The role of recombinant Human erythropoietin in neonatal anemia

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ORIGINAL RESEARCH REPORT

The role of recombinant Human erythropoietin in neonatal anemia Dalia M. El-Lahony a, Nagwan Y. Saleh a, Mona S. Habib b Mohammed A. Shehata a, Mahmoud A. El-Hawy a,* a b

Pediatrics Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt Medical Biochemistry Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Received 15 March 2019; received in revised form 29 June 2019; accepted 30 August 2019

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KEYWORDS AOP; r-Hu EPO; Late hypo-regenerative anemia

Abstract Aim: To estimate the blood level of Erythropoietin (EPO) in neonates with anemia of prematurity (APO) and in late hypo-regenerative anemia and to clarify role of EPO in correction of anemia and reducing the number of blood transfusions. Methods: This study was carried out on 80 neonates divided into; group I (30 preterm neonates) with AOP received EPO (250 IU/kg/dose subcutaneously 3 times weekly for 4 weeks), compared to group II (30 neonates) with AOP treated only with blood transfusion; Group III (10 neonates, GA  37 weeks) with late hypo-regenerative post haemolytic anemia, treated with the same dose of r-Hu EPO and compared to group IV (10 neonates) treated only with blood transfusion. Hematological measurements and transfusion requirements were followed during therapy. Serum level of EPO was measured by ELISA technique. Results: By the end of the 4th week of therapy, there was significant increase in group I post rHu EPO compared to group II regarding reticulocyte counts (P < 0.001) leading to rise of the Hb (P < 0.001), Hct levels (P < 0.001) with subsequent reduction in the overall number of blood transfusions (P < 0.001). There were significant higher levels of reticulocytes (P < 0.001), Hb (P < 0.001) and Hct (P < 0.001) values in group III post r-Hu EPO compared to group IV, while number of blood transfusions did not differ significantly among them (P = 1.0).

* Corresponding author at: Pediatrics Department, Faculty of Medicine, Menoufia University, Shebin el Kom, 32511 Menoufia, Egypt. E-mail address: [email protected] (M.A. El-Hawy). https://doi.org/10.1016/j.hemonc.2019.08.004 1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: D. M. El-Lahony, N. Y. Saleh, M. S. Habib et al., The role of recombinant Human erythropoietin in neonatal anemia, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.08.004

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D.M. El-Lahony et al. Conclusion: EPO therapy in conjunction with iron, vitamin E and folic acid, stimulated erythropoiesis and significantly reduced the need for blood transfusion in AOP and corrected late hyporegenerative post hemolytic anemia.

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Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

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Introduction

Materials and methods

All newborns exhibit varying degrees of physiological asymptomatic anemia in the first weeks after birth due to postnatal decline of hemoglobin (Hb) [1,2]. Exacerbation of this physiological anemia occurs in preterm infants and is referred to as anemia of prematurity (AOP) with larger and faster drop in Hb [3,4]. AOP is a normocyticnormochromic and hyporegenerative anemia that is characterized by the existence of a low serum erythropoietin (EPO) level with a remarkably low Hb concentration [4,5]. The etiology of AOP includes several reasons: shortened gestational age (GA), immature hematopoietic system, expansion of extracellular volume resulting from rapid body growth, nutritional imbalances, and more blood loss due to phlebotomy for laboratory testing [4,6,7]. Inadequate EPO response is one of the incriminating causes in the generation of AOP [7,8]. EPO is a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development [9]. It stimulates erythroid cell proliferation, survival, and differentiation [10]. The clinical findings of AOP include pallor, poor weight gain, decreased activity, tachypnoea, tachycardia, and feeding problems that prompt blood transfusions [8], which is the chief therapeutic intervention in these infants [2]. There is considerable disagreement about the indication, timing, and efficacy of blood transfusion [11]. Although it represents the backbone treatment of AOP [4,11,12], transmission of infection, volume overload allo-immunization, immunosuppression, electrolyte, and acid–base disruption are alarming hazards of blood transfusion [13,14]. Moreover, the safety of blood transfusion, in terms of transmission of infections, is a matter of doubt in developing countries in comparison to developed ones [7,15–17]. For these reasons, r-Hu EPO therapy provides guarantee in avoiding these hazards [4,18,19]. At this time, a controversy exists regarding the therapeutic validity and efficacy of r-Hu EPO therapy in either prevention or treatment of AOP. Late hyporegenerative anemia is a condition that develops in full-term neonates by the second or third month of life following acute hemolysis because of either Rh or ABO incompatibility, low levels of endogenous EPO, and bone marrow suppression [20–22]. It usually resolves spontaneously but causes significant morbidity due to the prolonged need for blood transfusions [23]. This provides rationale for r-Hu EPO use as an adjuvant therapy with the intention of reducing blood transfusion requirements. Therefore, this study was performed to estimate the blood level of EPO in neonates with AOP and to clarify its role in correction of anemia and reducing the number of blood transfusions.

