Blood Disorders

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Chapter 97 Blood Disorders

97.1 Anemia in the Newborn Infant

Akhil Maheshwari, Waldemar A. Carlo

Hemoglobin increases with advancing gestational age: at term, cord blood hemoglobin is 16.8 g/dL (14-20 g/dL); hemoglobin levels in very low birthweight (VLBW) infants are 1-2 g/dL below those in term infants (Fig. 97-1). A hemoglobin value less than the normal range of hemoglobin for birthweight and postnatal age is defined as anemia (Table 97-1). A “physiologic” decrease in hemoglobin content is noticed at 8-12 wk in term infants (hemoglobin, 11 g/dL) and at about 6 wk in premature infants (7-10 g/dL).

Figure 97-1 Range (mean and 95% confidence limits) of hemoglobin concentration from 10 to 40 wk of gestational age in normal (zone I) fetuses obtained by cordocentesis (percutaneous umbilical blood sample). Solid circles depict maternal red blood cell isoimmunization; open circles indicate hemoglobin levels in fetuses with ultrasonographic evidence of hydrops (zone III).

(From Soothill PW: Cordocentesis: role in assessment of fetal condition, Clin Perinatol 16:755–770, 1989.)

Table 97-1 NORMAL RED BLOOD CELL VALUES FROM 18 WEEKS OF GESTATION TO 14 WEEKS OF LIFE

Infants born by cesarean section may have a lower hematocrit (Hct) than those born vaginally. Anemia at birth is manifested as pallor, heart failure, or shock (Fig. 97-2). It may be due to acute or chronic fetal blood loss, hemolysis, or underproduction of erythrocytes. Specific causes include hemolytic disease of the newborn, tearing or cutting of the umbilical cord during delivery, abnormal cord insertion, communicating placental vessels, placenta previa or abruptio, nuchal cord, incision into the placenta, internal hemorrhage (liver, spleen, intracranial), α-thalassemia, congenital parvovirus infection or other hypoplastic anemias, and twin-twin transfusion in monozygotic twins with arteriovenous placental connections (Chapter 92).

Figure 97-2 Diagnostic approach to anemia in newborn infants. DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; MCV, mean corpuscular volume.

(Modified from Blanchette VS, Zipursky A: Assessment of anemia in newborn infants, Clin Perinatol 11:489–510, 1984.)

Transplacental hemorrhage with bleeding from the fetal into the maternal circulation has been reported in 5-15% of pregnancies, but, unless severe, it is not usually sufficient to cause clinically apparent anemia at birth. The cause of transplacental hemorrhage is not clear, but its occurrence has been proven by demonstration of significant amounts of fetal hemoglobin and red blood cells (RBCs) in maternal blood on the day of delivery by the Kleihauer-Betke test or by flow cytometry methods to detect fetal cells in maternal blood. If the infant has severe anemia with heart failure, emergency exchange transfusion to restore Hct and oxygen-carrying capacity may be needed.

Acute blood loss usually results in severe distress at birth, initially with a normal hemoglobin level, no hepatosplenomegaly, and early onset of shock. In contrast, chronic blood loss in utero produces marked pallor, less distress, a low hemoglobin level with microcytic indices, and, if severe, heart failure.

Anemia appearing in the first few days after birth is also most frequently a result of hemolytic disease of the newborn. Other causes are hemorrhagic disease of the newborn, bleeding from an improperly tied or clamped umbilical cord, large cephalohematoma, intracranial hemorrhage, and subcapsular bleeding from rupture of the liver, spleen, adrenals, or kidneys. Rapid decreases in hemoglobin or Hct values during the first few days of life may be the initial clue to these conditions.

Later in the neonatal period, delayed anemia may develop as a result of hemolytic disease of the newborn, with or without exchange transfusion or phototherapy. Congenital hemolytic anemia (spherocytosis) occasionally appears during the 1st mo of life, and hereditary nonspherocytic hemolytic anemia has been described during the neonatal period secondary to deficiency of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase. Bleeding from hemangiomas of the upper gastrointestinal tract or from ulcers caused by aberrant gastric mucosa in a Meckel diverticulum or duplication is a rare source of anemia in newborns. Repeated blood sampling of infants requiring frequent monitoring of blood gas and chemistry parameters is a common cause of anemia among hospitalized infants. Deficiency of minerals such as copper may cause anemia in infants maintained on total parenteral nutrition.

Anemia of prematurity occurs in LBW infants 1-3 mo after birth, is associated with hemoglobin levels <7-10 g/dL, and is clinically manifested as pallor, poor weight gain, decreased activity, tachypnea, tachycardia, and feeding problems. Repeated phlebotomy for blood tests, shortened RBC survival, rapid growth, and the physiologic effects of the transition from fetal (low PaO₂ and hemoglobin saturation) to neonatal life (high PaO₂ and hemoglobin saturation) contribute to anemia of prematurity. The oxygen available to neonatal tissue is lower than that in adults, but a neonate’s erythropoietin response is attenuated for the degree of anemia, and as a result, hemoglobin and reticulocyte levels are low. In VLBW infants, delayed clamping of the umbilical cord with the infant held below the level of the placenta may enhance placental-infant transfusion and reduce postnatal transfusion needs. This maneuver should not delay any needed resuscitation and may lead to hyperviscosity.

