Fetal nutrient flux and oxidative metabolism during hypoxia: adaptive responses to defend fetal growth

Fetal oxidative metabolism, the primary determinant of growth, depends on oxygen and nutrient supply. Fetuses with fetal growth restriction (FGR) are exposed to hypoxia and an altered nutrient milieu. Here, we examine hypoxia-associated metabolic adaptations in FGR fetuses and explore how these adaptations may function to maintain rates of oxidative metabolism to enable the fetus to defend its growth rate. We highlight adaptations related to oxygen, glucose, lactate, pyruvate and amino acid flux and metabolism. Given limited human data, we present data from ovine models of chronic placental insufficiency (PI) and sustained maternal hypoxia in late gestation (HOX). These data demonstrate that PI fetuses have lower oxygen consumption rates, increased hepatic glucose production, lower glutamine-glutamate shuttling with the placenta, increased lactate production and accelerated lactate-pyruvate shuttling with the placenta. HOX fetuses have many of these metabolic responses yet have maintained oxygen consumption rates and growth. Thus, hypoxia during gestation may initiate these adaptations to enable the FGR fetus to defend its rate, albeit lower, of oxidative metabolism. During PI, with constraints from chronic hypoxia and nutrient deficiencies across gestation, we speculate that FGR fetuses develop a lower metabolic set point with these metabolic adaptations to ensure survival <i>in utero</i>.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.