This prospective case–control study was performed on 80 neonates enrolled from the Neonatal Intensive Care Unit, Menoufia University Hospitals, during the study period from November 2015 to May 2016 and was approved by the local ethical committee with written consent given by their parents. The neonates were divided as follows: Group I, which included 30 preterm neonates fulfilling all clinical criteria of AOP, namely, birth weight  1500 g, GA 30–34 weeks with total caloric intake >50 kcal/kg/day with more than 50% enteral, hematocrit <40% or 40%–50% but falling 2% per day, postnatal age >6 days, and phlebotomy losses >5 mL/ kg/week [24]. These neonates received r-Hu EPO (250 IU/ kg/dose) subcutaneously three times per week for 4 weeks. Treatment was established immediately after developing anemia, and outcomes compared with Group II, which included 30 neonates with AOP who did not receive r-Hu EPO and were treated only with blood transfusion. Both groups received 6 mg/kg/day elemental iron in two divided doses, 1 mL/kg/day of multivitamin preparation containing 5 IU/mL vitamin E, 1 mg/day folic acid, and adequate caloric intake. We excluded neonates who were mechanically ventilated or had sepsis, congenital anomalies, intrauterine growth retardation, intraventricular hemorrhage Grade 3 or 4, cyanotic congenital heart disease, renal or hepatic failure, convulsions, or congenital infection. All study patients were subjected to the following: full history taking, thorough clinical examination, and laboratory investigations. Venous blood (1.5 mL) was withdrawn from all patients, which was divided into two parts: one part was delivered into an EDTA tube to obtain complete blood and reticulocyte counts; the remaining blood was delivered into a glass tube, left to clot at room temperature, and then centrifuged at 4000 rpm for 15 minutes. Serum was stored at 80 °C until analysis of serum EPO level. Investigations to confirm the presence of anemia included Hb and hematocrit levels, red blood corpuscles/cells counts, mean corpuscular volume, mean corpuscular hemoglobin concentration, and reticulocyte count. Serum EPO level was measured using RayBio Human EPO ELISA Kit according to manufacturer’s guidelines (RayBiotech, Inc). Demographic data including GA, birth weight, gender, age at study entry were collected for each case. Laboratory monitoring by blood sampling was performed at the time of enrollment to obtain complete blood counts and every week to obtain reticulocyte count and serum EPO levels. Hematological measurements and transfusion requirements were followed during therapy. Clinical data recorded during and at completion of this study were daily vital signs, daily calo-

Please cite this article as: D. M. El-Lahony, N. Y. Saleh, M. S. Habib et al., The role of recombinant Human erythropoietin in neonatal anemia, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.08.004

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Erythropoietin in neonatal anemia

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ric intake, weekly weight gain, and presence or absence of signs of anemia.

Group II regarding total leukocyte count and platelets count (Table 2).

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Statistical analysis

Discussion

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Results were collected, tabulated, and statistically analyzed by a statistical package (SPSS version 20, SPSS Inc., Chicago, IL, USA). Quantitative data were presented as mean ± standard deviation, and chi-square (v2) test was used for qualitative variables. All p values  0.05 were considered significant.

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Results

AOP is normocytic normochromic and hyporegenerative anemia in infants born at less than 34 weeks’ gestation [4,5,25]. Low EPO level is one of the incriminating causes [26]. Therefore, enhancing erythropoiesis by administering r-Hu EPO would reduce the need for blood transfusions and consequently its hazards [8,19,27]. In this study we evaluated the role of r-Hu EPO as an adjuvant therapy for AOP, late hyporegenerative anemia, to reduce blood transfusion requirements. In this study 66.7% of Group I neonates were males, whereas 33.3% were females. The mean GA was 32.33 ± 1.6 weeks and the mean weight was 1451.60 ± 173.1 g with no significant difference between Groups I and II. This is quite similar to that observed by Yasmeen et al. [4] (mean GA 30.4 ± 0.9 weeks and mean birth weight 1348.3 ± 50.1 g). In our study, Hb, hematocrit values, and reticulocyte count were significantly higher in Group I neonates after treatment with r-Hu EPO in comparison with levels before r-Hu EPO administration or with Group II treated only with blood transfusion. Consistently, Maier et al. [18], Whitehall et al. [28], Donato et al. [29], and Yasmeen et al. [4] found that neonates who received r-Hu EPO showed significant rise in Hb, hematocrit, and reticulocytes as an evidence of stimulation of erythropoiesis resulting in correction of anemia and reducing the number of blood transfusions required. This means that when given in sufficient doses to infants, r-Hu EPO and iron enhance endogenous erythropoiesis as evidenced by increased red blood cell and reticulocyte counts. Chang and his colleagues showed that the postnatal decline of Hb and hematocrit levels were reduced in the rHu EPO-treated infants with higher reticulocytes [30].

