Elevated catecholamine derivatives homovanillic acid and vanillylmandelic acid in the plasma and amniotic fluid of growth-restricted fetal sheep.

Fetal growth restriction (FGR) caused by placental insufficiency is characterized by fetal hypoxemia and elevated catecholamines. We hypothesized that the catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) would be elevated in a sheep model of placental insufficiency and FGR. We measured HVA and VMA in fetal arterial plasma and amniotic fluid and analyzed their relationships with fetal weight, sex, and concentrations of fetal arterial norepinephrine (NE), oxygen, insulin, and IGF-1. Compared to controls, FGR fetuses had higher arterial plasma concentrations of HVA (39%), VMA (53%), and NE (369%), and lower arterial blood oxygen (26%) and plasma insulin (62%) and IGF-1 (59%). Fetal arterial HVA and VMA were positively correlated with NE and inversely correlated with fetal oxygen and IGF-1 concentrations and fetal weight. Amniotic fluid concentrations of HVA and VMA were also elevated in FGR fetuses. These findings support HVA and VMA as biochemical markers of chronically elevated fetal catecholamine concentrations, with potential utility for identifying fetuses with chronic hypoxemia. The presence of these metabolites in amniotic fluid also suggests the feasibility of non-invasive assessment at the time of or shortly after birth. This manuscript identifies homovanillic acid (HVA) and vanillylmandelic acid (VMA) as biochemical markers of chronic fetal hypoxemia in a sheep model of FGR and are elevated in both plasma and amniotic fluid of FGR fetuses. These data demonstrate strong correlations between HVA/VMA and fetal NE, oxygen content, IGF-1, and fetal weight. This work supports future studies assessing HVA/VMA as potential non-invasive biomarkers in amniotic fluid sampled at delivery to improve newborn risk stratification beyond size-based criteria.