Delayed cord clamping (≈1-2 min or after cessation of cord pulsation) may be beneficial in otherwise well newborns in preventing anemia in full-term infants, with effects extending beyond the neonatal period. The benefits of delayed cord clamping persist for 2-6 mo as improved hematocrit, iron status as measured by ferritin concentration and stored iron, and a clinically important reduction in the risk of anemia in infancy. Late clamping may result in delivery of an extra 20-40 mL of blood and 30-35 mg of iron to the newborn. Polycythemia is a risk with delayed clamping but is often asymptomatic.

Treatment of neonatal anemia by blood transfusion depends on the severity of symptoms, the hemoglobin level, and the presence of co-morbid diseases (bronchopulmonary dysplasia, cyanotic congenital heart disease, respiratory distress syndrome) that interfere with oxygen delivery. The need for treatment with blood should be balanced against the risks of transfusion, including hemolytic transfusion reactions, exposure to blood product preservatives and other potential toxins, volume overload, possible increased risk of retinopathy of prematurity and necrotizing enterocolitis, graft-versus-host (GVH) reaction, and transfusion-acquired infection (cytomegalovirus [CMV], HIV, parvovirus, hepatitis B and C) (Chapter 468). The risk of CMV infection can be almost eliminated by the use of leukoreduced blood. In the infant <1,500 g, CMV antibody-negative leukoreduced blood should be used. The risk of acquiring HIV and hepatitis B and C viruses is reduced but not eliminated by antibody screening of donated blood. Blood banking techniques that limit multiple donor exposure should be encouraged.

Although transfusion guidelines for preterm infants have been proposed (Table 97-2), they have not been subjected to rigorous clinical study. Nonetheless, these guidelines have led to a decline in the number of unnecessary transfusions. The use of restrictive vs more liberal transfusion guidelines has been examined in two randomized trials, one conducted at University of Iowa and a second multicentric trial known as the PINT (Premature Infants in Need of Transfusion) study. The restrictive guidelines in the two groups were generally similar. In the Iowa trial, the transfusion thresholds in the liberal- and restrictive-transfusion groups were <46% and <34%, respectively, in tracheally intubated infants receiving assisted ventilation; <38% and <28%, respectively, in infants receiving nasal continuous positive airway pressure or supplemental oxygen; and <30% and <22%, respectively, in infants breathing room air. The transfusion thresholds for the liberal groups were higher in the Iowa trial than in the PINT study. In both trials, the use of restrictive thresholds resulted in fewer transfusions and also increased the number of infants who received no transfusions at all. However, in the Iowa trial (but not in the PINT study), restrictive transfusion thresholds were associated with increases in major cranial ultrasonographic abnormalities and in the frequency of apneic spells. Although these findings need further evaluation in clinical studies, the issue of finding an appropriate transfusion threshold in premature infants remains unresolved.

Table 97-2 TRANSFUSION PROTOCOL

Asymptomatic full-term infants with a hemoglobin level of 10 g/dL may be monitored, whereas symptomatic neonates born after abruptio placentae or with severe hemolytic disease of the newborn need immediate transfusion. Preterm infants who have repeated episodes of apnea and bradycardia despite theophylline therapy and a hemoglobin level ≤8 g/dL may benefit from RBC transfusion. In addition, infants with respiratory distress syndrome or severe bronchopulmonary dysplasia may need hemoglobin levels of 12-14 g/dL to improve oxygen delivery. No transfusion is needed to replace blood removed for testing or for mild asymptomatic anemia. Asymptomatic neonates with reticulocytopenia and hemoglobin levels ≤7 g/dL may require transfusion; if a transfusion is not provided, close observation is essential. Packed RBC transfusion (10-20 mL/kg) is given at a rate of 2-3 mL/kg/hr to raise the hemoglobin concentration; 2 mL/kg raises the hemoglobin level 0.5-1 g/dL. Hemorrhage should be treated with whole blood if available; alternatively, fluid resuscitation is initiated, followed by packed RBC transfusion.

Recombinant human erythropoietin (r-HuEPO) may be considered in the treatment of chronic or anticipated anemia in an attempt to decrease or eliminate transfusions when families, for religious reasons, request all possible measures to avoid transfusions. Therapy with r-HuEPO must be supplemented with oral iron. Doses and regimens vary. In anemia of prematurity, r-HuEPO does not provide a major reduction in transfusion requirements or the number of donors; therefore, routine use of erythropoietin in VLBW infants is not recommended. Early initiation of r-HuEPO therapy may produce a small reduction in the total transfusion volume per infant. There were concerns about an increased risk of severe retinopathy of prematurity in the r-HuEPO group. The effects of late initiation of r-HuEPO (≥8 days) have also been associated with small reductions in the total blood volume transfused per infant and the number of transfusions per infant.

