Etiology and Pathogenesis

ABO incompatibility primarily occurs in blood group O mothers with fetuses who have blood group A or B. All group O individuals have anti-A and anti-B antibodies that are produced as a result of immune stimulation by the A or B antigens contained in food and bacteria. Interactions between these maternal isoantibodies and fetal red blood cells (RBCs) result in hemolysis. Fifteen percent of pregnancies are ABO incompatible, yet evidence of ABO incompatibility disease is found in only 3% of pregnancies and necessitates exchange transfusion (ET) in fewer than 1% of pregnancies. This is because ABO hemolytic disease tends to occur in newborns whose mothers have high levels of immunoglobulin G (IgG) antibody. Although anti-A and anti-B antibodies are found in the plasma as IgA, IgM, and IgG, only the latter can cross the placenta and interact with fetal RBCs.

Rh incompatibility affects one of every 15 pregnancies and causes a wide variety of symptoms in the fetus, ranging from mild to severe hemolytic anemia and hydrops fetalis. Sensitization to the Rh (D) antigen is the result of exposure of an Rh-negative mother to Rh-positive blood. Possible exposures include prior pregnancy with an Rh-positive fetus, fetomaternal hemorrhage, and obstetric procedures (e.g., amniocentesis, chorionic villus sampling, abortion). Unlike A or B antigens, which are expressed on a number of different tissues, Rh antigens are expressed only on RBCs. Thus, maternal anti-Rh (anti-D) IgG antibodies (Rh-negative mother) cross the placenta and interact with a greater number of fetal RBCs (Rh-positive infant), resulting in significant fetal hemolysis.

Clinical Presentation and Differential Diagnosis

Both ABO incompatibility and Rh disease are associated with jaundice within the first 24 hours of life. In cases of severe hemolytic disease (i.e., erythroblastosis fetalis), infants also present with signs of hydrops fetalis (ascites, pleural or pericardial effusions, edema), pallor (secondary to anemia), petechiae or purpura (caused by thrombocytopenia), and hepatosplenomegaly (result of extramedullary hematopoiesis and splenic sequestration) (Figure 104-1). Each manifestation has a long list of possible causes, but the combination of jaundice and anemia with any of the above findings should focus clinical attention on diseases associated with hemolysis.

Figure 104-1 Erythroblastosis fetalis.

The differential diagnosis of neonatal anemia includes chronic or acute blood loss, congenital disorders of erythrocyte production (e.g., Fanconi’s anemia, Diamond-Blackfan), erythrocyte membrane defects (e.g., hereditary spherocytosis, hereditary elliptocytosis), congenital enzyme deficiencies (e.g., G6PD [glucose-6-phosphate dehydrogenase], pyruvate kinase), infection, and hemoglobin disorders (Figure 104-2). Of the hemoglobinopathies, α-thalassemias are the most common and severe. The switch from fetal (α₂γ₂) to adult (α₂β₂) hemoglobin occurs during the first year of life. As a result, defects in α-globin synthesis manifest in utero, whereas defects in β-globin synthesis become apparent in late infancy. Deletion of three (hemoglobin H disease) or four (hemoglobin Barts) α-globin genes can cause significant hemolytic anemia and present as hydrops fetalis. Newborn screening enables early detection and treatment of infants with major hemoglobinopathies and therefore reduces the mortality and morbidity associated with these conditions.

Figure 104-2 Differential diagnosis of neonatal anemia.

(Modified from Blanchette VS, Zipursky A. Assessment of anemia in newborn infants. Clin Perinatol 11(2):489-510, 1984.)

Diagnostic Approach

Hemolytic disease of newborns is associated with rapidly progressive or prolonged indirect hyperbilirubinemia, signs of hemolysis on peripheral blood smear (e.g., schistocytes and spherocytes), an elevated reticulocyte count, and anemia. Blood group testing reveals evidence of ABO or Rh incompatibility between the mother and newborn. Direct and indirect Coombs’ testing is positive in Rh disease but only weakly positive in ABO incompatibility. Infants with Rh disease should be monitored for thrombocytopenia (caused by liver dysfunction or disseminated intravascular coagulation [DIC]), hypoglycemia (secondary to islet cell hyperplasia of the pancreas), and direct hyperbilirubinemia (may be the result of hepatocellular damage).

Management and Therapy

Phototherapy and ET are the primary modes of treatment for infants with hemolytic disease. In Rh incompatibility, intensive phototherapy should be started immediately after birth. Prompt initiation of phototherapy might prevent the need for ET.

Treatment of neonatal hyperbilirubinemia with ET was introduced in the early 1950s. Although ET is proven to reduce mortality and the risk of kernicterus, it is associated with serious complications, including hemodynamic instability, apnea, coagulopathies, electrolyte imbalance, vascular thromboses, sepsis, arrhythmias, and necrotizing enterocolitis (NEC) (see Chapter 100). Efforts to reduce perinatal mortality and the need for ET have led to the development of several prenatal care strategies, including RhoGAM, use of Doppler ultrasound to detect fetal anemia, and intrauterine blood transfusions.

The use of RhoGAM (anti-D prophylaxis) in Rh-negative women has led to a marked decline in Rh sensitization and hemolytic disease of the newborn. Studies have demonstrated that of all Rh-sensitized pregnancies with Rh-positive fetuses, 51% require no treatment, 31% require treatment after full-term delivery, 10% are delivered early and need ET, and 9% require intrauterine fetal transfusion. In developed countries, a high proportion of clinically significant hemolytic disease is now caused by antibodies to antigens other than D (i.e., anti-C, anti-E, or anti-Kell) and therefore is not preventable with RhoGAM.

Intravenous immunoglobulin (IVIG) is a supplemental therapy that may be effective in reducing the need for ET in infants with immune-mediated hemolytic disease. In isoimmune hemolysis, RBCs are destroyed by an antibody-dependent cytotoxic process directed by Fc receptor–bearing cells of the reticuloendothelial system. IVIG’s mechanism of action is postulated to be attributable to nonspecific blockade of Fc receptors. Potential benefits of IVIG over ET include relative ease of administration, reduced invasiveness, and improved safety profile. Preliminary studies have demonstrated lower maximum bilirubin levels and shorter durations of hospitalization among patients receiving IVIG treatment.

Etiology and Pathogenesis

Polycythemia can be subdivided into three categories based on the underlying etiology: (1) increased RBC mass and plasma volume secondary to maternal diabetes or “blood transfusion” (e.g., delayed cord clamping, twin–twin, or maternal–fetal transfusion); (2) increased RBC mass and normal plasma volume related to a congenital syndrome (trisomies 13, 18, and 21); and (3) increased RBC mass and normal or decreased plasma volume caused by intrauterine growth retardation, placental insufficiency, maternal hypertension, or smoking. The incidence of polycythemia is 1% to 5% in all neonates versus 10% to 15% in neonates who are small for gestational age.

Clinical Presentation and Differential Diagnosis

Polycythemic infants appear ruddy and plethoric with sluggish capillary refill and poor peripheral perfusion. Hyperviscosityof blood results in increased resistance to blood flow and decreased oxygen delivery. Although most neonates with polycythemia are asymptomatic, it can cause abnormalities in central nervous system function (lethargy, apnea, tremors or jitteriness, poor feeding, and hypotonia), decreased renal function (oliguria, proteinuria, and hematuria), cardiorespiratory distress (tachypnea, cyanosis, and cardiomegaly), and coagulation disorders. Rare complications include strokes, seizures, congestive heart failure, renal vein thrombosis, DIC, and NEC. Studies have also noted associations between hyperviscosity and long-term motor and cognitive neurodevelopmental disorders.