Overproduction of fHbF and inadequate heme defence may contribute to foetal distress, suggests study

There is excess free fHbF in FGR neonatal cord blood at late preterm or term gestations. Authors have also demonstrated that fHbF increases fetoplacental vascular resistance by sequestering nitric oxide (NO), promoting matrix damage to the placental stroma, compromising placenta barrier function. They also reported compromised effects of fHbF on placental endothelial junctions in the pro-inflammatory and pro-angiogenic effects. The circulating scavengers, haptoglobin, hemopexin and alpha-1-microglobin (A1M) protect against fHbF. These endogenous substances are pleiotropic, but within the context of this study, bind fHbF to protect against the sequestration of endothelial-derived nitric oxide and prevent fHbF from binding to the inflammation-evoking TLR4 receptor which is strongly expressed in the placenta, which activates to elicit expression of numerous inflammatory cytokines placental in a primary trophoblast cell line. Normally, small amounts of fHbF are efficiently handled by these systems with limited impact on vascular function. However, in haemolytic conditions, where there is increased erythrocyte turnover, including megaloblastoma, excess free Hb occurs, either oversaturating existing defences, or leading to their compensatory upregulation.

Authors hypothesised that fHbF is elevated in cases of early-onset FGR, with reduced heme scavenging, and is associated with clinical features of foetal blood flow redistribution. Previous observations in PE have demonstrated sexual dimorphism in response to biological challenges, which they further explored in early-onset FGR.

It was a prospective study severe early-onset foetal growth restriction pregnancies with close clinical management (estimated foetal weight (EFW)< 3rd centile and<600 g at 20–26+6weeks; N=20). Temporal foetal 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 foetuses 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).

Fetal cord plasma had significantly higher levels of fHbF in the EVERREST cohort compared to normal pregnancy delivered at term. Authors reported significant cord plasma reductionsn hemopexin in both FGR groups compared to the normal group; being 4–6 times lower in the early- and late-onset groups, respectively, with an apparent inverse relationship to the heme load.

To give further strength to the calculation of heme handling, they derived a composite calculation for each sample. Using this measure, authors found that earlyonset FGR foetal plasma had a lower score than normal term samples (p0.0001), more significant than for late-onset FGR(p<0.05). Overall, they did not show any difference between absolute A1M levels in controls and FGR groups, though the inclusion of A1M in the aforementioned composite measure strengthened the separation between early- and late FGR cases.

The haptoglobin heme-defence, was below the level of detection in all groups using a manual ELISA method (AbCam, ab219048 Human Haptoglobin SimpleStep ELISA Kit) and by an automated immunoassay analyser method. Two significant sexual dimorphism findings related only to males: (i) the foetal plasma fHbF level was higher in early FGR pregnancies than occurred normally at term; and (ii) matched by an equally significant reduction in hemopexin.

Authors have demonstrated that fHbF is overrepresented in the severest cases of early onset FGR, with a consequential overwhelming of heme defences, a scenario linked to poor foetal vascular performance, severe foetoplacental insufficiency, and preterm delivery. In the early-onset FGR group, sex-specific variations in response to fHbF and heme appear to exist with female foetuses displaying higher MCA PI values and a greater proportion of female foetuses showing MCA/UA ratios in excess of 1, a clinical threshold below which is associated with increased stillbirth risk. Among this group they also observed a tendency for female foetuses to have higher hemopexin levels and more active heme handling profiles

Source: Adam Brook, Georgia Baynes, Jonathan Scargill; BJOG: An International Journal of Obstetrics & Gynaecology, 2025; 0:1–11 https://doi.org/10.1111/1471-0528.18104