Every drop of blood counts for the most fragile of newborns.

Phlebotomy-induced blood loss in preterm infants has long been known to contribute to the development of anemia.¹ It is not such a simple matter, however, that avoiding blood loss in this population will prevent anemia entirely. To understand phlebotomy's clinical significance, first we must take a look at premature infants' physiology.

All neonates experience a decrease in hemoglobin concentration during the transition from the relatively hypoxic in utero state to the relatively hyperoxic state. This occurs with the onset of breathing room air which leads to higher tissue oxygenation. The resulting process is a down-regulation of erythropoietin mRNA and a subsequent decrease in the synthesis of hormone erythropoietin (EPO) by the liver-the main site of EPO production. EPO initiates the creation of red blood cells.

With relatively lower circulating levels of EPO, a predictable physiologic anemia occurs around 8 to 12 weeks in term infants; however, this process typically occurs between 3 to 12 weeks in preterm infants in a manner that is exaggerated and often pathologic. Sometimes, profound anemia occurs, and the infant requires a blood transfusion. This condition is aptly named anemia of prematurity (AOP), and it may take as long as 3 months to resolve.^2,3

While a blood smear from infants with AOP will reveal normochromic and normocytic red blood cells, a look at bone marrow cells and erythropoietic cells will reveal further the erythrocyte precursors are not proliferating-they are in a hyporegenerative state. This is reflected in a low reticulocyte count. With younger gestational ages, there is an inverse relationship with the incidence of AOP and gestational age, such that more than 50 percent of neonates less than 32 weeks' gestation will have AOP.^2,3

Further, the earlier the gestational age, the more likely the neonate will be sicker with a greater need for repeated blood laboratory tests, and thus blood loss occurs through repeated blood sampling.³ The infant may become symptomatic from the anemic state and consequently require a blood transfusion.

Some preterm infants will show adverse clinical signs and symptoms, such as poor growth, tachycardia, increased apneic and bradycardic events, metabolic acidosis and an increased requirement for supplemental oxygen; however, many preterm infants with AOP are asymptomatic.

Hemoglobin Declines
In addition to the lower circulating levels of EPO, preterm infants have lower hemoglobin levels due to decreased iron stores, a decrease in red blood cell mass, a decrease in red blood cell survival time and marrow erythroid elements, and rapid postnatal growth with an associated increase in circulating blood volume.

Neonates have a larger volume of distribution and a faster elimination of EPO. In premature infants, the volume of distribution as well as the clearance are three- to fourfold greater than that of adults.^4,5

The hematocrit at delivery also affects an infant's hematological status. Delayed umbilical cord clamping has been shown to provide a higher starting hematocrit without increasing risk factors.⁶

A study involving 40 very-low-birth-weight (VLBW) infants less than 1,500 g further delineated the entity of AOP. In this cohort, the average hemoglobin concentrations reached a nadir of 9.5 g/dL at 6 weeks of age; with values of 7 to 8 g/dL common even in the absence of significant phlebotomy losses^.7

Hematocrit values were lowest in the smallest infants, with average nadirs of 21 percent and 24 percent in infants with birth weights less than 1,000 g and between 1,000 to 1,500 g respectively. An explanation for these findings came in a study involving an untransfused cohort of premature infants (mean gestational age 31 weeks; mean birth weight 1,378 g; n = 27).⁸ Mean EPO levels fell and remained significantly and substantially lower than in concurrently studied healthy adults at 30 days. During the ensuing second month, mean EPO values rose gradually to adult levels. 

Clearly, superimposed blood losses due to phlebotomy would influence the degree of anemia in this period of relative EPO refractivity. As in the previous study, mean hemoglobin values fell significantly during the 60-day period.7 In the second postnatal month, preterm infants essentially had the same EPO values as adults despite a mean hemoglobin concentration that was approximately two-thirds the adult value. This failure to mount a greater EPO response was thought to explain the hemoglobin declines to such low values at 2 months of age.