Fetal Anemia and Hemodynamic Adaptation in Hemoglobin H Disease: A Longitudinal Prospective Study

Hemoglobin H (Hb H) disease, including deletional (Hb H-del) and non-deletional forms such as Hb H-Constant Spring disease (Hb H-CS), is highly prevalent in Asia. Its natural history and fetal hemodynamic changes remain inadequately characterized. The objective of this study is to characterize the natural history of fetal anemia and associated hemodynamic alterations in Hb H-del and Hb H-CS. At-risk pregnancies identified through α-thalassemia carrier screening prospectively underwent serial assessment of fetal anemia using middle cerebral artery-peak systolic velocity (MCA-PSV) and hemodynamic parameters using fetal echocardiography. Cordocentesis and intrauterine transfusion (IUT) were performed when indicated. Neonatal hematologic and genotypic evaluations were conducted postnatally. Among 389 at-risk pregnancies, 60 fetuses had Hb H-del and 22 had Hb H-CS. MCA-PSV MoM was significantly elevated in affected fetuses, particularly in Hb H-CS. In affected fetuses, MCA-PSV increased after mid-gestation, reached the highest level in the late second to early third trimester, and partially normalized near term. Cardiac enlargement, Tei index, and cardiac output were significantly increased, more prominently in Hb H-CS. Rates of significant anemia, reflected by MCA-PSV>1.5 MoM, and hydrops were higher in Hb H-CS than Hb H-del; 22.7% vs 13.6% and 8.3% vs 1.7%, respectively. In conclusion, Hb H disease is characterized by an exacerbation of fetal anemia and cardiac overload after mid-gestation with more severity in Hb H-CS fetuses. These findings provide a rationale for incorporating antenatal assessment into the management of pregnancies affected by Hb H disease and support further evaluation of proactive intrauterine management strategies in selected cases.