1 HEMOLYTIC DISEASE 1 Hemolytic Disease in the Fetus and Newborn Rosa Carranza University of Texas Medical Brach School of Graduate Nursing Debra Armentrout, RN, MSN, NNP-BC, PhD Leigh Ann Cates, PhD, RN, NNP-BC, RRT-NPS In Partial Fulfillment of GNRS 5633: NNPIII November 20, 2014
2 HEMOLYTIC DISEASE 2 Abstract Hemolytic disease of the fetus and newborn may develop when fetal red blood cells (RBCs) enter the maternal circulation and trigger an immune response resulting in the production of maternal antibodies against the surface antigens of fetal RBCs. Intrauterine hemolysis may be severe enough to result in fetal hydrops or death. The newborn infant may develop significant anemia and hyperbilirubinemia with risk for kernicterus and permanent neurologic impairment. Prophylactic use of RhoGAM to prevent sensitization in susceptible pregnancies has markedly reduced the incidence of Rh hemolytic disease; however, other incompatibilities such as ABO and atypical antigens can still result in hemolysis. With the decreasing incidence of hemolytic disease seen today, providers may be unfamiliar with this condition and its management strategies. A thorough understanding of hemolytic disease will allow neonatal providers to improve the outcomes of affected infants. Introduction Hemolytic disease of the newborn (HDN) is the clinical syndrome resulting in the destruction of fetal and or neonatal red blood cells by maternal antibodies. Hemolytic disease may develop if a mother and her unborn fetus have incompatible Rh or ABO blood groups. Hemolysis of fetal RBCs can result in anemia, hypoalbuminemia, high output cardiac failure, hydrops or death. Advances in obstetric care have resulted in improved detection and prophylactic treatment of susceptible pregnancies; however, HDN has not been completely eradicated, and may still contribute to increased mortality in the fetal and neonatal period. HDN can still be encountered in mothers without access to prophylactic treatment, as in cases of women who do not seek prenatal care, in immigrants from countries where prophylaxis is not the standard of care, or in mothers who did not receive prophylaxis following abortion or invasive
3 HEMOLYTIC DISEASE 3 procedures. 1 Neonatal providers must be familiar with the pathophysiology, incidence, and management of affected infants in order to improve survival and long-term outcomes. Pathophysiology The body s cells have markers, or antigens, on their surface. These cell surface antigens are self antigens and therefore do no trigger an immune response. RBCs also have surface antigens that determine an individual s blood group. The two main blood subgroups are ABO and Rh. The ABO group determines an individual s blood type (A, B, AB, O). The Rh blood group system is complex and includes various cell surface proteins including the D, Cc, Ee, as well as numerous other surface antigens. However, the commonly used terms Rh positive or Rh negative refer to the presence or absence of the D antigen. 2 In utero, fetal RBC hemolysis usually results from Rh (D) incompatibility. This happens when an Rh-negative woman (lacking the D antigen) becomes pregnant with a fetus that has inherited the D antigen from the father and is Rh-positive (has the D antigen). If fetal RBCs move across the placenta to the mother s circulation, the mother s immune system identifies the fetal D antigen as foreign and begins to produce anti-d antibodies against it. With an initial expose during the first pregnancy, the production of anti-d IgM is triggered. IgM antibodies have a high molecular weight, which render them incapable of crossing the placenta. For that reason, the fetus of a first pregnancy is not affected. However, subsequent exposures of an Rhnegative mother to an Rh-positive fetus will trigger the production of anti-d IgG antibodies; anti- D IgG antibodies are capable of crossing the placenta. Once in the fetal circulation, anti-d IgG antibodies target the fetus Rh-positive RBCs and begin to destroy them. Incompatibilities involving atypical antigens including the Kell, Duffy, Kidd, MNSs, Diego, Xg, P, Ee, and Cc, although less frequently seen, can also result in hemolysis. 3
