Prematurity as Predictor of Children's Cardiovascular-renal Health (PREMATCH)

STATE OF THE ART The cardiovascular system (both macro- and microcirculation) undergoes extensive maturation throughout fetal, perinatal and pediatric life. Extreme preterm birth interferes with the normal development of the cardiovascular and microcirculatory systems. Disruption in vascular ontogenesis leads to abnormalities in the microvascular structure and circulation in various organs, such as retina (retinopathy of prematurity [O'Connor et al.]), kidney (abnormal glomerulogenesis [Sutherland et al.]) and glycocalyx in sublingual capillaries [Nieuwdorp et al.], among microvascular-driven disruptions observed in other organs (e.g. periventricular leukomalacia [Takashima et al.], bronchopulmonary dysplasia [Gien et al.]). Besides the well known retinopathy of prematurity, microvascular growth drives glomerulogenesis in the kidney and terminates after 34-36 weeks of gestational age under normal fetal conditions.

Perinatal (fetal or neonatal) growth restriction or preterm birth therefore impairs glomerulogenesis [Sutherland et al., Abitbol et al., Barker et al., Faa et al., Gubhaju et al., Zaffanello et al.]. Other cardiovascular abnormalities following from premature birth in later life include decreased heart rate variability [Rakow et al.], endothelial dysfunction [Norman et al.] and hypertension [Abitbol et al., Keijzer-Veen et al.].

Epidemiological observations further confirm that former preterm born infants are indeed at increased risk to develop cardiovascular disease and chronic kidney disease during adulthood [Brenner et al., Carmody et al., Vieux et al., Zandi-Nejad et al.]. The concept that fetal and perinatal conditions affect normal cardiovascular and renal ontogeny is in itself not new. Epidemiological studies showed that there is an association between low birth weight and vascular dysfunction in later life, suggesting that vascular impairment in early life is a harbinger of a poorer long-term prognosis [Sutherland et al., Bacchetta et al., Keijzer-Veen et al., Puddu et al.]. Intra-uterine growth retardation and children small for gestational age can be regarded as a failure of a fetus to reach the genetic potential of growth due to nutritional deprivation, the so-called Barker hypothesis [Barker et al.]. In adult life, this early growth retardation is associated with impaired renal and (micro)vascular function, hypertension, glucose intolerance and cardiovascular disease [Sutherland et al., Abitbol et al., Faa et al., Zaffanello et al., Carmody et al., Keijzer-Veen et al.].

The same sequence of vascular impairment serving as an indicator for long-term prognosis applies to the (early) postnatal life of preterm infants. According to the Brenner hypothesis, the decreased number of nephrons causes hyperfiltration, sodium loss with activation of the renin-angiotensinaldosterone system and hypertension [Brenner et al.], a process that entails further nephron loss, predisposition to develop proteinuria and possibly chronic kidney disease [Vieux et al., Puddu et al.].

MOVING BEYOND THE CURRENT STATE OF THE ART This project aims to move beyond the state-of-the-art by studying association between macro- and microvascular structure and function in children (8-13 years) born prematurely (extremely low birth weights, ELBW, i.e. birth weight below 1000 grams), and sex- and age-matched controls. The specific strengths hereby are that this ELBW cohort has been well characterized on its perinatal aspects [George et al.]. The characterization in the postnatal period includes biometry, perinatal characteristics (e.g. Apgar score, drugs, respiratory support), creatinine trends in the first 6 weeks of postnatal life and psychomotor development (Bayley Scales of Infant Development) at the age of nine months and two years.