Bibliography

Aher S, Ohlsson A: Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants, Cochrane Database Syst Rev (3):CD004868, 2006.

Anderson C. Critical haemoglobin thresholds in premature infants. Arch Dis Child Fetal Neonatal Ed. 2001;84:F146-F148.

Bell EF, Strauss RG, Widness JA, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115:1685-1691.

Bizzarro MJ, Colson E, Ehrenkranz RA. Differential diagnosis and management of anemia in the newborn. Pediatr Clin North Am. 2004;51:1087-1107.

Christensen RD, Henry E. Hereditary spherocytosis on neonates with hyperbilirubinemia. Pediatrics. 2010;125:120-125.

Ferguson D, Hébert PC, Lee SK, et al. Clinical outcomes following institution of universal leukoreduction of blood transfusions for premature infants. JAMA. 2003;289:1950-1956.

Hébert PC, Fergusson D, Blajchman MA, et al. Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. JAMA. 2003;289:1941-1949.

Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates. JAMA. 2007;297:1241-1252.

Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149:301-307.

Nicaise C, Gire C, Casha P, et al. Erythropoietin as treatment for late hyporegenerative anemia in neonates with Rh hemolytic disease after in utero exchange transfusion. Fetal Diagn Ther. 2002;17:22-24.

Ohlsson A, Aher SM: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants, Cochrane Database Syst Rev (3):CD004863, 2006.

Rabe H, Reynolds G, Diaz-Rossello J: Early versus delayed umbilical cord clamping in preterm infants, Cochrane Database Syst Rev (4):CD003248, 2004.

97.2 Hemolytic Disease of the Newborn (Erythroblastosis Fetalis)

Akhil Maheshwari, Waldemar A. Carlo

Erythroblastosis fetalis is caused by the transplacental passage of maternal antibody active against paternal RBC antigens of the infant and is characterized by an increased rate of RBC destruction. It is an important cause of anemia and jaundice in newborn infants despite the development of a method of preventing maternal isoimmunization by Rh antigens. Although more than 60 different RBC antigens are capable of eliciting an antibody response, significant disease is associated primarily with the D antigen of the Rh group and with incompatibility of ABO factors. Rarely, hemolytic disease may be caused by C or E antigens or by other RBC antigens, such as C^W, C^X, D^U, K (Kell), M, Duffy, S, P, MNS, Xg, Lutheran, Diego, and Kidd. Anti-Lewis antibodies do not cause disease.

Hemolytic Disease of the Newborn Caused by Rh Incompatibility

The Rh antigenic determinants are genetically transmitted from each parent, determine the Rh type, and direct the production of a number of blood group factors (C, c, D, d, E, and e). Each factor can elicit a specific antibody response under suitable conditions; 90% are due to D antigen and the remainder to C or E antigens.

Pathogenesis

Isoimmune hemolytic disease from D antigen is approximately three times more frequent among white persons than among black persons. When Rh-positive blood is infused into an Rh-negative woman through error or when small quantities (usually > 1 mL) of Rh-positive fetal blood containing D antigen inherited from an Rh-positive father enter the maternal circulation during pregnancy, with spontaneous or induced abortion, or at delivery, antibody formation against D antigen may be induced in the unsensitized Rh-negative recipient mother. Once sensitization has taken place, considerably smaller doses of antigen can stimulate an increase in antibody titer. Initially, a rise in immunoglobulin (Ig) M antibody occurs, which is later replaced by IgG antibody; the latter readily crosses the placenta to cause hemolytic manifestations.

Hemolytic disease rarely occurs during a first pregnancy because transfusion of Rh-positive fetal blood into an Rh-negative mother occurs near the time of delivery, too late for the mother to become sensitized and transmit antibody to her infant before delivery. The facts that 55% of Rh-positive fathers are heterozygous (D/d) and may have Rh-negative offspring and that fetal-to-maternal transfusion occurs in only 50% of pregnancies reduce the chance of sensitization, as does small family size, in which the opportunities for its reoccurrence are reduced. The disparity between the numbers of incompatible vs alloimmunized maternal-fetal pairs can also be due to a threshold effect of fetomaternal transfusions (a certain amount of the immunizing blood cell antigen is required to activate the maternal immune system), the type of antibody response (IgG antibodies are more efficiently transferred across the placenta to the fetus), differential immunogenicity of blood group antigens, and differences in maternal immune response, presumably related to differences in the efficiency of antigen presentation by various major histocompatibility loci. Thus, the overall incidence of isoimmunization of Rh-negative mothers at risk is low, with antibody to antigen D detected in >10% of those studied, even after five or more pregnancies; only about 5% ever have babies with hemolytic disease.

