Seminars in Fetal & Neonatal Medicine (2008) 13, 239e247
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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 Infants who rapidly lose large volumes of blood appear blood transfusion on religious grounds.10 Although concern to be in acute distress (pallor, tachycardia, tachypnea, was raised over two EPO-treated infants in one study who weak pulse, hypotension, and shock). The hemoglobin subsequently died of sudden infant death syndrome concentration immediately after an acute hemorrhage (SIDS),11 SIDS has not been a feature of EPO treatment in might be normal because the initial response to acute other studies. Early concerns about EPO-induced neutrope- volume depletion is vasoconstriction. Decreased hemo- nia have similarly not been born out. The current consensus globin might not be seen until the plasma volume has is therefore that the use of this agent appears to be safe in re-expanded several hours later. The diagnosis of acute premature infants. hemorrhagic anemia is therefore based largely on To date, studies have clearly demonstrated that EPO physical findings and evidence of blood loss. Treatment increases both erythropoiesis and the reticulocyte count. is directed at rapid expansion of the vascular space However, it is not clear whether the overall numbers of (20 mL/kg fluid). This is most quickly accomplished by transfusions are decreased with EPO use as results have rapid infusion of crystalloids, followed by type-specific, been inconsistent. Vamvakas and Strauss12 conducted cross-matched packed RBC transfusion. In infants in a meta-analysis of 21 EPO trials. All the trials examined whom anemia and hypoxia are severe, non-cross-matched used conservative transfusion guidelines. Although there group O, Rh-negative RBCs are an acceptable alternative were considerable variations in findings from these to cross-matched RBCs.2 studies they concluded that the use of EPO reduced the amount of blood transfused over the course of the infants hospital stay by an average of 11 mL/kg. They also Hematological changes following hemorrhage concluded only modest effects overall on transfusion requirement. Immediately after hemorrhage there is no significant Cochrane reviews by Aher and Ohlsson13e15 of prospec- decrease in hemoglobin and the packed cell volume tive controlled trials of EPO treatment in anemia of (PCV), as the RBCs and the plasma both are reduced prematurity have been published. Meta-analysis of early proportionately.18 Itcantakemorethan3daysforthe EPO therapy, initiated within 8 days of birth, concluded PCV to reduce significantly. Initially, the anemia is normo- that, due to the limited benefits and the increased risk of cytic, normochromic. The reticulocytes start appearing retinopathy of prematurity (ROP), early administration of and reach about 15% between 6 and 12 days. During the EPO is not recommended.15 Another Cochrane review, by phase of regeneration, macrocytosis, polychromatophilia, the same authors, of late EPO initiated at 8 days or later and other signs of erythrocyte regeneration are seen in reduces the use of one or more RBC transfusion but the donor the peripheral blood film, which might be mistaken for exposure is probably not avoided as most studies included hemolytic anemia. Absence of hyperbilirubinemia differ- infants who had received transfusions prior to trial entry.13 entiates it except when there is bleeding in tissues or Late EPO does not significantly reduce or increase any of body cavities. Neutrophilia and thrombocytosis might the neonatal adverse outcomes including mortality and ROP. occur. 242 S. Aher et al.
