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ORIGINAL CONTRIBUTIONS

Received: October 19^th 2015

Accepted: December 10^th /2015

Decreased transfusions in preterm infants with anemia treated with erythropoietin

José Francisco López-Catzín,^a Patricia Berenice Bolado-García,^a Gonzalo de Jesús Gamboa-López,^a Carolina Elizabeth Medina-Escobedo,^a Leydi Rubí Cambranes-Catzim^a

^aHospital de Especialidades, Centro Médico Nacional “Ignacio García Téllez”, Instituto Mexicano del Seguro Social, Mérida, Yucatán, México.

Communication with: Patricia Berenice Bolado-García

Telephone: (999) 922-56-56, extensión 61677

Email: patricia.bolado@imss.gob.mx

Background: Treating anemia of prematurity is transfused red blood cells and the use of erythropoiesis-stimulating agents. The aim of this article is to determine the correlation between the number of blood transfusions and the use of recombinant human erythropoietin in preterm infants with anemia.

Methods: A correlation study was performed in 80 cases of patients with anemia treated with transfusions and erythropoietin, were randomized into two groups: one was treated with transfusions (T) and one with transfusions and erythropoietin (E). Demographic variables, hemoglobin and hematocrit at the beginning and end of treatment and number of transfusions received were measured. The correlation was obtained through Spearman Rho, considering p < 0.05 as statistically significant.

Results: The total number of units transfused in each group was lower in group E, which received two units less than the T group (p < 0.05). The average CE transfused in group E was 4 ± 1.2 and 7 ± 1.2 for the group T. For the group E the correlation between gestational age and number of transfusions was moderately negative (-0348); birth weight and the number of packed red blood cells transfused were slightly negative (-0239). T group for the negative correlation between the same variables moderate slight negative (-0300) and (-0109), respectively.

Conclusions: Erythropoietin reduces the number of blood transfusions in preterm infants with anemia. Its use does not preclude the transfusion, the patient remains exposed to the risk of communicable diseases in this way.

Keywords: Anemia; Erythropoietin; Blood transfusion

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Anemia of prematurity is the most common hematological disorder in the newborn with very low weight (less than 1500 g) and the newborn with extremely low weight (less than 1000 g).¹ Its incidence is related to prematurity and low birth weight, and is characterized by being hyporegenerative, presenting reticulocytopenia and varying degrees of erythroid hypoplasia in bone marrow and low levels of plasma erythropoietin.² The causes of anemia include several factors, such as reduced half-life of erythrocytes, their increased sensitivity to oxidation, changing fetal hemoglobin to adult hemoglobin, hemodilution due to a rapid increase in body mass due to growth, and low levels of serum erythropoietin.^2,3 After birth, hemoglobin levels (Hb) of the preterm baby suffer a more pronounced and earlier physiological decline than that of term newborns. At 8 weeks it reaches an average nadir of 9.4 g/dL (8.0-11.5 g/dL) in preterm babies with weight between 1500 and 2000 g.⁴ Hb values ​​as low as 6- 7 g/dL have been described without clinical disorders.⁵ This physiological drop in Hb is mainly due to a reduced response to generate erythropoietin in the face of anemia.^6,7 

Treatment of anemia includes red blood cell transfusion and the use of erythropoiesis-stimulating agents, such as recombinant human erythropoietin (rHuEPO).¹ Blood transfusion has immediate effect in correcting anemia of prematurity, mainly in patients requiring rapid replacement of red cell volume in the first days of life.⁸ It is estimated that 38,000 premature infants annually receive more than 300,000 transfusions, which is done based on the symptoms and signs of anemia, as well as hematocrit (Ht) measurement and criteria established by each institution.⁹ However, the risks of immunological sensitization by exposure to multiple donors and the transmission of serious infections such as hepatitis B, C, cytomegalovirus, and human immunodeficiency virus (HIV) are its main limitations.^10,11