4 HEMOLYTIC DISEASE 4 The isoimmunization of the Rh-negative mother to the fetus Rh positive RBCs can occur in numerous ways, including after transfusion with unmatched blood, during birth or abortion, through transplacental passage during pregnancy, trauma, placental abruption, after amniocentesis, chorionic villus sampling, cordocentesis, or external version. It has also been reported in Rh-negative women who are intravenous drug users and share needles with Rhpositive users. 3 In pregnancies affected by Rh incompatibility, maternal antibodies that cross the placenta into the fetal circulation result in destruction of fetal RBCs. The rate of hemolysis will determine the severity of the disease. With increasing anti-d IgG titers and worsening hemolysis, anemia develops. The anemia will stimulate bone marrow to increase erythropoiesis. The fetal liver and spleen will also increase erythropoiesis in an effort to replace RBCs. The drive to increase RBC production results in hepatosplenomegaly and may also yield hepatic dysfunction. 4 The fetus outcome will depend on the severity of hemolysis and its own erythropoietic capability. If fetal erythropoiesis is unable to compensate for overwhelming hemolysis of RBCs, severe anemia may develop. With marked anemia, the fetus will experience hypoxia due to the decreased oxygen carrying capacity of the blood. 5 Cardiac output will be increased in order to maintain normal ph, partial pressure of oxygen, and carbon dioxide. When the fetal hemoglobin reaches a deficit of 8mg/dl, lactic acidosis develops because the placenta s capacity to clear lactic acid is exceeded. The fetus methods of compensation usually fail when the hematocrit decreases to 15%, leading to the development of hydrops fetalis. The hydropic fetus may develop pericardial and pleural effusions, ascites, edema of the skin, hepatosplenomegaly, hydramnios, and placental thickening. 3
5 HEMOLYTIC DISEASE 5 Hemolysis of fetal erythrocytes also yields large amounts of bilirubin. Total bilirubin levels in utero are kept below 5mg/dl by placental clearance of unconjugated bilirubin. However, once the infant is born and the placenta is removed, ongoing hemolysis continues to yield large amounts of bilirubin, which the neonate s immature liver is unable to metabolize. The infant may become jaundiced within the first 24 hours of life, and in severe cases, as soon as 30 minutes after delivery. Rising bilirubin levels place the infant at risk for kernicterus and permanent neurologic impairment. 1 Hemolysis can also be caused by ABO incompatibility. This results when a mother with blood type O becomes pregnant with a fetus that is blood type A, B, or AB. The mother produces anti-a and or anti-b IgG antibodies that are each capable of crossing the placenta and destroying fetal RBCs. Hemolysis in ABO incompatibility typically is less severe than that caused by Rh incompatibility for several reasons. The first reason is, compared with adults fetal RBCs express less of the ABO antigen. Second, ABO blood group antigens are expressed by a number of different tissues, not just RBCs; thereby reducing the fetal RBC s chance of binding with the anti-a, anti-b antibodies. 2 Furthermore, ABO incompatibility offers some protection against Rh incompatibility by destroying all fetal RBCs in the maternal circulation, preventing the Rh(D) antigen from being detected and eliciting and immune reaction. Due to this protective effect, ABO incompatibility reduces the risk of Rh isoimmunization from 16% to 1-2%. 3 Although more rare, hemolytic disease among the minor blood group antigens, including Kell, Duffy, Lewis, Kidd, M and S can also occur. Isoimmune hemolytic anemia in infants of mothers with ABO or Rh incompatibility can extend past the immediate newborn period. The half-life of the IgG antibodies that cause hemolysis is approximately 28 days. For that reason, hemolysis should resolve within the first
6 HEMOLYTIC DISEASE 6 three or four months of life. Resolution may occur sooner if therapeutic interventions are used to clear the antibodies from the newborn s system. 6 Incidence The incidence of Rh hemolytic disease depends on the prevalence of Rh negativity in a certain population. Eleven to 21% of European whites, 14.4% of U.S. whites, 8% of Indians, and 5.5% of U.S. African Americans are Rh-negative. 