Anemia due to iatrogenic causes infection in newborn, such as parvovirus, and acquired nutritional deficiencies, such as iron, copper, folate, Anemia in the newborn can also be due to iatrogenic causes vitamin B12, vitamin B6, vitamin A, vitamin C and vitamin E, 23 secondary to blood sampling required for the care of can result in reduced RBC production. critically ill neonates and premature babies. One milliliter of blood represents 1% of total blood volume, especially in Increased erythrocyte destruction preterm babies. Removal of 8e10 ml of blood in a 1500-g baby constitutes 8% of the blood volume. To avoid excess The normal life span of a fetal RBC in a term neonate is iatrogenic blood loss, the amount of blood collected should approximately 70 days.24 Certain intrinsic, extrinsic, con- be recorded. genital, and acquired abnormalities of the erythrocyte can expedite this process, resulting in premature destruc- Diagnosis tion of RBCs (i.e. hemolysis) and profound anemia.1
Bleeding in the newborn is usually obvious because external Immune-mediated erythrocyte destruction bleeding can be perceived. It becomes difficult if the Immune-mediated RBC destruction occurs when fetal bleeding is not obvious. Rapidly developing anemia with erythrocytes, bearing surface antigens different from those hyperbilirubinemia and reticulocytosis, and absence of expressed on maternal RBCs, enter the maternal circulation specific signs of the different types of hemolytic anemia, (e.g. via fetomaternal hemorrhage, amniocentesis). This should lead to the diagnosis of internal bleeding. Thus the stimulates a humoral response in the mother, the end result presence of signs of regeneration, without evidence of of which is production of immunoglobulin G (IgG) antibody. blood destruction, should lead to the suspicion of bleeding The IgG crosses the placenta, enters the fetal circulation, inside the body. A Kleihaur Betke’s test on the mother’s and coats fetal RBCs. These erythrocytes are then targeted blood smear showing fetal pink cells is diagnostic of by the reticuloendothelial system for removal from the fetomaternal hemorrhage and routine examination of the peripheral circulation. The most common of the immune- placenta and umbilical cord should be mandatory before mediated hemolytic anemias involve rhesus (Rh) and ABO disposal, for all deliveries. incompatibilities, although minor blood group incompati- bilities (e.g. Kell, Duffy) should be considered in the Decreased erythrocyte production differential diagnosis.
The bone marrow is the predominant site of hematopoiesis Rhesus isoimmunization from approximately 6 months gestation. Disorders in pro- The Rh antigen is a protein on the erythrocyte comprised of duction or differentiation of progenitor or precursor cells several antigenic sites (i.e. C, c, D, E, e), of which D is the can result in pancytopenia (e.g. Fanconi’s anemia) or in most significant. Those who lack the D antigen on their decreased production of a specific cell line (e.g. erythrocytes are termed ‘Rh-negative’. DiamondeBlackfan anemia).19 The disorders of erythrocyte Exposure normally occurs during the first pregnancy with production are an infrequent cause of neonatal anemia. an Rh-positive fetus, via fetomaternal hemorrhage or obstet- ric procedures (e.g. amniocentesis, chorionic villous sam- Congenital disorders of erythrocyte production pling, abortion), and results in sensitization to the D antigen. Two common conditions presenting with congenital disor- The second pregnancy with an Rh-positive fetus thus ders of erythropoiesis are Fanconi’s anemia and Diamonde results in an IgG-mediated response to fetal erythrocytes Blackfan anemia. Fanconi’s anemia is an autosomal that, in the presence of large quantities of maternal recessive condition that results in progressive bone marrow antibodies, can result in significant fetal hemolysis. The failure.18 Progenitor cells in the bone marrow are hypersen- hemolysis produced by Rh sensitization can affect the fetus sitive to certain glycoproteins, such as interferon-g, or the newborn. In the immediate newborn period, ongoing resulting in premature apoptosis and eventual hematopoi- hemolysis can result in significant anemia and hyperbilir- etic failure.1 It often presents as macrocytic anemia with ubinemia because, in the absence of the maternal liver, the reticulocytopenia and eventual pancytopenia.20 newborn has a difficult time conjugating large quantities of 25 DiamondeBlackfan anemia is a congenital disorder of bilirubin. bone marrow suppression that also results in macrocytic 21 anemia with reticulocytopenia. DiamondeBlackfan ane- ABO incompatibility mia is caused by failure of erythropoiesis alone. The exact ABO incompatibility tends to be more common and less etiology is unknown but is believed to be the result of severe than Rh incompatibility.26 It is a condition that a defect in stem-cell differentiation into the erythroid primarily affects type A or type B newborns born to type 1 cell line. Many infants with