When the mother and fetus are also incompatible with respect to group A or B, the mother is partially protected against sensitization by the rapid removal of Rh-positive cells from her circulation by her preexisting anti-A or anti-B antibodies, which are IgM antibodies and do not cross the placenta. Once a mother has been sensitized, her infant is likely to have hemolytic disease. The severity of Rh illness worsens with successive pregnancies. The possibility that the first affected infant after sensitization may represent the end of the mother’s childbearing potential for Rh-positive infants argues urgently for the prevention of sensitization. The injection of anti-D gamma globulin (RhoGAM) into the mother immediately after the delivery of each Rh-positive infant has been a successful strategy to reduce Rh hemolytic disease (see later).

Clinical Manifestations

A wide spectrum of hemolytic disease occurs in affected infants born to sensitized mothers, depending on the nature of the individual immune response. The severity of the disease may range from only laboratory evidence of mild hemolysis (15% of cases) to severe anemia with compensatory hyperplasia of erythropoietic tissue leading to massive enlargement of the liver and spleen. When the compensatory capacity of the hematopoietic system is exceeded, profound anemia occurs and results in pallor, signs of cardiac decompensation (cardiomegaly, respiratory distress), massive anasarca, and circulatory collapse. This clinical picture of excessive abnormal fluid in two or more fetal compartments (skin, pleura, pericardium, placenta, peritoneum, amniotic fluid), termed hydrops fetalis, frequently results in death in utero or shortly after birth. With the use of anti-D gamma globulin to prevent Rh sensitization, nonimmune (nonhemolytic) conditions have become frequent causes of hydrops (Table 97-3). The severity of hydrops is related to the level of anemia and the degree of reduction in serum albumin (oncotic pressure), which is due in part to hepatic dysfunction. Alternatively, heart failure may increase right heart pressure, with the subsequent development of edema and ascites. Failure to initiate spontaneous effective ventilation because of pulmonary edema or bilateral pleural effusions results in birth asphyxia; after successful resuscitation, severe respiratory distress may develop. Petechiae, purpura, and thrombocytopenia may also be present in severe cases as a result of decreased platelet production or the presence of concurrent disseminated intravascular coagulation.

Table 97-3 ETIOLOGY OF HYDROPS FETALIS *

CATEGORY	DISORDER(S)
Anemia	Immune (Rh, Kell) hemolysis
	α-Thalassemia
	Red blood cell enzyme deficiencies (glucose-6-phosphate dehydrogenase)
	Fetomaternal hemorrhage
	Donor in twin-to-twin transfusion
	Diamond-Blackfan syndrome
Cardiac dysrhythmias	Supraventricular tachycardia
	Atrial flutter
	Congenital heart block
Structural heart lesions	Premature closure of foramen ovale
	Tricuspid insufficiency
	Hypoplastic left heart
	Endocardial cushion defect
	Cardiomyopathy
	Endocardial fibroelastosis
	Tuberous sclerosis with cardiac rhabdomyoma
	Pericardial teratoma
Vascular	Chorioangioma of placenta, chorionic vessels, or umbilical vessels
	Umbilical artery aneurysm
	Angiomyxoma of umbilical cord
	True knot of umbilical cord
	Hepatic hemangioma
	Cerebral arteriovenous malformation (aneurysm of vein of Galen)
	Angiosteohypertrophy (Klippel-Trénaunay syndrome)
	Thrombosis of renal or umbilical vein or inferior vena cava
	Recipient in twin-to-twin transfusion
Lymphatic	Lymphangiectasia
	Cystic hygroma
	Chylothorax, chylous ascites
	Noonan syndrome
	Multiple pterygium syndrome
Central nervous system	Absent corpus callosum
	Encephalocele
	Intracranial hemorrhage
	Holoprosencephaly
Thoracic lesions	Cystic adenomatoid malformation of lung
	Mediastinal teratoma
	Diaphragmatic hernia
	Sequestered lung
Teratomas	Choriocarcinoma
Teratomas	Sacrococcygeal teratoma
Tumors and storage diseases	Neuroblastoma
	Hepatoblastoma
	Gaucher disease
	Niemann-Pick disease
	Mucolipidosis
	GM₁ gangliosidosis
	Mucopolysaccharidosis
Chromosome abnormalities	Trisomy 13, 15, 16, 18, 21
	XX/XY, 45XO
	Partial duplication of chromosome 11, 15, 17, 18
	Partial deletion of chromosome 13, 18
	Triploidy
	Tetraploidy
Bone diseases	Osteogenesis imperfecta
	Asphyxiating thoracic dystrophy
	Skeletal dysplasias
Congenital infections	Cytomegalovirus
	Parvovirus
	Rubella
	Toxoplasmosis
	Syphilis
	Leptospirosis
	Chagas disease
Others	Bowel obstruction with perforation and meconium peritonitis, volvulus
	Hepatic fibrosis
	Beckwith-Wiedemann syndrome
	Prune-belly syndrome
	Congenital nephrosis
	Infant of a diabetic mother
	Myotonic dystrophy
	Neu-Laxova syndrome
	Maternal therapy with indomethacin
	Fetal akinesia
Idiopathic	Multiple congenital anomaly syndromes

* The incidence of nonimmune (nonhemolytic) hydrops fetalis is 1/2,000-1/3,500 births.

