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During their first few months of life, early preterm infants are among the most common of all patient groups to undergo transfusions(1). Because of the frequency of this therapeutic intervention, it would be helpful for clinicians to be aware of the life span of the transfused erythrocytes that these infants receive (e.g. whether a decrease in the level of Hb after a transfusion is due to a concealed hemorrhage). In adults, when compatible red cells are transfused in therapeutic amounts, the number of red cells in the recipients circulation diminishes steadily over a period of 110-120 d(2). Because of technical and ethical difficulties in carrying out erythrocyte survival studies in infants, little recent work has been done. The only information available on the survival of adult erythrocytes transfused to newborn infants is the estimates obtained in the 1940s(3, 4). These studies were based on the Ashby(5) differential agglutination technique, a methodology that had serious limitations. The Ashby method of estimation carried a considerable error, and the estimates are affected by the different rates of growth in different infants. However, based on this technique, adult cells whether they were transfused to infants or adults had similar survival rates(6). Although there are data on the survival of autologous and allogenic fetal red cells transfused to term newborn and adult recipients(7, 8) there is none available on the life span of adult red cells transfused to preterm infants.

Early preterm infants are born at a time when more than 90% of their red cells are of the fetal type containing HbF(9), whereas, in contrast, the erythrocytes that they receive by transfusion contain HbA. The first few months after an early preterm birth is a period when preterm infants, even when anemic, have a very limited minimal intrinsic red cell production(10). Due to the early postconceptional age, any erythropoiesis that occurs would contain predominately HbF(11). Because of these factors, a study on transfused preterm infants measuring the changes in the proportions of HbA and HbF over a period of time could provide the information required for determining the life span of transfused erythrocytes. The number of days it takes after the last red blood cell transfusion to attain the highest level of HbF could be considered a good measure of the life span of the transfused red cells.

The effect of a blood transfusion to a preterm infant is an immediate increase in proportion of circulating adult red cells and a concomitant decrease in the proportion of fetal red cells. However, soon after a transfusion the removal of donor erythrocytes begins because of senescence. This results in a gradual increase in the proportion of the autologous fetal red cells, causing a slow eventual return toward the levels of HbF that correspond to the developmental age of the infant(12, 13).

As the allogenic red cells disappear from the circulation, the proportion of autologous erythrocytes steadily increases until there are no longer any allogenic red cells in the circulation. When that point is reached the post transfusion increase in HbF ends and the proportions of circulating HbA and HbF follow the physiologic ratio, which is dependent on the postconceptional age of the preterm infant(11).

A study was therefore planned to determine the life span of red blood cells transfused to preterm infants by documenting the changes in the levels of HbA and HbF in the circulation of these infants after a blood transfusion.

METHODS

The infants included in the study were early preterm infants (defined as<1250 g and <30 wk of gestation at birth) who required transfusions for anemia of prematurity and had their blood routinely sampled weekly to follow their Hb levels. The blood used for transfusion was always less than 10 d old(6 ± 2 d). The volume of blood transfused was 15 mL/kg. Seven of these infants were followed at the University of Iowa Hospital and Clinics, Iowa City (these infants were part of a previously reported study(12), and 12 at l'Hôpital Sainte-Justine in Montreal. The infants at the time of their last transfusion were generally stable growing preterm infants being transfused for anemia of prematurity. Parental informed consent was obtained in accordance with both Institutions' Human Investigation Committees. Two microliters of blood were subjected to reverse phase HPLC to separate the globin chains that make up their hemoglobins. Globin chain separation by C4-reverse phase HPLC equipped with an integrator was conducted as previously described(14). The percent HbF was expressed as γ/γ + β × 100.

The life span of transfused adult red blood cells given to preterm infants(15 mL/kg) was defined as the number of days between the last transfusion and the return of the HbF level to that existing in the autologous red cells. The autologous level of HbF would be attained when the post transfusion increase in the percent of HbF reached its maximum point. Because many of these infants required multiple transfusions, only the data obtained after the last transfusion were included in the study. Phlebotomy would not have any effect on the red blood cell survival of the transfused cells because the method that was used would still give an accurate assessment of red blood cell life span. All data were expressed as a mean ± SD.

