Dr Mohammmad Torkaman Neonatologist Associate professor ANEMIA OF PREMATURITY Dr Mohammmad Torkaman Neonatologist Associate professor

Physiologic anemia The postnatal changes in tissue oxygenation and erythropoietin production result in a physiologic anemia of infancy with a mean minimal hemoglobin concentration in healthy term infants of about 11g/dL at 8 to 12 weeks of life

Anemia of prematurity (AOP) is an exaggerated, pathologic response of the preterm infant to this transition. AOP is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum EPO level, often despite a remarkably reduced hemoglobin concentration.

Because of the shorter life span of RBCs in preterm infants with low EPO levels, the nadir is noted by 6 weeks of age and ranges from 7 to 10g/dL. In ELBW infants whose nadir falls below 7g/dL, this so-called physiologic anemia of prematurity can be associated with pallor, tachypnea, tachycardia, poor feeding, and poor weight gain

This exaggerated physiologic anemia of prematurity is related to a combination of Decreased RBC mass at birth Increased iatrogenic losses from laboratory blood sampling Shorter RBC life span(40-60 days) Inadequate erythropoietin production Rapid body growth

dietary factors Folic acid deficiency Unless there has been significant blood loss, iron stores should be sufficient to maintain erythropoiesis early on. Vitamin E deficiency does not play a role in anemia of prematurity

Erythropoietin (EPO) Binds to erythropoietin receptors on early erythroid progenitor cells and via the JAK2 signaling pathway regulates RBC production by protecting them from apoptosis. Erythropoietin is produced primarily in the fetal liver and later in the cortical peritubular cells of the kidney, so that in adults renal production of EPO is the most important.

Erythropoiesis is highly responsive to blood oxygenation Erythropoiesis is highly responsive to blood oxygenation. Hypoxia inducible factors (HIFs), constitutively expressed EPO transcription factors, are destroyed in the presence of oxygen. Under hypoxic conditions, EPO production increases. Levels of EPO in cord blood are higher than in adult blood samples. but there is a dramatic decrease after birth in response to higher levels of tissue oxygenation. By 1 month of age, serum levels in healthy term infants reach their nadir. This is followed by a rise to maximal levels at 2 months of age and then a slow drift down to adult value

The reason for diminished EPO levels is not fully understood. During fetal life, EPO synthesis is handled primarily by the liver, whose oxygen sensor is relatively insensitive to hypoxia when compared to the oxygen sensor of the kidney. The developmental switch from liver to kidney EPO production is not accelerated by early birth, and thus the preterm infant must rely on the liver as the primary site for synthesis, leading to diminished responsiveness to anemia. An additional mechanism thought to contribute to diminished EPO levels may be accelerated EPO metabolism.

Although preterm infants will respond to hypoxia with a rise in EPO levels, the increase is lower than that expected for term infants. The suboptimal EPO response may be due to developmental changes in transcription factors or to the site of fetal EPO production.

Frequent blood sampling The physiologic anemia of infancy can be exaggerated in the sick or premature infant by frequent blood sampling: the smaller the infant, the proportionally greater the volume of blood that is withdrawn for laboratory testing

Blood transfusion Most RBC transfusions in neonates occur within the first 3 to 4 weeks of life, with the majority being in the first 2 weeks. Physiologically lower levels of EPO in neonates provided the rationale for the pharmacologic use of erythropoietin to reduce the volume and risks of blood transfusions.

Blood transfusion A restrictive strategy does not increase infant morbidity or mortality. In addition, long-term neurodevelopmental outcomes have been found to be poorer in liberally transfused neonates. Late exposure to packed RBC may be related to the development of necrotizing enterocolitis, and early transfusions may be associated with the risk of intraventricular hemorrhage.

Increased risks in adult patients Death Myocardial infarction Stroke Venous thrombosis Cancer progression.

Erythropoietin (EPO) Early Starting on day 1 or 2, 1200–1400 U/kg/wk. r-HuEPO is added to the total parenteral nutrition solution, and 1 mg/kg/d of iron is added. Late(after 8 days) 500–700 U/kg/wk given 3–5 times per week subcutaneously. Supple- mental oral iron needs to be provided at 3 mg/kg/d in 3 divided doses. The iron dose is increased to 6 mg/kg/d as soon as the infant is tolerating full enteral feeds

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Aher SM1, Ohlsson A. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant but not the total volume of RBCs transfused per infant. [Cochrane Database Syst Rev. 2006]

[Cochrane Database Syst Rev. 2012] Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Ohlsson A1, Aher SM. Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure In this update there was no significant increase in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment [Cochrane Database Syst Rev. 2012]

Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Aher SM1, Ohlsson A. Cochrane Database Syst Rev. 2012 Oct A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I(2) = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) No other important favourable or adverse neonatal outcomes or side effects were reported.

Stable and larger preterm infants have a better response to EPO therapy when compared with ELBW infants.

Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Song J1, Sun H2, Xu F1,3, Kang W2, Gao L1, Guo J1, Zhang Y1, Xia L1, Wang X1,4, Zhu C1,2,3,5. Repeated low-dose rhEPO treatment reduced the risk of long-term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24-34.

When transfusions are necessary, an RBC volume of 10-15 mL/kg is recommended It is good practice to split units derived from a single donor so that sequential transfusions can be given as required and donor exposure can be minimized.

Delayed cord clamping or umbilical cord milking at birth results in fewer transfusions and a reduction in both intraventricular hemorrhage and necrotizing enterocolitis in preterm infants. Given the impact of phlebotomy losses during monitoring in the neonatal ICU, attention to reducing unnecessary blood draws also has been advocated.

Spontaneous recovery of mild anemia of prematurity (AOP) may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.