem this is, you would need larger numbers of patients and clinically relevant endpoints."

Alan Penzias, MD, associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston, Massachusetts, agreed that the study's size limits interpretation of the findings.

"This is a quite small study and attribution of the issues identified is unclear," Penzias, who is the chair of the Practice Committee of the American Society for Reproductive Medicine, told theheart.org | Medscape Cardiology.

"Time will tell if any of the findings result in a condition that warrants treatment as they presently do not."

Penzias argued that evidence continues to show that factors associated with infertility, and not necessarily ART itself, could play a role in the risk.

"Attribution to treatment is premature," he said, noting that previous studies have indicated that children born to couples with infertility show differences from the general population regardless of whether they were conceived spontaneously or with fertility treatment.

"This would suggest that the disease of infertility is the root cause," Penzias said.

The good news, however, is that most studies on children conceived through ART have been reassuring. "Fortunately, with 40 years of experience and millions of healthy offspring, the general experience is good," Penzias said. "Of course, it is incumbent upon us to continue to monitor, study, and seek answers to causality of disease."

The study received support from the Swiss National Science Foundation, the Placide Nicod Foundation, the Swiss Society of Hypertension, the Swiss Society of Cardiology, and the Mach-Gaensslen Stiftung Schweiz. The authors and Louis have disclosed no relevant financial relationships. Penzias is a practicing reproductive endocrinology and infertility specialist and partner at Boston IVF in Waltham, Massachusetts.

J Am Coll Cardiol. 2018;72:1267-1274. Abstract

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