Modified from Phibbs R. In Polin N, Fox W, editors: Fetal and neonatal physiology, ed 2, Philadelphia, 1998, WB Saunders.

Jaundice may be absent at birth because of placental clearance of lipid-soluble unconjugated bilirubin, but in severe cases, bilirubin pigments stain the amniotic fluid, cord, and vernix caseosa yellow. Jaundice is generally evident on the 1st day of life because the infant’s bilirubin-conjugating and excretory systems are unable to cope with the load resulting from massive hemolysis. Indirect-reacting bilirubin therefore accumulates postnatally and may rapidly reach extremely high levels and present a significant risk of bilirubin encephalopathy. The risk of development of kernicterus from hemolytic disease is greater than from comparable nonhemolytic hyperbilirubinemia, although the risk in an individual patient may be affected by other complications (hypoxia, acidosis). Hypoglycemia occurs frequently in infants with severe isoimmune hemolytic disease and may be related to hyperinsulinism and hypertrophy of the pancreatic islet cells in these infants.

Infants born after intrauterine transfusion for prenatally diagnosed erythroblastosis may be severely affected because the indications for transfusion are evidence of already severe disease in utero (hydrops, fetal anemia). Such infants usually have very high (but extremely variable) cord levels of bilirubin, reflecting the severity of the hemolysis and its effects on hepatic function. Infants treated with intraumbilical vein transfusions in utero may also have a benign postnatal course if the anemia and hydrops resolve before birth. Anemia from continuing hemolysis may be masked by the previous intrauterine transfusion, and the clinical manifestations of erythroblastosis may be superimposed on various degrees of immaturity resulting from spontaneous or induced premature delivery.

Laboratory Data

Before treatment, the direct Coombs test result is usually positive and anemia is generally present. The cord blood hemoglobin content varies and is usually proportional to the severity of the disease; with hydrops fetalis it may be as low as 3-4 g/dL. Alternatively, despite hemolysis, it may be within the normal range because of compensatory bone marrow and extramedullary hematopoiesis. The blood smear typically shows polychromasia and a marked increase in nucleated RBCs. The reticulocyte count is increased. The white blood cell count is usually normal but may be elevated; thrombocytopenia may develop in severe cases. Cord bilirubin is generally between 3 and 5 mg/dL; the direct-reacting (conjugated) bilirubin content may also be elevated, especially if there was an intrauterine transfusion. Indirect-reacting bilirubin content rises rapidly to high levels in the 1st 6 hr of life.

After intrauterine transfusions, cord blood may show a normal hemoglobin concentration, negative direct Coombs test result, predominantly type O Rh-negative adult RBCs, and relatively normal smear findings.

Diagnosis

Definitive diagnosis of erythroblastosis fetalis requires demonstration of blood group incompatibility and corresponding antibody bound to the infant’s RBCs.

Antenatal Diagnosis

In Rh-negative women, a history of previous transfusions, abortion, or pregnancy should suggest the possibility of sensitization. Expectant parents’ blood types should be tested for potential incompatibility, and the maternal titer of IgG antibodies to D antigen should be assayed at 12-16, 28-32, and 36 wk of gestation. Fetal Rh status may be determined by isolating fetal cells or fetal DNA (plasma) from the maternal circulation. The presence of elevated antibody titers at the beginning of pregnancy, a rapid rise in titer, or a titer of 1:64 or greater suggests significant hemolytic disease, although the exact titer correlates poorly with the severity of disease. If a mother is found to have antibody against D antigen at a titer of 1:16 (15 IU/mL in Europe) or greater at any time during a subsequent pregnancy, the severity of fetal disease should be monitored by Doppler ultrasonography of the middle cerebral artery and then percutaneous umbilical blood sampling (PUBS) if indicated (Chapter 90). If the mother has a history of a previously affected infant or a stillbirth, an Rh-positive infant is usually equally or more severely affected than the previous infant, and the severity of disease in the fetus should be monitored.

Assessment of the fetus may require information obtained from ultrasonography and PUBS. Real-time ultrasonography is used to detect the progression of disease, with hydrops defined as skin or scalp edema, pleural or pericardial effusions, and ascites. Early ultrasonographic signs of hydrops include organomegaly (liver, spleen, heart), the double–bowel wall sign (bowel edema), and placental thickening. Progression to polyhydramnios, ascites, pleural or pericardial effusions, and skin or scalp edema may then follow. If pleural effusions precede ascites and hydrops by a significant time, causes other than fetal anemia should be suspected (see Table 97-4). Extramedullary hematopoiesis and, less so, hepatic congestion compress the intrahepatic vessels and produce venous stasis with portal hypertension, hepatocellular dysfunction, and decreased albumin synthesis.