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Regarding demographic data of preterm neonates with AOP, males represented 66.7% and 73.3% in Groups I and II, respectively. The GA was 32.33 ± 1.6 weeks in Group I versus 32.5 ± 1.4 weeks in Group II. The birth weight of neonates was 1451.60 ± 173.1 g and 1453.20 ± 147.5 g in Groups I and II, respectively. There were nonsignificant differences regarding gender, GA, and birth weight between Groups I and II (Table 1). The baseline hematological values (total leukocyte count, Hb, hematocrit, platelets count, and reticulocyte count), EPO level, and number of blood transfusions required did not differ significantly between Groups I and II at the time of enrollment (Table 1). During the follow-up period, there were significantly higher levels of Hb and hematocrit in Group I neonates treated with rHu EPO than those in Group II neonates treated only with blood transfusion (Table 2). Reticulocyte count and serum EPO level were significantly higher in Group I neonates in comparison to those in Group II (Table 2). The number of blood transfusions required were significantly reduced in Group I neonates treated with r-Hu EPO than in Group II (Table 2). Moreover, a nonsignificant difference was seen between Group I cases post-r-Hu EPO administration and

GA (wk) Weight (g) TLC  103/mm3 Hb (g/dL) Hct, % PLT  103/mm3 Retics, % EPO level (mlu/mL) Number of BTs 0.00 1.0 2.0 3.0

Female Male

no (%) no (%)

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Table 1 Demographic Data, Different Hematological Parameters, Serum EPO Level and Number of Blood Transfusions of Group I (Pre-r-Hu EPO Administration) in Comparison to Group II (No r-Hu EPO Administration).

Gender

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Group I (N = 30)

Group II (N = 30)

v2

p

10 (33.3) 20 (66.7) 32.33 ± 1.6 1451.60 ± 173.1 11.41 ± 3.067 10.41 ± 1.443 29.62 ± 4.137 258.40 ± 101.676 1.6833 ± 0.652 7.70 ± 1.765 N (%) 14 (46.7) 7 (23.3) 7 (23.3) 2 (6.7)

8 (26.7) 22 (73.3) 32.5 ± 1.4 1453.20 ± 147.5 11.41 ± 3.067 10.53 ± 1.332 29.82 ± 3.391 258.47 ± 101.636 1.683 ± 0.652 7.57 ± 1.716 N (%) 20 (66.7) 6 (20.0) 4 (13.3) 0 (0.0)

0.317

.573

0.424a 0.039a 0.000a 0.177a 0.212a 0.003a 0.000a 0.297a

.673 .969 >.99 .860 .833 .998 >.99 .768

3.9

.266

BTs = blood transfusions; EPO = erythropoietin; GA = gestational age; Hb = hemoglobin; Hct = hematocrit; PLT = platelets count; Retics = reticulocyte count; TLC = total leukocyte count; v2 = chi-square test. a t test. Please cite this article as: D. M. El-Lahony, N. Y. Saleh, M. S. Habib et al., The role of recombinant Human erythropoietin in neonatal anemia, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.08.004

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D.M. El-Lahony et al. Table 2 Comparison Between Group I Post-r-Hu EPO Administration and Group II (No r-Hu EPO Administration; Transfusion Only) Regarding Different Hematological Parameters, Serum EPO Level and Number of Blood Transfusions. Group I (Post-r-Hu EPO administration; N = 30)

Group II (no r-Hu EPO administration; N = 30)

