Vascular dysfunction in children conceived by assisted reproductive technologies: underlying mechanisms and future implications

Abstract

Epidemiological studies in humans have demonstrated a relationship between pathological events during fetal development and increased cardiovascular risk later in life and have led to the so called "Fetal programming of cardiovascular disease hypothesis". The recent observation of generalised vascular dysfunction in young apparently healthy children conceived by assisted reproductive technologies (ART) provides a novel and potentially very important example of this hypothesis. This review summarises recent data in ART children demonstrating premature subclinical atherosclerosis in the systemic circulation and pulmonary vascular dysfunction predisposing to exaggerated hypoxia-induced pulmonary hypertension. These problems appear to be related to the ART procedure per se. Studies in ART mice demonstrating premature vascular aging and arterial hypertension further demonstrate the potential of ART to increase cardiovascular risk and have allowed to unravel epigenetic alterations of the eNOS gene as an underpinning mechanism. The roughly 25% shortening of the life span in ART mice challenged with a western style high-fat-diet demonstrates the potential importance of these alterations for the long-term outcome. Given the young age of the ART population, data on cardiovascular endpoints will not be available before 20 to 30 years from now. However, already now cohort studies of the ART population are needed to early detect cardiovascular alterations with the aim to prevent or at least optimally treat cardiovascular complications. Finally, a debate needs to be engaged on the future of ART and the consequences of its exponential growth for public health.

Fetal programming and epigenetic mechanisms in arterial hypertension

“…Based on emerging data showing that the early embryo is particularly sensitive to environmental insults, we speculated that ART alters cardiovascular function in the offspring. In line with this speculation, we found that young, apparently healthy ART children display signs of premature vascular ageing of the systemic circulation together with pulmonary vascular dysfunction predisposing to exaggerated hypoxic pulmonary hypertension [17][18][19][20]. Most importantly, recent data indicate that ART-induced vascular dysfunction translates into increased arterial blood pressure.…”

Agonist depot versus OCP programming of frozen embryo transfer: a retrospective analysis of freeze-all cycles

“…However, if FET is going to replace fresh ET universally for reasons of better periimplantation outcomes [13], we will first have to address the concerns raised in a number of perinatal studies reporting large for gestational age, extreme preterm birth, and vascular dysfunction in off-spring conceived after FET [27][28][29]. Even with the reassurance that other FET perinatal outcomes are more optimal than after fresh ET and very similar to those of natural conceptions, further studies are necessary to investigate the possible mechanisms involved in the epigenetic modifications that might result from extended embryo culture and cryopreservation.…”

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media

“…ART induces vascular dysfunction in young apparently healthy children, which may predispose them to premature cardiovascular disease (20,23,25,26). In industrialized countries, these children make up 2-5% of births, and there is an urgent need to find ways to prevent this problem.…”