Anemia of Prematurity: An Individualized Approach

Introduction: Anemia of prematurity (AOP) is a frequent finding in very-low-birth-weight infants (VLBWIs). Impaired erythropoietin (EPO) production, reduced red blood cell life span, nutritional deficiencies, and phlebotomy losses are the mechanisms involved.¹ Delayed cord clamping (DCC) and limiting phlebotomy losses are effective measures to prevent AOP.^2,3 To avoid potential adverse effects, low transfusion thresholds are used in most recent blood transfusion (BT) protocols.⁴ Erythropoiesis-stimulating agents decrease the number of transfusions in VLBWIs, but their use is not universally accepted due to the partial clinical benefit and to the cost.⁵ In this report, we describe the protocol used in our NICU for management of AOP in VLBWIs. The main goal of the protocol is the prevention of anemia and individualized use of ßEPO.

Materials and Methods: Measures to prevent AOP were DCC, drawing all initial laboratory blood tests from cord/placental blood, limiting phlebotomy losses, and nutritional support.

Hemoglobin (Hb) values were monitored by hemochrome with reticulocyte count at birth and in the 2nd or 3rd week of life, then every 3 weeks. Other evaluations were performed by hemogas analysis to reduce losses. Iron supplementation started from 21st day of life (DOL) or earlier if reticulocyte hemoglobin content (CHr) was  < 30 pg. Vitamin E, vitamin B12, and folic acid were administrate from 7th DOL. BT was administered according to published guidelines.⁴

ßEPO (dose: 250 UI/kg IV or sc for three times/week) was administered from the 8th DOL in patients with Hb levels  <  50° percentile for age, referring to preterm reference values.⁶ Treatment was started at any time before 32 weeks of postconceptional age (PCA), when Hb levels falled under 50° percentile. Treatment was stopped at 34 to 36 weeks of PCA or before in case of neutropenia, thrombocytosis, and retinopathy of prematurity (ROP).

Results: We enrolled a total of 21 patients, admitted in NICU from May 15, 2017, to November 15, 2017. Eight newborns were ELBWs (mean gestational age [GA]: 26.97 weeks, mean Hb at birth 15.51 g/dL) and 13 were > 1,000 g (mean GA: 30.12 weeks, mean Hb at birth 18.22 g/dL).

We performed DCC at birth for at least 30 seconds in all patients who did not need resuscitation. Blood drawn from umbilical cord was used for cultures (instead of phlebotomy), while was not reliable for hemochrome. Phlebotomy rate was low, with a mean value of 0.13 mL/d per newborn (0.16 mL/d for ELBWIs, 0.11 mL/d for newborns > 1,000 g). BT rate was low: two patients were transfused, one in course of sepsis and the other in course of acute hemorrhage.

Nine patients (42.9%) underwent EPO treatment: seven were ELBWIs (five started in the 2nd week of life, one in the 3rd week of life, and one in the 7th week of life) and two were > 1,000 g (one in the 4th week of life and one in the 6th week of life). To describe safety and efficacy of EPO treatment, we divided our cohort in three groups: group A (EPO started before 3 weeks), group B (EPO started after 3 weeks), and group C (no EPO). In group A (six patients), mean Hb at birth was 15.12 g/dL and mean Hb at 6 weeks was 11.30 g/dL. In group B (three patients), mean Hb at birth was 15.33 g/dL and mean Hb at 6 weeks was 10.77 g/dL. In group C (12 patients), mean Hb at birth was 18.68 g/dL and mean Hb at 6 weeks was 10.41 g/dL. Mean Hb levels in three groups until discharge are reported in [Fig. 1]. No patients experienced adverse effects of EPO treatment.

Conclusion: In our cohort, a preventive approach to AOP, based on DCC and avoidance of unnecessary phlebotomies, resulted in a very low rate of transfusions. Individualized use of ßEPO maintained sufficient Hb levels in patients at higher risk of AOP. EPO treatment in lower Hb patients is useful to join a higher percentile of Hb level than predicted. Conversely, unnecessary treatment was avoided in patients with higher Hb at birth and uncomplicated clinical course. Further data are necessary to better define criteria for targeted EPO treatment.

Fig. 1 Mean Hb levels in groups A, B, and C until discharge