Seminars in Fetal & Neonatal Medicine (2008) 13, 239e247 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/siny Neonatal anemia Sanjay Aher a,*, Kedar Malwatkar a, Sandeep Kadam b a Kilbil Hospital for Precious Kids, City Plaza, opp. Kalika Temple, Old Agra Road, Nashik, Maharashtra, 422002, India b KEM Hospital, Pune, Maharashtra, India KEYWORDS Summary Neonatal anemia and the need for red blood cell (RBC) transfusions are very Anemia; common in neonatal intensive care units. Neonatal anemia can be due to blood loss, decreased Erythropoietin; RBC production, or increased destruction of erythrocytes. Physiologic anemia of the newborn Infant; and anemia of prematurity are the two most common causes of anemia in neonates. Phlebot- Newborn; omy losses result in much of the anemia seen in extremely low birthweight infants (ELBW). Transfusion Accepting a lower threshold level for transfusion in ELBW infants can prevent these infants being exposed to multiple donors. ª 2008 Elsevier Ltd. All rights reserved. Introduction extrauterine life is controlled in part by erythropoietin (EPO) produced by kidney. Neonatal anemia is defined by a hemoglobin or hematocrit Hemoglobin, hematocrit, and RBC count increase concentration of greater than 2 standard deviations below throughout fetal life. Extremely large RBCs with an the mean for postnatal age.1 The etiology of neonatal ane- increased content of hemoglobin (Hb) are produced early mia is commonly subdivided into three major categories: in fetal life. The size and Hb content of these cells decrease blood loss, decreased production, and increased destruc- throughout gestation, but the mean corpuscular hemoglo- tion of erythrocytes (Box 1). Hematopoiesis in the fetus bin concentration (MCHC) does not change significantly. and neonate is in a constant state of flux and evolution as During the neonatal period, the newborn leaves the the newborn adapts to a new milieu. relatively hypoxic in-utero environment and emerges into Fetal erythropoiesis occurs sequentially during a different physiologic setting. embryonic development in three different sites: yolk sac, liver, and bone marrow.2 Yolk-sac formation of red blood Physiologic anemia of infancy cells (RBCs) is maximal between 2 and 10 weeks of gesta- tion. Myeloid (bone marrow) production of RBCs begins When infants take their first breath, considerably more at around week 18 and, by the 30th week of fetal life, oxygen is available for binding to Hb, and Hb oxygen bone marrow is the major erythropoietic organ. At birth, saturation increases from approximately 50% to 95% or almost all RBCs are produced in the bone marrow, more. The normal developmental switch from fetal to adult although a low level of hepatic erythropoiesis persists Hb synthesis actively replaces high-oxygen-affinity fetal Hb through the first few days of life. RBC production in with low-oxygen-affinity adult hemoglobin, which can de- liver a greater fraction of Hb-bound oxygen to the tissues. * Corresponding author. Tel.: þ91 996 063 6509. Therefore, immediately after birth the increase in blood E-mail address: [email protected] (S. Aher). oxygen content and tissue oxygen delivery downregulate 1744-165X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2008.02.009 240 S. Aher et al. Box 1. Causes of anemia in neonates Pyruvate kinase deficiency Glycolytic deficiency 1. Blood loss Erythrocyte nucleotide deficiencies A. Before delivery C. RBC membrane defects (hereditary RBC Fetomaternal hemorrhage disorders) Fetoplacental hemorrhage Spherocytosis Twinetwin transfusion syndrome Elliptocytosis B. During delivery Stomatocytosis Malformation of the umbilical cord Pyropoikilocytosis Velamentous insertion D. Hemoglobin disorders Vasa previa Thalassemia syndromes: a-thalassemias, Hematomas b and g thalassemias Aneurysms E. Vitamin E deficiency Nuchal cord F. Infections Malformation of the placenta Bacterial or viral sepsis Placenta previa Congenital infections (TORCH) Abruptio placenta G. Anemia of prematurity Obstetric complications H. Disseminated intravascular coagulation (DIC) Placental incision during cesarean section I. Inherited metabolic disorders Traumatic amniocentesis Galactosemia Umbilical cord rupture with precipitous delivery Osteopetrosis or rupture of short or entangled umbilical cord J. Unstable hemoglobinopathies C. Internal bleeding HbE Intracranial Congenital Heinz body hemolytic anemia Cephalhematoma Subdural Intraventricular erythropoietin production so that erythropoiesis is Subgaleal suppressed. The Hb concentration continues to decrease Intraabdominal until tissue oxygen needs are greater than oxygen delivery. Ruptured liver, spleen, kidney or adrenal Normally, this point is reached between 6 and 