Hydrops is present with a fetal hemoglobin level <5 g/dL, frequent with a level <7 g/dL, and variable with levels between 7 and 9 g/dL. Real-time ultrasonography predicts fetal well-being by means of the biophysical profile (see Table 90-2), whereas Doppler ultrasonography assesses fetal distress by demonstrating increased vascular resistance in fetal arteries (middle cerebral). In pregnancies with ultrasonographic evidence of hemolysis (hepatosplenomegaly), early or late hydrops, or fetal distress, further and more direct assessment of fetal hemolysis should be performed.

Amniocentesis was classically used to assess fetal hemolysis. Hemolysis of fetal RBCs produces hyperbilirubinemia before the onset of severe anemia. Bilirubin is cleared by the placenta, but a significant proportion enters the amniotic fluid and can be measured by spectrophotometry. Ultrasonographically guided transabdominal aspiration of amniotic fluid may be performed as early as 18-20 wk of gestation. Spectrophotometric scanning of amniotic fluid wavelengths demonstrates a positive optical density (OD) deviation of absorption for bilirubin from normal at 450 nm. Amniocentesis and cordocentesis are invasive procedures with risks to both the fetus and mother, including fetal death, bleeding, or bradycardia, worsening of alloimmunization, premature rupture of membranes, preterm labor, and chorioamnionitis. Noninvasive measurements to detect fetal anemia are desirable. In fetuses without hydrops, moderate to severe anemia can be detected noninvasively by demonstration of an increase in the peak velocity of systolic blood flow in the middle cerebral artery by Doppler ultrasonography.

PUBS is the standard approach to assessment of the fetus if Doppler and real-time ultrasonography findings suggest that the fetus has erythroblastosis fetalis. PUBS is performed to determine fetal hemoglobin levels and to transfuse packed RBCs in those with serious fetal anemia (Hct 25-30%).

Postnatal Diagnosis

Immediately after the birth of any infant to an Rh-negative woman, blood from the umbilical cord or from the infant should be examined for ABO blood group, Rh type, Hct and hemoglobin, and reaction to the direct Coombs test. If the Coombs test result is positive, a baseline serum bilirubin level should be measured, and a commercially available RBC panel should be used to identify RBC antibodies present in the mother’s serum, both tests being performed not only to establish the diagnosis but also to ensure selection of the most compatible blood for exchange transfusion should it be necessary. The direct Coombs test result is usually strongly positive in clinically affected infants and may remain so for a few days up to several months.

Treatment

The main goals of therapy are to (1) prevent intrauterine or extrauterine death from severe anemia and hypoxia, and (2) avoid neurotoxicity from hyperbilirubinemia.

Treatment of An Unborn Infant

Survival of severely affected fetuses has been improved by the use of fetal ultrasonography to identify the need for in utero transfusion. Intravascular (umbilical vein) transfusion of packed RBCs is the treatment of choice for fetal anemia, replacing intrauterine transfusion into the fetal peritoneal cavity. Hydrops or fetal anemia (Hct < 30%) is an indication for umbilical vein transfusion in infants with pulmonary immaturity (see Fig. 97-1). Intravascular fetal transfusion is facilitated by maternal and hence fetal sedation with diazepam and by fetal paralysis with pancuronium. Packed RBCs are given by slow-push infusion after being cross-matched against the mother’s serum. The cells should be obtained from a CMV-negative donor and irradiated to kill lymphocytes to avoid GVH disease. Of note, leukoreduction alone (without irradiation) does not prevent GVH disease. Transfusions should achieve a post-transfusion Hct of 45-55% and can be repeated every 3-5 wk. Indications for delivery include pulmonary maturity, fetal distress, complications of PUBS, and 35-37 wk of gestation. The survival rate for intrauterine transfusions is 89%; the complication rate is 3%. Complications include rupture of the membranes and preterm delivery, infection, fetal distress requiring emergency cesarean section, and perinatal death.

Treatment of A Liveborn Infant

The birth should be attended by a physician skilled in neonatal resuscitation. Fresh, low-titer, group O, leukoreduced, and irradiated Rh-negative blood cross-matched against maternal serum should be immediately available. If clinical signs of severe hemolytic anemia (pallor, hepatosplenomegaly, edema, petechiae, ascites) are evident at birth, immediate resuscitation and supportive therapy, temperature stabilization, and monitoring before proceeding with exchange transfusion may save some severely affected infants. Such therapy should include correction of acidosis with 1-2 mEq/kg of sodium bicarbonate; a small transfusion of compatible packed RBCs to correct anemia; volume expansion for hypotension, especially in those with hydrops; and provision of assisted ventilation for respiratory failure.

Exchange Transfusion

When an infant’s clinical condition at birth does not require an immediate full or partial exchange transfusion, the decision to perform one should be based on a judgment that the infant has a high risk of rapid development of a dangerous degree of anemia or hyperbilirubinemia. Cord hemoglobin value of 10 g/dL or less and bilirubin concentration of 5 mg/dL or more suggest severe hemolysis but inconsistently predict the need for exchange transfusion. Some physicians consider previous kernicterus or severe erythroblastosis in a sibling, reticulocyte counts >15%, and prematurity to be additional factors supporting a decision for early exchange transfusion (Chapters 96.3 and 96.4). Intrauterine, intravascular transfusions have decreased the need for exchange transfusion.