Paired sample t test

p

Mean ± SD

Mean ± SD

First week TLC  103/mm3 Hb (g/dL) Hct, % PLT  103/mm3

9.13 ± 2.688 10.87 ± 1.415 31.76 ± 3.524 217.76 ± 80.063

8.17 ± 2.681 10.11 ± 1.354 30.07 ± 3.532 217.16 ± 80.129

1.385 2.116 1.855 0.029

.171 .039 .069 .977

Second week TLC  103/mm3 Hb (g/dL) Hct, % PLT  103/mm3

8.74 ± 2.502 11.60 ± 1.705 33.33 ± 4.971 238.83 ± 79.875

8.31 ± 2.583 9.83 ± 1.386 29.00 ± 3.658 254.43 ± 96.059

0.684 4.404 3.846 0.904

.497 <.001 <.001 .374

Third week TLC  103/mm3 Hb (g/dL) Hct, % PLT  103/mm3

8.92 ± 2.344 12.07 ± 1.916 35.23 ± 6.307 296.27 ± 84.912

8.56 ± 2.134 9.55 ± 1.457 27.67 ± 3.827 277.57 ± 87.824

0.838 5.734 5.613 1.301

.405 <.001 <.001 .203

Fourth week TLC  103/mm3 Hb (g/dL) Hct, % PLT  103/mm3 Retics, % EPO level (mlu/mL)

7.13 ± 2.085 12.56 ± 2.235 37.60 ± 7.177 336.90 ± 139.306 5.1500 ± 1.421 15.37 ± 3.731

7.29 ± 1.962 9.43 ± 1.169 27.67 ± 2.963 337.07 ± 139.10 1.670 ± 0.713 7.80 ± 1.864

0.293 6.804 7.007 0.005 11.986 9.943

.770 <.001 <.001 .996 <.001 <.001

Number of Blood transfusions 0.00 1.00 2.00

N (%) 27 (90) 1 (3.3) 2 (6.7)

N (%) 10 (33.3) 19 (63.3) 1 (3.3)

v2 = 24.344

<.001

EPO = erythropoietin; Hb = hemoglobin; Hct = hematocrit; PLT = platelets count; Retics = reticulocyte count; SD = standard deviation; TLC = total leukocyte count.

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In this study, there was no significant difference regarding total leukocytic and platelet counts. This result agrees with that in the study by Yeo et al. [31] who found that there was no significant difference in EPO-treated infants compared with controls regarding platelet count. Mizuno et al. [32] reported that there was no evidence suggesting that administration of r-Hu EPO has a toxic effect on granulopoiesis in preterm infants. By contrast, Halpe ´rin et al. [33] and Ohls and Christensen [34] stated that r-Hu EPO administration results in reduction of the absolute neutrophil count in premature infants. In our study, the number of blood transfusions was significantly reduced in Group I after r-Hu EPO administration. Such positive results are in agreement with the study by Schefels et al. [35] on 33 infants with GA 30 ± 2 weeks treated with r-Hu EPO beginning from the fifth day of life for 6 weeks; in their study group, 1.39 ± 1.94 transfusions per infant were required after using EPO, whereas prior to this 2.7 ± 1.93 transfusions per infant were needed. Dollberg and Mimouni [36], Donato et al. [29] and Yasmeen et al. [4] found that EPO therapy reduces the need for blood transfusions in premature very-low-birth weight infants, as in their study a significant but lesser number of infants

required blood transfusion in the EPO-treated group than before EPO administration. Moreover, Maier et al. [37], in their study performed over 9 years on 256 infants, found that after using EPO as a therapy for AOP, the median number of transfusions per infant decreased from 7 to 2 and blood volume transfused decreased from 131 to 37 mL/kg; however, the overall survival rate was 75% and remained unchanged. This in contrast to Atasay et al. [38] who concluded that under the neonatal intensive care circumstances of developing countries where blood volumes needed for analysis are still very high, phlebotomy losses cannot be avoided and stated that early EPO and iron therapy are not effective in decreasing the need for transfusion. Furthermore, in studies performed by Donato et al. [29] and Ohls et al. [39] the numbers of blood transfusions were not significantly reduced.

Conclusion Our study demonstrated that r-Hu EPO therapy at a dose of 250 IU/kg per dose three times weekly in conjunction with 6 mg/kg/day elemental iron stimulated erythropoiesis and

Please cite this article as: D. M. El-Lahony, N. Y. Saleh, M. S. Habib et al., The role of recombinant Human erythropoietin in neonatal anemia, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.08.004

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significantly reduced the need for erythrocyte transfusion in AOP. [19]

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Declaration of Competing Interest The authors declared that there is no conflict of interest.

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Please cite this article as: D. M. El-Lahony, N. Y. Saleh, M. S. Habib et al., The role of recombinant Human erythropoietin in neonatal anemia, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.08.004

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