RESULTS

The characteristics of the 19 infants included in the study are presented in the Table 1. The distribution of the percent of HbF levels after the last transfusion in relation to postconceptional age in the population studied is illustrated in Figure 1. Also added to the same figure, for comparison purposes, are lines representing the normal mean values of both HbF synthesis and total HbF (obtained from nontransfused preterm infants) in relation to postconceptional age, taken from other reports(9, 13). It is interesting to note that the lines depicting the increase in percent HbF for the individual infants have similar and approximately linear slopes. The “tailing” at the top of slope of the survival curve is most likely due to the persistence of a few remaining transfused cells and/or the appearance of autologous red cells containing HbA. There were eight infants, because of their discharge from the hospital, who could not be followed to the maximum post transfusion HbF level.

Table 1 Characteristics of the 19 early preterm study infants
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Figure 1
figure 1

Post transfusion percentages of HbF in relation to postconceptional age in 19 preterm infants. The lines joining the different symbols represent the individual infants. - represents the mean physiologic levels of total HbF in non transfused preterm infants(13) and - - - - - the HbF synthesis(9) in relation to postconceptional age.

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The 11 infants who were followed up to and beyond their post transfusion HbF peak are illustrated in Figure 2. These infants were considered as having reached the point where there was no further increase in HbF, and it was assumed that they had no transfused cells remaining in their circulation. From this group of 11 infants the mean survival of red cells transfused to preterm infants was determined and was 56.4 ± 7.5 d(range, 46-68 d). There was no correlation between red blood cell survival and storage age of the red cell, nor was there any difference in the survival time of the cells between the two institutions.

Figure 2
figure 2

Post transfusion percentages of HbF in relation to days after a transfusion in 11 preterm infants. These infants were followed until there was no surviving transfused red blood cells in their circulation. The symbols and lines represent the same infants as in Figure 1. The mean red blood cell life span, - - - - -; SD, -.

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DISCUSSION

Because of frequent blood sampling, hemorrhagic complications, and anemia of prematurity, early preterm newborn infants represent a group of patients considered the most frequent recipients of blood transfusions. It is important for the clinical care of these infants to have a good estimate of the life span of the transfused red cells that they receive.

There have been studies in the past attempting to determine autologous newborn red cell survival. However, it is almost three decades since Pearson(7) provided a review that came to some general conclusions on the red cell life span in the newborn infant. Namely, it is shorter in the full-term infant than in adults, and the shortness is more pronounced in preterm infants. The estimates of the survival of transfused erythrocytes carried out in the 1940s(3, 4) based on the Ashby(5) differential agglutination technique were considered to carry a considerable error. After the advent of radioisotopes, the Ashby method was quickly replaced by isotopic methods. The 51Cr technique was the method of choice, and these studies(7) reported a mean 51Cr half-life of erythrocytes from term infants of 23.3 d (range 13-35 d), a mean value for red cells from preterm infants of 16.6 d (range 9-26 d). Conversion of these fetal red cell life spans for term infants from 51Cr half-life to true red cell survival indicated an actual life span of approximately 60-70 d. Similar calculations for the red cells of preterm infants provided values of 35-50 d.

Based on the data obtained in the present study, the mean life span of adult red cells transfused to preterm infants is 56.4 ± 7 d (range 46-68 d). This length of survival is within the range of what has been generally accepted for labeled cord blood cells when transfused either to newborns(3) or adults(4), but is much shorter than the 110-120 d life span expected for adult red cells transfused to adults(2). Fetal red cells have a shorter life span than adult red cells, which could be due to differences in physical properties related to surface charge, aggregation, deformability, filterability, and fragility(15). However, the findings in this study could also suggest the existence of unknown endogenous environmental factors specific to immature infants that affect the life span of both autologous and allogenic erythrocytes. It is interesting to note that it has been suggested in the past that there is a relationship between red blood cell life span and body weight, the red blood cells of large mammals live longer than those of small ones(16).

The results obtained in this report imply that the half-life (that is the number of days after transfusion at which half the cells infused remain in the circulation) is about 30 d (a 1.7% elimination rate). This information could be a useful reference for guiding clinicians caring for preterm infants, after a transfusion or an exchange transfusion, as well as for those who are responsible for in utero fetal transfusions.