Free Fetal Haemoglobin in Severe Early-Onset Fetal Growth Restriction: A Prospective Multi-Centre Study

To assess fetal circulating free fetal haemoglobin (fHbF) levels and heme defences, correlated to fetal circulatory biometry and fetal sex in severe early-onset fetal growth restriction (FGR).

A prospective study severe early-onset fetal growth restriction pregnancies with close clinical management (estimated fetal weight (EFW) < 3rd centile and < 600 g at 20-26 + 6 weeks; N = 20).

Temporal fetal vascular obstetric biometry was recorded. Cord blood fHbF and key heme-scavenger defences were measured and compared with normal term births (N = 26) and births with late-onset FGR (N = 12).

fHbF was elevated in early-onset FGR compared with normal pregnancy: 0.437(0.337/0.753) mg/mL; and 0.098 (0.045/0.264) mg/mL, respectively (p < 0.0001); whilst hemopexin was downregulated in early- (p < 0.001) and late-onset FGR (p < 0.0001), compared to normal pregnancy: 36(14/81) μg/mL, 25(19/40) μg/mL, and 155(132/219) μg/mL, respectively; median (interquartile ranges). Early-onset FGR male fetuses had higher HbF compared with the normal males: 0.710(0.433/0.857) mg/mL; (p < 0.001); 0.099(0.043/0.246) mg/mL, respectively; median (interquartile ranges). In early-onset FGR, ratios of mid-cerebral artery and umbilical artery pulsatility indices correlated positively with heme-scavenger levels (hemopexin and a heme-handling composite measure: p < 0.05, r = 0.672; and p < 0.01, r = 0.620; respectively), indicating lower levels are associated with cerebral vascular redistribution. These heme handling measures also positively correlated with gestational age at delivery (r = 0.713 and r = 0.642, respectively, p < 0.01, both) and birthweight (r = 0.742, p < 0.001; and r = 0.523, p < 0.05; respectively).

Overproduction of fHbF and an inadequate heme defence may contribute to fetal distress and poor umbilical arterial Dopplers in early onset FGR due to elevated placental vascular resistance and vascular inflammation.