Childhood Kidney Outcomes in Relation to Fetal Blood Flow and Kidney Size

Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5–32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7–6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, −6.36 ml/min per 1.73 m²; 95% confidence interval, −11.78 to −0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children.The third trimester of pregnancy is a critical period for fetal kidney development.¹ Nephrogenesis continues until 36 weeks of gestation, after which the induction of nephron numbers ceases.² A permanent reduction of kidney size and number of nephrons leads to a smaller glomerular filtration surface area, which might predispose the individual to decreased kidney function in childhood and subsequently to kidney disease and hypertension in adulthood.^3,4 This hypothesis is supported by studies showing consistent associations of low birth weight with higher risks of kidney disease and hypertension in later life.^5,6 Although the observed effect estimates from these studies were small, they are important from an etiologic perspective.^5,6 In addition, post mortem studies showed that the nephron number is lower in hypertensive individuals than in normotensive controls⁷ and is positively correlated with birth weight and kidney size.^8,9 Animal studies demonstrated a reduction in nephron number as a result of vascular placental insufficiency.¹⁰ Placental insufficiency is an important risk factor for fetal growth restriction and low birth weight.¹¹ We recently demonstrated that increased third trimester placental insufficiency is associated with a higher BP in childhood.¹² Placental insufficiency is characterized by a preferential fetal blood flow to the brain at the expense of the trunk.¹³ This fetal blood flow redistribution is caused by higher peripheral and lower cerebral arterial resistance,¹¹ and can be measured as a higher umbilical artery pulsatility index (PI) and lower cerebral artery PI, respectively. This combination leads to a higher ratio of these measures (higher umbilical/cerebral (U/C) ratio).¹⁴ It is unknown whether and to what extent impaired abdominal or kidney blood flow and kidney growth restriction during fetal life lead to risk factors for kidney disease in later life.In this population-based prospective cohort study among 923 pregnant women and their children, we evaluated the associations of third trimester fetal blood flow redistribution, at the expense of the abdominal organs, and smaller fetal kidney size with kidney function outcomes in school-aged children. We also explored whether any association was explained by childhood kidney size.