The hemoglobin concentration, Hct, and serum bilirubin level should be measured at 4-6 hr intervals initially, with extension to longer intervals if and as the rate of change diminishes. The decision to perform an exchange transfusion is based on the likelihood that the trend of bilirubin levels plotted against hours of age indicates that serum bilirubin will reach the levels indicated in Figure 96-12 and Table 96-7. Term infants with bilirubin levels ≥20 mg/dL have an increased risk of kernicterus. Ordinary transfusions of compatible Rh-negative, leukoreduced, and irradiated RBCs may be necessary to correct anemia at any stage of the disease up to 6-8 wk of age, when the infant’s own blood-forming mechanism may be expected to take over. Weekly determinations of hemoglobin or Hct values should be performed until a spontaneous rise has been demonstrated.

Careful monitoring of the serum bilirubin level is essential until a falling trend has been demonstrated in the absence of phototherapy (Chapter 96.3). Even then, an occasional infant, particularly if premature, may experience an unpredicted significant rise in serum bilirubin as late as the 7th day of life. Attempts to predict the attainment of dangerously high levels of serum bilirubin on the basis of observed levels exceeding 6 mg/dL in the 1st 6 hr or 10 mg/dL in the 2nd 6 hr of life or on rates of rise exceeding 0.5-1.0 mg/dL/hr can be unreliable. Measurement of unbound bilirubin may be a more sensitive predictor of the risk associated with hyperbilirubinemia.

Blood for exchange transfusion should be as fresh as possible. Heparin or citrate-phosphate-dextrose-adenine solution may be used as an anticoagulant. If the blood is obtained before delivery, it should be taken from a type O, Rh-negative donor with a low titer of anti-A and anti-B antibodies and should be determined compatible with the mother’s serum by the indirect Coombs test. After delivery, blood should be obtained from an Rh-negative donor whose cells are compatible with both the infant’s and the mother’s sera; when possible, type O donor cells are generally used, but cells of the infant’s ABO blood type may be used when the mother has the same type. A complete cross match, including an indirect Coombs test, should be performed before the 2nd and subsequent transfusions. Blood should be gradually warmed and maintained at a temperature between 35 and 37°C throughout the exchange transfusion. It should be kept well mixed by gentle squeezing or agitation of the bag to avoid sedimentation; otherwise, the use of supernatant serum with a low RBC count at the end of the exchange will leave the infant anemic. Whole blood or packed leukoreduced and irradiated RBCs reconstituted with fresh frozen plasma to an Hct of 40% should be used. The infant’s stomach should be emptied before transfusion to prevent aspiration, and body temperature should be maintained and vital signs monitored. A competent assistant should be present to help monitor, tally the volume of blood exchanged, and perform emergency procedures.

With strict aseptic technique, the umbilical vein is cannulated with a polyvinyl catheter to a distance no greater than 7 cm in a full-term infant. When free flow of blood is obtained, the catheter is usually in a large hepatic vein or the inferior vena cava. Alternatively, the exchange may be performed through peripheral arterial (drawn out) and venous (infused in) lines. The exchange should be carried out over 45-60 min, with aspiration of 20 mL of infant blood alternating with infusion of 20 mL of donor blood. Smaller aliquots (5-10 mL) may be indicated for sick and premature infants. The goal should be an isovolumetric exchange of approximately two blood volumes of the infant (2 × 85 mL/kg).

Infants with acidosis and hypoxia from respiratory distress, sepsis, or shock may be further compromised by the significant acute acid load contained in citrated blood, which usually has a pH between 7 and 7.2. The subsequent metabolism of citrate may result in metabolic alkalosis later if citrated blood is used. Fresh heparinized blood avoids this problem. During the exchange, blood pH and PaO₂ should be serially monitored because infants often become acidotic and hypoxic during exchange transfusions. Symptomatic hypoglycemia may occur before or during an exchange transfusion in moderately to severely affected infants; it may also occur 1-3 hr after exchange. Acute complications, noted in 5-10% of infants, include transient bradycardia with or without calcium infusion, cyanosis, transient vasospasm, thrombosis, apnea with bradycardia requiring resuscitation, and death. Infectious risks include CMV, HIV, and hepatitis. Necrotizing enterocolitis is a rare complication of exchange transfusion.

The risk of death from an exchange transfusion performed by an experienced physician is 0.3/100 procedures. With the decreasing use of this procedure because of the use of phototherapy and prevention of sensitization, the general level of physician competence is diminishing. Thus, it is best if this procedure is performed in experienced neonatal referral centers.

After exchange transfusion, the bilirubin level must be determined at frequent intervals (every 4-8 hr) because bilirubin may rebound 40-50% within hours. Repeated exchange transfusions should be carried out to keep the indirect fraction from exceeding the levels indicated in Table 96-7 for preterm infants and 20 mg/dL for term infants. Symptoms suggestive of kernicterus are mandatory indications for exchange transfusion at any time.