Since the early nineties, the administration of rHuEPO has been incorporated into treatment measures for anemia of prematurity.^6,12 Asher and Ohlsson,¹³ in a Cochrane systematic review in 2008, concluded that the administration of rHuEPO reduced the need for transfusion of concentrated red blood cells, the number of concentrates, and the volume transfused per patient. Figueras Aloy et al.¹⁴ in 2010 concluded that very immature and critical premature babies required more blood samples and needed more transfusions; the administration of rHuEPO decreased transfusion requirements by up to 40%, with greater impact on premature babies weighing between 1000 and 1249 g. Therefore, according to the above, the use of rHuEPO is a therapeutic option for treating anemia of prematurity; however, the real impact on reducing transfusions and response produced is not known in our medical unit, so the aim of this study was to determine whether the use of rHuEPO reduced the need for blood transfusions in preterm infants with anemia.

Methods

With prior approval of the protocol by the Local Committee on Research and Health Research Ethics No. 3203, a correlation study was conducted between erythropoietin administration and the decrease in the number of red cell concentrates transfused to infants with anemia treated in Unidad Médica de Alta Especialidad during 2014. We reviewed medical records of all preterm infants with anemia who were admitted to the neonatology with less than 34 weeks of gestation (WG), weighing less than 1500 g, who were transfused with and without administration of rHuEPO. The study excluded records of preterm infants with anemia from hemolytic disease due to group incompatibility or because of severe hemorrhage, major congenital malformations, diaphragmatic hernia, wall defects, central nervous system defects, or fetal hydrops. Records of newborns who died or were voluntarily discharged were eliminated. 

Patients diagnosed with anemia were treated with rHuEPO and/or transfusions based on the criteria established in the IMSS 2012 Clinical Practice Guide for the treatment of anemia of prematurity. Of these, 80 cases were selected for the study and were randomized into two groups: one was treated with transfusions and the second was treated with rHuEPO and transfusions.

The variables studied were gestational age, sex, birth weight, hemoglobin and hematocrit at the beginning and end of treatment, duration of treatment with erythropoietin in weeks, and number of transfusions received. The recorded data were analyzed with SPSS v20. Descriptive statistics were used for demographic variables; Spearman's rho was used for interferential analysis considering p < 0.05 as statistically significant.

Results

Records were reviewed of 80 preterm infants at the neonatology service of the Unidad Médica de Alta Especialidad who met the selection criteria. Subjects were randomized into two groups to record data. One group was treated with transfusions and was called Group T; another group was treated with transfusions and rHuEPO and designated Group E. 

In Group E 50% were female and 50% were male. In Group T, 47.5% were female and 52.5% were male.

Data on age, birth weight, and baseline Hb and Ht are presented in Table I.

In Group E, the average Hb and Ht after the administration of blood and erythropoietin was 12.73 ± 0.74 and 37.97 ± 0.77, respectively. The correlation between these values ​​and erythropoietin administration was zero (p> 0 05). 

In Group T, Hb and Ht after treatment were 12.41 ± 0.72 and 37.85 ± 0.97, respectively. Correlating these results with the amount of blood transfused, there was no statistical significance (p > 0 05).

The initial administration of concentrated erythrocytes (CE) in Group E was two units; in Group T, treatment was initiated with a minimum of four units of CE. The total units transfused in each group was lower in Group E, which received two units less than Group T (Table II). The average CE transfused in Group E was 4 ± 1.2, and 7 ± 1.2 for Group T (p < 0.05).

By observing the behavior of the hematocrit of patients in both groups, it was found that in Group E, Ht declined from its initial level, and then recovered; in Group T, the hematocrit had an upward trend from the beginning to the end of treatment (figure 1).

The correlations between gestational age, birth weight, and the number of units of concentrated erythrocytes transfused were negative (-0.348 [moderate] and -0.239 [mild]) for Group E. Group T had negative correlation between these variables (-0.300 [moderate] and -0.109 [mild]).

