Folic Acid Supplementation to Reduce the Severity of Anemia and Blood Transfusions in Extremely Preterm Infants

Anemia of prematurity (AOP) affects nearly all extremely preterm or extremely low birthweight (ELBW; birthweight <1000 g) infants. AOP's development involves various factors such as exacerbation of newborn physiological anemia, reduced response to erythropoietin after birth, frequent blood sampling, short lifespan of red blood cells, and rapid blood volume increase during growth.

To manage this anemia, most infants receive packed red blood cell transfusions, often based on specific hemoglobin thresholds. Despite efforts to minimize transfusion needs in ELBW infants, over 80% still require transfusions during their initial hospital stay. However, these transfusions come with potential adverse effects like infections, immune imbalances, lung and gut injuries, bronchopulmonary dysplasia, and retinopathy of prematurity.

Folic acid is crucial for fetal and postnatal development, playing a central role in DNA synthesis and supporting cell division. Its deficiency can hinder DNA synthesis, cause erythroblast apoptosis, and lead to anemia due to ineffective erythropoiesis. Preterm infants often lack sufficient folic acid, even more so in unfortified breast milk, which contains lower levels than recommended for adequate intake.

Supplementing folic acid for preterm infants began in the early 1990s based on limited studies on low-birth-weight (LBW) infants, primarily formula-fed and weighing >1000 grams. Despite its widespread use, there's insufficient robust evidence specifying the ideal dosage or confirming its effectiveness in preventing AOP or improving hemoglobin levels.

Unfortified breast milk's folic acid content falls short of recommended levels, especially for ELBW infants due to limited hepatic stores and rapid growth. Fortified breast milk or preterm formulas provide varying amounts of folic acid but might still be insufficient, especially for infants on restricted fluid intake due to lung injury.