Intravenous Immunoglobulin

Early administration of intravenous immunoglobulin (IVIG) may reduce hemolysis, peak serum bilirubin levels, and the need for exchange transfusions. IVIG administration reduces the need for exchange transfusion, the duration of phototherapy, and the length of hospitalization. A dose of 0.5-1 gm/kg may be used.

Late Complications

Infants who have hemolytic disease or who have had an exchange or an intrauterine transfusion must be observed carefully for the development of anemia and cholestasis. Late anemia may be hemolytic or hyporegenerative. Treatment with supplemental iron, blood transfusion, or erythropoietin may be indicated. A mild GVH reaction may manifest as diarrhea, rash, hepatitis, or eosinophilia.

Inspissated bile syndrome refers to the rare occurrence of persistent icterus in association with significant elevations in direct and indirect bilirubin levels in infants with hemolytic disease. The cause is unclear, but the jaundice clears spontaneously within a few weeks or months.

Portal vein thrombosis and portal hypertension may occur in children who have been subjected to exchange transfusion as newborn infants. It is probably associated with prolonged, traumatic, or septic umbilical vein catheterization.

Prevention of Rh Sensitization

The risk of initial sensitization of Rh-negative mothers has been reduced to less than 1% by the intramuscular injection of 300 µg of human anti-D globulin (1 mL of RhoGAM) within 72 hr of delivery of an Rh-positive infant, ectopic pregnancy, abdominal trauma in pregnancy, amniocentesis, chorionic villus biopsy, or abortion. This quantity is sufficient to eliminate ≈ 10 mL of potentially antigenic fetal cells from the maternal circulation. Large fetal-to-maternal transfers of blood may require proportionately more human anti-D globulin. RhoGAM Administration of human anti-D globulin at 28-32 wk and again at birth (40 wk) is more effective than a single dose. The use of this technique, combined with improved methods of detecting maternal sensitization and measuring the extent of fetal-to-maternal transfusion, plus the use of fewer obstetric procedures that increase the risk of such fetal-to-maternal bleeding (version, manual separation of the placenta), should further reduce the incidence of erythroblastosis fetalis.

Hemolytic Disease of the Newborn Caused by Blood Group A and B Incompatibility

ABO incompatibility is the most common cause of hemolytic disease of the newborn. Approximately 15% of live births are at risk, but manifestations of disease develop in only 0.3-2.2%. Major blood group incompatibility between the mother and fetus generally results in milder disease than Rh incompatibility does. Maternal antibody may be formed against B cells if the mother is type A or against A cells if the mother is type B. Usually, the mother is type O and the infant is type A or B. Although ABO incompatibility occurs in 20-25% of pregnancies, hemolytic disease develops in only 10% of the offspring in such pregnancies, and the infants are generally type A₁, which is more antigenic than A₂. Low antigenicity of the ABO factors in the fetus and newborn infant may account for the low incidence of severe ABO hemolytic disease relative to the incidence of incompatibility between the blood groups of the mother and child. Although antibodies against A and B factors occur without previous immunization (“natural” antibodies), they are usually IgM antibodies that do not cross the placenta. However, IgG antibodies to A antigen may be present and these do cross the placenta, so A-O isoimmune hemolytic disease may be found in first-born infants. Mothers who have become immunized against A or B factors from a previous incompatible pregnancy also exhibit IgG antibody. These “immune” antibodies are the primary mediators in ABO isoimmune disease.

Clinical Manifestations

Most cases are mild, with jaundice being the only clinical manifestation. The infant is not generally affected at birth; pallor is not present, and hydrops fetalis is extremely rare. The liver and spleen are not greatly enlarged, if at all. Jaundice usually appears during the 1st 24 hr. Rarely, it may become severe, and symptoms and signs of kernicterus develop rapidly.

Diagnosis

A presumptive diagnosis is based on the presence of ABO incompatibility, a weakly to moderately positive direct Coombs test result, and spherocytes in the blood smear, which may at times suggest the presence of hereditary spherocytosis. Hyperbilirubinemia is often the only other laboratory abnormality. The hemoglobin level is usually normal but may be as low as 10-12 g/dL. Reticulocytes may be increased to 10-15%, with extensive polychromasia and increased numbers of nucleated RBCs. In 10-20% of affected infants, the unconjugated serum bilirubin level may reach 20 mg/dL or more unless phototherapy is administered.

Treatment

Phototherapy may be effective in lowering serum bilirubin levels (Chapter 96.4). In severe cases, IVIG administration can reduce the rate of hemolysis and the need for exchange transfusion. Exchange transfusions with type O blood of the same Rh type as the infant may be needed in some cases to correct dangerous degrees of anemia or hyperbilirubinemia. Indications for this procedure are similar to those previously described for hemolytic disease due to Rh incompatibility. Some infants with ABO hemolytic disease may require transfusion of packed RBCs at several weeks of age because of slowly progressive anemia. Post-discharge monitoring of hemoglobin or Hct is essential in newborns with ABO hemolytic disease.