Hemoglobin is the protein within red blood cells that transports oxygen from the lungs to the body’s tissues. Humans produce different types of hemoglobin throughout their lives, driven by developmental needs. The unique version produced during gestation is Fetal Hemoglobin (HbF), which is structurally and functionally distinct from the adult version. The body is programmed to transition away from this specialized form shortly after birth.
The Unique Structure and Function of Fetal Hemoglobin
Fetal Hemoglobin (HbF) is chemically composed of four protein chains: two alpha (a) chains and two gamma (g) chains, forming an a2g2 structure. This composition differs from Adult Hemoglobin (HbA), which contains two alpha chains and two beta (b) chains, or a2b2. This subtle change in the protein subunits results in a significant functional difference necessary for life in the womb.
The primary function of HbF is to effectively transfer oxygen from the mother’s bloodstream across the placenta to the developing fetus. HbF achieves this by having a much higher affinity for oxygen compared to HbA. This difference is largely due to how the two types of hemoglobin interact with a molecule called 2,3-bisphosphoglycerate (2,3-BPG).
The 2,3-BPG molecule binds to HbA, lowering its affinity for oxygen and causing it to release oxygen more easily to the tissues. Conversely, the gamma chains in HbF prevent 2,3-BPG from binding strongly, allowing HbF to retain a tighter grip on oxygen. This higher affinity allows the fetal blood to effectively “pull” oxygen away from the maternal HbA in the placenta, ensuring the fetus receives an adequate supply.
The Timeline of the Hemoglobin Switch
The hemoglobin switch is genetically programmed and begins well before birth. The synthesis of the adult beta globin chain starts around the third trimester of pregnancy, typically between 32 and 36 weeks of gestation. At the moment of birth, Fetal Hemoglobin still accounts for a large percentage of the total hemoglobin, sometimes making up as much as 50% to 95%.
The physiological switch accelerates rapidly after birth, primarily triggered by the change in the infant’s oxygen environment as they begin breathing air. The newborn body actively suppresses the production of the gamma chains and upregulates the production of the beta chains. This shift is a coordinated developmental process.
The functional transition to Adult Hemoglobin dominance is largely complete by about six months of age. HbA becomes the major form of hemoglobin in the infant’s red blood cells, and the concentration of HbF continues to decrease steadily after this time.
Fetal Hemoglobin levels typically reach the standard adult range (less than 1% of total hemoglobin) by the end of the first year of life. For some individuals, this final decline may take up to two years to complete. The mechanism is governed by the gradual silencing of the gamma-globin gene, regulated by transcriptional repressors such as BCL11A.
When Fetal Hemoglobin Production Persists
While the body is programmed to turn off HbF production, the genetic mechanism for its creation is not entirely lost, and its persistence can have significant clinical consequences. In genetic blood disorders affecting the adult beta-globin chain, such as Sickle Cell Disease (SCD) and Beta-Thalassemia, the continued presence of HbF is highly beneficial. HbF lessens the severity of these diseases by compensating for or diluting the defective HbA.
In Sickle Cell Disease, for example, HbF inhibits the polymerization of the abnormal sickle hemoglobin (HbS) protein, which causes red blood cell sickling and painful crises. This protective effect has prompted significant therapeutic research. Clinicians have developed drug treatments, such as hydroxyurea, specifically to reactivate the gamma-chain production in adults suffering from severe hemoglobinopathies.
A genetic condition known as Hereditary Persistence of Fetal Hemoglobin (HPFH) is characterized by the failure of the fetal-to-adult switch. Individuals with HPFH continue to produce high levels of HbF into adulthood, sometimes up to 30% or more of their total hemoglobin. This condition is usually benign and asymptomatic, but it offers a natural model for how increased HbF can be protective when co-inherited with a disease like Sickle Cell Disease.