Folic Acid Supplementation to Reduce Anemia in Extremely Preterm Infants

Overview

Anemia of Prematurity (AOP) is very common in extremely preterm infants and often leads to blood transfusions. Folic acid, essential for growth and DNA synthesis, is deficient in premature infants. Despite the adoption of folic acid supplementation, evidence supporting its effectiveness in preventing AOP remains scarce. Recommendations for folic acid intake exceed what's naturally found in breast milk, particularly for extremely low birthweight infants. Practices regarding folic acid supplementation vary widely, prompting the need for research. The FACINATE trial aims to determine if additional folic acid supplementation improves hemoglobin levels and reduces late blood transfusions in extremely preterm infants, a question not addressed in current literature.

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. The FACINATE trial aims to investigate whether additional supplementation of 50 mcg/day of folic acid improves hemoglobin levels and reduces late (\>14 days of age) blood transfusions in extremely preterm infants, a specific question not yet explored in existing literature.