DiamondeBlackfan anemia O mothers. Hemolysis tends to be minimal, probably due also have associated congenital anomalies such as micro- to a paucity of A and B antigenic binding sites on the fetal cephaly, cleft palate, web neck, and anomalies of the RBC.27 The maternal anti-A and anti-B immunoglobulin that 22 thumbs (i.e. triphalangeal, bifid, and duplicated thumbs). is produced is IgM, which does not cross the placenta; the direct antiglobulin test determined in the neonate is often Acquired disorders of erythrocyte production negative or weakly positive.27 It usually results in mild Various infections and nutritional deficiencies can result in anemia and hyperbilirubinemia and rarely needs aggressive acquired disorders of erythrocyte production. Congenital treatment. Neonatal anemia 243
Erythrocyte membrane defects Hemoglobin defects of the erythrocyte Defects in the red cell membrane and cytoskeleton can These are uncommon causes of anemia in neonates. The cause abnormalities in the shape of the RBCs, resulting in erythrocytes of the newborn infant contain approximately their removal from the peripheral circulation.28 Hereditary 60e80% HbF (a2g2), 15e40% HbA (a2b2), and <1% Hb Bart’s spherocytosis and elliptocytosis are the more common (g4).31 Defects or deficiencies in production of globin chains disorders. (e.g. thalassemias), particularly of a and g types, can there- fore result in the formation of unstable hemoglobin with Hereditary spherocytosis a higher affinity for oxygen and a propensity toward hemoly- Hereditary spherocytosis is predominantly a disorder of sis.33 In the newborn period, a globin defect tends to be the autosomal dominant inheritance caused by a defect in the most common and most severe, because g chain defects are attachment of spectrin to the red cell membrane. The exceedingly rare and b chain production does not usually result is a spherocytic, fragile, nondeformable erythrocyte peak until about 3 months of life.34 prone to lysis and targeted for removal.29 The diagnosis of Deletions of one or more of these genes can result in hereditary spherocytosis should be considered in the alterations in the hemoglobin composition of the newborn. setting of hyperbilirubinemia with evidence of nonim- Significant hemolytic anemia, however, is usually seen only in mune-mediated hemolysis and the presence of spherocytes association with deletion of three (HbH disease) or four on peripheral blood smear.29 It can be difficult to differen- (homozygous a-thalassemias) of these regulatory genes.31 tiate between ABO incompatibility. A family history of The result is a predominance of unstable HbH (b4) and Bart’s, spherocytosis is often positive in these cases. which can cause a significant microcytic, hemolytic anemia and, in homozygous conditions, can present as hydrops fetalis. Hereditary elliptocytosis Hereditary elliptocytosis is a condition of autosomal Iron supplementation dominant inheritance that is caused by defects in various structural proteins, resulting in the erythrocyte taking on Preterm infants exhibit a wide range of iron status at an elliptical shape. The elliptocytes are unstable and discharge, depending on their degree of prematurity, nondeformable, and thus hemolyzed by the reticuloendo- amount of transfusion, phlebotomy losses, number of RBC thelial system.1 Diagnosis in these instances is often transfusions, bouts of infection, and timing of iron supple- facilitated by the presence of elliptocytes on peripheral mentation. Limiting phlebotomy losses and starting iron blood smear, in addition to a family history of the disorder. therapy at 2 weeks (as opposed to 2 months) of postnatal age might be an effective preventive strategy against 35,36 Erythrocyte enzyme deficiencies subsequent iron deficiency. Defects in enzymatic production and alterations in meta- The American Academy of Pediatrics recommends that e 37 bolic pathways can result in significant damage to the preterm infants receive 2 4 mg elemental iron/kg per day; erythrocyte, and in premature cell death. In the newborn infants receiving EPO therapy should receive at least 6 mg/kg period, deficiencies of the enzymes glucose-6-phosphate per day. After discharge, preterm infants continue to have dehydrogenase (G6PD) and pyruvate kinase can result in increased iron needs because of rapid growth rate during a significant hemolytic anemia. the first postnatal year. There is a high rate of iron deficiency in preterm infants fed low-iron formula or breast milk. Recent data suggest that preterm infants with low serum ferritin Glucose-6-phosphate dehydrogenase deficiency concentrations might require additional iron supplementa- G6PD is active in the pentose phosphate pathway of the tion. It might be prudent to supplement formula-fed preterm erythrocyte, which results in production of nicotinami- infants with iron at a dose of 1 mg/kg per day.37 deeadenine dinucleotide phosphate (NADPH). NADPH, in turn, is responsible for detoxification of free radicals and hydrogen peroxide within the RBC.30 