Correlation of changes in circulating levels of hypoxia-induced factor-1α, erythropoietin, and cell-free fetal hemoglobin with feto-maternal pregnancy outcomes

Pregnancy feto-maternal complications (PFMCs) contribute significantly to morbidity and mortality, with placental hypoxia as a key factor. Current methods for detecting fetal hypoxia are limited. This study aimed to evaluate the roles and biomarker potential of hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), and cell-free fetal hemoglobin (cf-HbF) in PFMCs. In a cross-sectional study, we quantitatively immunoassayed plasma levels of these biomarkers in 136 healthy pregnant women (age 29.618±5.19 years) and 118 women with complications (age 30.53±5.46 years) who had voluntarily consented and were enrolled sequentially and anonymously. Results indicated significantly higher biomarker levels in complicated pregnancies (P<0.001), with worsening trends for preeclampsia, ectopic pregnancy, abortion, gestational diabetes, and preterm labor with premature rupture of membranes. Only EPO levels showed pregnancy duration-dependent changes in healthy controls (encompassing 6 to 41 weeks; r=0.230, P=0.015). Strong correlations among the three biomarkers were found in both groups (r=0.402/P<0.001; r=0.724/P<0.001), with HIF-1α correlating with body mass index (BMI) in healthy controls (r=0.204/P=0.032). ROC analysis demonstrated high sensitivity and specificity in differentiating between groups (P<0.001), with cf-HbF showing the highest performance (AUC=0.923), followed by HIF-1α (AUC=0.882) and EPO (AUC=0.826). In conclusion, HIF-1α, EPO, and cf-HbF were associated with PFMCs and showed promising potential as biomarkers for distinguishing healthy from complicated pregnancies, with cf-HbF being the most significant. Their high levels also pointed to hypoxic adaptation dysfunction and/or resistance, as a pathogenic culprit.