Assisted Reproductive Technologies Are Associated With Cardiovascular Remodeling In Utero That Persists Postnatally

Abstract

A ssisted reproductive technologies (ARTs), mainly standard in vitro fertilization or intracytoplasmic sperm injection, permit childbirth in many infertile couples and nowadays represent 1% to 4% of births in developed countries.1 Although these technologies are generally considered safe, the potential association of ART with poorer pregnancy outcomes has long been investigated. There is evidence that ART is associated with increased risk for adverse perinatal outcome and congenital malformations.2 This notwithstanding, it is not possible to separate ART-related risks from those secondary to the underlying reproductive pathology of the infertile couple. [3][4][5] In this scenario, preliminary evidence has recently suggested that ART could be associated with long-term cardiovascular changes. Ceelen et al 6 first suggested the presence of increased blood pressure in late childhood after ART conception. More recently, another study demonstrated the presence of signs of systemic and pulmonary vascular dysfunction in 12-year-old children conceived by ART. Editorial see p 1398 Clinical Perspective on p 1450Background-Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. Methods and Results-This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies.ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.

Effects of perinatal, late foetal, and early embryonic insults on the cardiovascular phenotype in experimental animal models and humans

“…Gratacos et al showed that ART is associated with in utero cardiac remodelling that persists in 6 month old infants [55]. We subsequently demonstrated that cardiac alterations persist into adolescence, as evidenced by larger right ventricular end-diastolic volume and diastolic dysfunction at high altitude [56].…”

Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization†

“…Since it was initially proposed that conception via ART might be linked to an increased risk of developing long-term cardiovascular health issues, several studies have confirmed an altered cardiovascular phenotype and elevated metabolic risk in children born following IVF [13,14]. For example, investigations have shown that IVF-conceived children have significantly higher blood pressure compared with spontaneously conceived children [41][42][43][44], something that has recently been supported by a meta-analysis of 2112 children conceived by ART, where data showed that there was a slight, yet statistically significant, increase in blood pressure compared with naturally conceived offspring [45].…”

“…Multicenter epidemiological studies have shown that the incidence of cardiovascular malformations in ART babies is markedly increased compared with that of naturally conceived offspring [9][10][11]. Furthermore, follow-up surveys of ART-conceived offspring have shown an increased risk of dysfunction [12] and remodeling in the cardiovascular system [13], including higher arterial blood pressure, altered vascular intima-media thickness, and compromised myocardial regulatory function [14]. Investigations using mouse models have further illustrated that ART-conceived offspring have abnormal vascular endothelial function and changes in lipid metabolism [15,16].…”

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

“…STUDIES IN ANIMALS AND HUMANS demonstrate that adverse events during early life induce vascular dysfunction that may predispose to premature cardiovascular morbidity and mortality (1,2,10,19,24). Assisted reproductive technologies (ART) represent a recent important example of this problem, since ART induces vascular and cardiac dysfunction in children (26,33,34) and causes premature vascular aging and arterial hypertension that are associated with a shortened life span in mice (20). Consistent with observations in humans suggesting that decreased nitric oxide [nitrate/nitrite (NOx)] bioavailability contributes to vascular dysfunction in the offspring of ART (22), data in ART mice indicate that epigenetic alterations of the endothelial nitric oxide synthase (eNOS) gene that translate into decreased vascular eNOS expression and NOx synthesis underpin premature vascular aging and arterial hypertension (20).…”