12 weeks of Retroperitoneal bleed age, when the Hb concentration is 9.5e11 g/dL. As hypoxia Pulmonary is detected by renal or hepatic oxygen sensors, erythropoi- D. Iatrogenic etin production increases and erythropoiesis resumes. The Phlebotomy losses supply of iron is sufficient for hemoglobin synthesis, even in the absence of dietary intake, until approximately 2. Decreased erythrocyte production 20 weeks of age. This condition is essentially benign and A. Disorders of the bone marrow does not require treatment. (hypoplastic anemia) DiamondeBlackfan anemia Fanconi’s anemia Anemia of prematurity Transient erythroblastopenia of childhood (TEC) B. Infections The physiologic anemia seen in preterm infants is more Parvovirus B19, HIV, syphilis, cytomegalovirus, profound and occurs earlier than anemia of infancy. Various rubella causes contribute to this condition. An important compo- Viral/bacterial sepsis nent in the first few weeks of life is blood loss due to C. Nutritional deficiencies sampling for the many laboratory tests that premature Iron, folate, vitamin B12, protein infants undergo. The erythropoietic response is also D. Congenital leukemia suboptimal, a significant problem because demands on erythropoiesis are heightened by the short survival of the 3. Increased erythrocyte destruction RBCs from premature infants (approximately 40e60 days A. Immune hemolytic anemia instead of 120 days as in adults) and the rapid expansion Rh of the RBC mass that accompanies growth.2 The cause for ABO this suboptimal erythropoiesis appears to be inadequate Minor blood group incompatibilities synthesis of erythropoietin in response to hypoxia. The Maternal autoimmune disorders magnitude of deficiency is greatest in the smallest, least Systemic lupus erythematosus mature infants.3 The liver is the predominant source of Autoimmune hemolytic anemia erythropoietin during fetal life; relative insensitivity of Drug induced: penicillin, valproic acid hepatic oxygen sensor to hypoxia explains blunted erythro- B. RBC enzyme abnormalities: poietin response seen in premature infants.4 Glucose-6-phosphate dehydrogenase deficiency Deficiency of folate, vitamin B12, or vitamin E can aggravate anemia in these extremely premature infants.5 Neonatal anemia 241 Vitamin E is an antioxidant that is vital to the integrity of Causes of neonatal anemia erythrocytes. In its absence, these cells are susceptible to lipid peroxidation and membrane injury. The logical Blood loss conclusion is that vitamin E deficiency might contribute to the anemia of prematurity. In fact, premature infants given Blood loss in neonates can occur before, during, or after daily vitamin E (15 IU/day) had higher hemoglobin levels delivery, and can account for 5e10% of all cases of severe and lower reticulocyte levels than a control group not given neonatal anemia.16 Anemia frequently follows fetal blood vitamin E.6 A study by Zipursky et al.7 found no hematolog- loss, bleeding from obstetric complications, and internal ical benefit for the administration of vitamin E to prema- hemorrhages associated with birth trauma. ture infants. Combined treatment with erythropoietin, Iatrogenic anemia due to repeated removal of blood for intravenous or oral iron, folate, and vitamin B12 during laboratory testing is common in premature infants. Most the first weeks reduces the need for transfusion in ex- affected infants are asymptomatic but when losses tremely low birthweight infants.8,9 The anemia in preterm approach 20% of total blood volume, signs and symptoms infants is largely caused by factors such as erythropoietin of hypovolemic shock can become apparent, warranting deficiency. replacement of blood loss in babies.17 Erythropoietin therapy Infants are generally asymptomatic in chronic blood loss and moderate hemorrhage; the only physical finding is pallor. Laboratory studies can range from a mild As a relative deficiency of EPO is present in the anemia of normochromic, normocytic anemia (Hb 9e12 g/dL) to prematurity, a number of studies have evaluated the a more severe hypochromic, microcytic anemia (Hb safety and efficacy of EPO therapy in this setting. Several 5e7 g/dL). The only therapy required in asymptomatic large, multicenter trials have documented a modest but infants is iron supplementation; RBC replacement is statistically significant reduction in the RBC transfusion indicated only if there is evidence of clinical distress. requirements of treated infants compared with control Severely anemic infants are frequently in incipient heart subjects. failure, these children should be transfused very slowly EPO treatment can play a particularly important role in (2 mL/kg per h).2 the management of infants whose parents refuse to allow