Defects in G6PD can Issues in transfusion result in accumulation of damaging agents, which can induce cell degradation and membrane injury, leading 31 The goal of transfusion in infants with anemia of pre- to hemolysis. It is an X-linked recessive disorder and maturity is to ‘restore or maintain oxygen delivery without presents as Heinz bodies (deposits of intracellular, increasing oxygen consumption’.38 Transfusion practices degraded hemoglobin) on peripheral smear. Newborns vary markedly across units and there is a lack of evi- with infection and evidence of hemolytic anemia should dence-based studies to guide practice.39 None of the therefore be evaluated for the presence of this enzyme e 31 clinical signs has been consistently useful either alone deficiency. or as a group e in determining when to transfuse an infant with low hemoglobin of (physiologic) anemia of prematurity Pyruvate kinase deficiency and iatrogenic losses. The decision to transfuse is based on Pyruvate kinase is an enzyme in the erythrocyte that is low hematocrit and clinical manifestations, unless hemato- responsible for the generation of adenosine triphosphate crit is very low (<20%) or another critical value is in opera- (ATP). A deficiency in pyruvate kinase therefore results in tion.40 For example, if an infant is in room air, without any decreased cellular energy production and premature cell signs of cardiac failure from the low hemoglobin, some death. This autosomal recessive disorder can result in clinicians prefer to wait and see if the infant will begin significant hemolysis and hyperbilirubinemia in the new- producing reticulocytes on their own. Others struggle daily born period, which might require exchange transfusion.32 over management, whether to transfuse a 6-week-old 244 S. Aher et al. preterm infant who is growing slowly, gaining some days Donor exposure can be reduced for infants who need small- and losing others, and having occasional apnea that could volume transfusions (<15e20 ml/kg) by using stored packed be from anemia, from gastroesophageal reflux, or from red blood cells (PRBCs) from a single unit (Table 1). This unit other reasons than just a low hematocrit. is divided into multiple aliquots that are reserved for In recent years, most institutes have implemented more a specific infant. This procedure has reduced donor exposure restrictive transfusion guidelines to reduce the number of to one or two donors for most infants. transfusions and donor exposures. Use of these restrictive Another issue is use of blood from related versus guidelines has reduced both the number of transfusions and unrelated individuals. Some units have developed protocols donor exposures by 70e80% in the last decade, without an for use of directed-donor donations when compatible. Data increase in length of stay or morbidity.41,42 These guidelines are not currently available to confirm whether these use specific hematocrit levels, clinical status, and e programs increase safety; there are also potential risks. sometimes e infant’s age to determine when to transfuse. In many cases, the hematocrit levels are lower than those used previously. In the Premature Infants in Need of Transfu- Preventive strategies sion (PINT) study, Kirplani et al.43 demonstrated that trans- fusion threshold in ELBW infants can be moved downwards Prevention of late nutritional anemia by at least 1 g/dL without incurring a clinically important increase in the risk of death or major neonatal morbidity. Both term and preterm infants should be discharged from the Another consideration is whether the infant has been hospital on supplemental iron, either as iron-fortified formu- transfused before and, if so, whether the same donor blood las or as an oral supplement of 2e3 mg/kg per day elemental is still available. A steady growth pattern and the ability to iron for breastfed infants. Enteral iron supplementation is wean out of significant amounts of oxygen are commonly feasible and probably safe in infants with birth weight cited reasons for not transfusing. Some clinicians transfuse <1301 g.44 Iron supplementation can reduce the incidence if a baby is being discharged home to a higher altitude than of iron deficiency and the number of late blood transfusions. where they have been hospitalized, especially if they are Iron deficiency can occur in very low birthweight infants going home on oxygen. despite early supplementation with iron and should be considered in the case of progressive anemia. Because of their limited body supplies of water-soluble vitamins and Donor issues their higher protein requirements, it is also prudent to supplement breastfed preterm infants at discharge with A concern for infants who might need multiple transfusions is a multivitamin supplement containing vitamin B12 and exposure to multiple donors. The use of multiple donors folate. It is important to monitor premature babies, espe- increases the risk of infection and transfusion reactions. cially after discharge, to diagnose late anemia in neonates.