As for sex, the group treated with transfusions and erythropoietin (Group E) had a slight positive correlation when correlated with the number of CE (0.184); in the group receiving transfusions (Group T), the correlation between sex and the number of CE administered was slightly positive (0.292).

Discussion

Premature newborn anemia is one of the most common clinical situations in neonatology services. Preterm infants are a vulnerable group of patients requiring transfusions more often. The lower the gestational age and birth weight, the greater the need for rapid replacement of red blood cells. We note that the group of premature babies weighing 850-1430 g and with gestational age < 34 weeks old, needed the largest number of transfusions and met the criteria to be treated with rHuEPO. Studies by Cabañas Guzman et al.^15.16 Sastre et al had similar findings. They concluded that birth weight and gestational age are the main predictive factors related to the need for transfusion and initiation of treatment with rHuEPO. This is because, at lower gestational age and lower weight, the concentration of hematocrit and the physiological drop in hemoglobin are greater, representing a higher risk for developing anemia with clinical manifestations. We found no correlation between sex and baseline hemoglobin levels. There was a slight positive correlation with the number of transfusions; this was higher in the group that was treated only with transfusions, where most of the patients were male; this suggests that males may be more likely to need blood replacement than females; however, a conclusion of this magnitude cannot be made. From the beginning there was bias that the proportion of males was higher, a situation that could influence different statistical results. Controlled trials are needed to confirm or deny whether sex is really a determining factor in the need for more transfusions. 

The indication for the administration of rHuEPO and transfusions was based on the 2012 IMSS Clinical Practice Guidelines for the treatment of anemia of prematurity. The rHuEPO dose administered was 750 IU/kg in divided into 3 doses of 250 IU, alternated during the week (every other day) for a duration of 5 weeks. Despite the known effect of rHuEPO on the increase in hemoglobin and hematocrit, this study did not find a significant increase after treatment. Similar results were reported in studies such as Sijo Yero et al.8 and Maier et al.¹⁷ One explanation for this result is likely to be the immaturity of the patient, contributing to the limited hematologic response to rHuEPO. Other variables that could influence the unfavorable response to rHuEPO are the short half-life of fetal red blood cells, accelerated body growth, low levels of endogenous erythropoietin, severe pathologies associated, and frequency and volume of blood drawn for biochemical analysis. As for the number of transfusions, this was significantly reduced in infants who received rHuEPO (p < 0.05). Despite the importance of the finding, the maximum reduction found was 2 units of concentrated erythrocytes. In a similar study, Maier et al.¹⁷ showed a reduction in the number of transfused concentrated erythrocytes in children who were included in the study who received erythropoietin. Similar data were reported by the group of Ohls et al.¹⁸ in a randomized study of low birth weight premature babies, where the erythropoietin-treated group on average received 0.2 concentrated erythrocytes versus 1.4 in the control group. One of the limitations of our study was not being able to assess whether this reduction in the number of concentrated erythrocytes also implied an important role in the exact volume (measured in mL) of blood administered to patients. This highlights the need for future studies to obtain more objective evidence of the impact of treatment of rHuEPO in reducing blood transfusion, to support or deny their effectiveness in our neonatal population. 

Conclusions

In conclusion, the results of our study show that the application of erythropoietin therapy reduces the number of blood transfusions in preterm infants with anemia; however, we found a significant increase in hematocrit and hemoglobin after treatment. The reduction of concentrates transfused was two, so it is necessary to increase prospective research through experimental protocols to accurately assess the efficacy of erythropoietin in our neonatal population, measuring the exact amount of transfused volume of concentrated erythrocytes and other biochemical variables of erythrocytes, blasts in peripheral blood, and factors that promote or inhibit erythropoiesis. The use of erythropoietin does not exclude blood transfusion, leaving the patient exposed to the risk of communicable diseases.

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