Table 1 Transfusion guidelines41 Hemoglobin Mechanical ventilation or symptoms of anemia PRBC volume (g/dL) 11 or less Moderate or significant mechanical ventilation requirement 15 mL/kg PRBCs over 2e4h
(MAP > 8cmH2O and FiO2 > 0.4) 10 or less Minimal mechanical ventilation requirement 15 mL/kg PRBCs over 2e4h
(any mechanical ventilation or CPAP > 6cmH2O and FiO2 > 0.4) 8 or less No mechanical ventilation requirement and one or 20 mL/kg PRBCs over 2e4h more of the following present: (divide into two 10-mL/kg 24 or more hours of tachycardia (HR > 180) or volumes if fluid sensitive) tachypnea (RR > 80) an increased oxygen requirement from the previous 48 h an elevated lactate concentration (2.5 mEq/L or more) weight gain < 10 g/kg over previous 4 days while receiving 100 kcal/kg per day or more an increase in episodes of apnea and bradycardia (10 or more episodes in a 24-h period or 2 or more episodes in 24 h requiring bag-mask ventilation) while receiving therapeutic doses of methylxanthines undergoing some surgery Less than 7 No symptoms and an absolute reticulocyte count 15 mL/kg PRBCs over 2e4h < 100,000 cells/mL (RBC % reticulocyte count) CPAP, constant positive airway pressure; HR, heart rate; MAP indicates mean airway pressure; PRBC, packed red blood cell; RBC, red blood cells; RR, respiratory rate. Neonatal anemia 245
Role of delayed cord clamping might be responsible. Less specifically, a history of relatives with anemia, jaundice, or splenectomy can also aid in Clamping and cutting the umbilical cord at birth is by far the directing further diagnostic evaluation. Finally, the history oldest and the most prevalent intervention in humans. of the newborn itself is essential for diagnosis. In particular, Despite this, the optimal timing of cord clamping has been the gestational age and day of life at the time of a controversial issue for decades. In a meta-analysis of presentation, the ethnicity/race (e.g. G6PD, thalassemias), controlled trials, Hutton and Hassan45 concluded that delay- and sex (e.g. G6PD) of the infant are all useful not only in ing clamping of the umbilical cord in full-term neonates for determining a diagnosis of anemia but also in establishing a minimal of 2 min after birth is beneficial to the newborn, etiology. The diagnosis and etiology of neonatal anemia can extending into infancy. Although there was an increase in often be determined with a thorough history; however, in polycythemia among infants in whom cord clamping was certain situations, further diagnostic work-up might be delayed, this condition appears to be benign. In preterm required. infants, delayed clamping appears to reduce the risk of intra- ventricular hemorrhage and the need for neonatal transfu- Physical examination sions.46 Although a tailored approach is required in the case of cord clamping, the balance of available data suggest that delayed cord clamping should be the method of choice. Physical examination of the anemic newborn can provide a helpful insight into the cause of the condition. Certain alterations from baseline normal values can be seen in the A diagnostic approach to the event of acute blood loss. In this case, the neonate might newborn with anemia present with evidence of intravascular volume loss repre- sented by tachycardia and hypotension; however, these e The establishment of an accurate diagnosis is essential to symptoms might not appear until approximately 15 20% of 47 directing the appropriate therapeutic interventions. Thor- the total blood volume is lost. If the blood loss is chronic, ough history taking and physical examination are the primary the neonate might present with no changes in vital signs, 48 steps in identifying the condition and establishing an etiology, despite significant intravascular depletion. As a result, but further investigations in the form of laboratory testing are in addition to determination of vital signs, other areas of often required to differentiate the many possible causes. the examination might be helpful. Examination of the skin is often useful, particularly if pallor or jaundice is present. Pallor can be seen with significant anemia of any etiology, History and jaundice in the presence of anemia is often the result of a hemolytic process. Hemolysis can also result in hepa- Several pertinent pieces of historical information can be tosplenomegaly as the reticuloendothelial system and the helpful in establishing a diagnosis in a suspected case of extramedullary hematopoietic system become hyperactive neonatal anemia. Information should be gathered from and, subsequently, enlarged and palpable. aspects of the maternal medical history, the pregnancy and delivery, and the newborn period. A focused maternal Laboratory investigations history should highlight any medical conditions (e.g. bleeding disorders, erythrocyte membrane or enzymatic Numerous laboratory investigations can aid in determining disorders) that predated the pregnancy, or that might have the underlying cause of neonatal anemia; however, it is arisen during or have been exacerbated by the pregnancy. In often difficult to decide which tests to obtain and how to addition, special attention to the antepartum period should interpret the results. It is therefore beneficial to proceed also be made, with regard to medication use, acquired or with investigation in a stepwise manner to avoid unneces- recurrent infections, history of trauma or vaginal bleeding, sary testing that will delay and confuse proper diagnosis. or any abnormal diagnostic findings acquired via serum The first step in laboratory investigation should be to studies, amniocentesis, or ultrasound. The maternal blood establish a diagnosis of anemia. This involves the proper type, complete blood count, and results of antibody interpretation of many of the routine laboratory values, screenings are aspects of the normal screening process in which encompass the complete blood count. pregnant women that can be extremely helpful in establish- Reticulocytes are immature RBCs that are usually reported ing the cause of anemia in the newborn. The peripartum as a percentage of the total RBC count.49 Normal reticulocyte period can also yield pertinent diagnostic information. and absolute reticulocyte counts in the term infant are 5% and Specifically, method of delivery (with or without instrumen- 250,000/mm3,respectively.49 During the first 2 weeks of life, tation), history of maternal hemorrhage (e.g. vaginal, the reticulocyte count drops to a value of approximately placental), evidence of fetal distress, or the presence of 0.0e1.0% by day 14 of life.50 In the presence of anemia, how- multiple gestations can all be beneficial pieces of informa- ever, the bone marrow often attempts compensation through tion. Further information regarding the pathology of the increased erythropoietic activity, reflected in an elevated placenta and the umbilical cord and its insertion is also reticulocyte count. If bone marrow production is compro- useful. Family history should also be ascertained when mised, however, the reticulocyte count will remain low. investigating causality of anemia in the newborn, because If a diagnosis of bone marrow suppression or dysfunction certain conditions of autosomal recessive (e.g. Fanconi’s is suspected as a result of this finding, further work-up anemia), autosomal dominant (e.g. hereditary spherocytosis should focus on the specific etiologies associated with and elliptocytosis), and X-linked inheritance (e.g. G6PD) decreased bone-marrow activity (i.e. parvovirus B19 titers, 246 S. Aher et al. specific vitamin or element levels, or bone-marrow biopsy) to direct further therapy. If, however, the reticulocyte Research agenda count is normal or elevated, laboratory investigation should proceed accordingly. Prospective studies to evaluate appropriate crite- In the anemic patient with a normal of elevated ria for transfusion in extremely preterm infants reticulocyte count, the diagnostic focus should turn toward are required. the hemolytic anemias. One useful laboratory investigation Further research is required in deciding the opti- for determining anemia as the result of an immune- mal dose, timing and gestational age for iron sup- mediated process is the direct antiglobulin test. After plementation in preterm infants. determining the maternal and neonatal blood types, a direct antiglobulin, or Coombs, test should be performed on the newborn. This detects the presence of antibodies bound to the surface of RBCs. If positive in the neonate, an References immune-mediated hemolysis (ABO, Rh, or a minor blood group incompatibility) is likely to be the cause of the 1. Luchtman-Jones L, Schwartz AL, Wilson DB. The blood and anemia. If negative, further investigation can be under- hematopoietic system. In: Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine. Disorders of fetus and infant. taken. The mean corpuscular volume (MCV) measures the 7th ed. St. Louis, MO: Mosby; 2002. p. 1182e254. size of RBCs, which changes significantly during the 2. Mentzer WC, Glader BE. Erythrocyte disorders in infancy. In: newborn period. Like the hemoglobin/hematocrit concen- Taeusch HW, Ballard RA, Gleason CA, editors. Avery’s diseases trations, the MCV varies with chronologic age. Under rare of the newborn. Elsevier Saunders; 2005. p. 1180e214. circumstances, a low MCV might be seen in the context of 3. Stockman III JA, Graeber JE, Clark DA, et al. Anemia of prema- anemia. In this case, the diagnoses of a-thalassemia and turity: determinants of the erythropoietin response. J Pediatr chronic intrauterine blood loss should be investigated.51 1984;105:786e92. The a-thalassemias are frequently seen in South-east Asian 4. 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