6 Even in Caucasian populations where Rh negativity is more prevalent, only a small percentage of pregnancies are complicated by Rh hemolytic disease. This can be attributed to several reasons. First, not all women who are Rh negative will produce anti-d antibodies. Another reason is that Rh immunization of the mother does not typically happen in the first pregnancy. Finally, it is possible that some of the infants in second pregnancies will be Rh negative. This last scenario results when the father is Rh (D) positive heterozygous. The resulting fetus will have a 50% chance of being Rh negative and not trigger the immune response. Furthermore, the use of RhoGAM prophylaxis has reduced the incidence of Rh sensitization to less than 1% in Rh incompatible pregnancies. However, other antibodies have become relatively more important as a cause of hemolytic disease. The anti-c, Kell, Duffy, Kidd, MSN, anti C, and anti E antibodies may cause severe hemolysis, which cannot be prevented with the administration of RhoGAM. With the reduced incidence of Rh isoimmunization thru RhoGAM administration, ABO incompatibility is now the leading cause of immune hemolytic disease in the newborn. Although typically milder than Rh hemolytic disease, severe hemolysis and hyperbilirubinemia can still occur with ABO incompatibility. ABO incompatibility occurs in approximately 12% of pregnancies. Mothers who are O positive can have naturally occurring anti A or anti B
7 HEMOLYTIC DISEASE 7 antibodies even before their first pregnancy. This is due to the fact that maternal anti A or anti B IgG antibodies may have been formed against A or B antigens occurring in food or bacteria. 1 Diagnosis Early in pregnancy, a woman s blood type and Rh status must be confirmed in order to identify those pregnancies that may be susceptible to Rh incompatibility. The indirect Coomb s test can be used to find out if an Rh-negative woman has been sensitized to the Rh D antigen. The test identifies the presence of anti-d antibodies in a pregnant woman s serum. If maternal anti-d antibodies are found, the Rh status of the fetus should be confirmed. Fetal Rh can be determined from fetal cell DNA found in maternal plasma, or through the more invasive techniques of amniocentesis or cordocentesis. 7 If the fetus is Rh D positive, the pregnancy must be carefully monitored for signs of hemolytic disease. There must be regular ultrasound scans to monitor for the development of hydrops. Maternal antibody titers must also be followed, since a rise in maternal anti-d levels indicates active hemolysis. 4 After delivery, an infant s blood type and Rh status must also be determined. A positive direct Coomb s test can identify the presence of antibodies on the newborn s red blood cells. This can be diagnostic of Rh incompatibility if found in an infant presenting with jaundice in the first 24 hours of life, anemia with reticulocytosis, hepatosplenomegaly, or hydrops. However, a false positive direct Coomb s test be seen if RhoGAM was administered at 28 weeks gestation because of the passive transfer of antibody during the pregnancy. 7 Management Screening and prevention remain paramount in the prevention of Rh disease. The Rh immunoglobulin, RhoGAM, can prevent the formation of Rh D antibodies in Rh-negative women who have not been previously sensitized. Also, recent advances in preimplantation
8 HEMOLYTIC DISEASE 8 technology have allowed for prevention of Rh disease by selectively implanting only Rh D negative embryos into a woman; although this technique remains invasive and costly. 3 The exact mechanism by which RhoGAM functions is not clear. Several theories have been proposed including the inhibition of B cells, antigen masking, and destruction of fetal RBCs from the maternal circulation. Currently, is recommended that all pregnant Rh-D negative women receive RhoGAM at 28 week s gestation, and within 72 hours after birth in those who deliver Rh D positive infants. However, RhoGAM can still be given up to 13 days after exposure for partial protection. Concerns remain that proper administration of Rh prophylaxis remains incomplete with missed opportunities for administration in the postpartum period, after abortion, following hemorrhage, or in those women with a history of IV drug use. 3 Intrauterine transfusion may be used if the fetus develops severe anemia in utero. Although extremely invasive, intrauterine transfusion may be indicated if there is risk of fetal demise or if hydrops is present. The goals of intrauterine transfusion are to maintain an adequate RBC mass in the fetal circulation, and to maintain the pregnancy until the fetus has a reasonable chance of survival outside the womb. Timing of delivery in affected pregnancies is based on disease severity and gestational age of the fetus. Delivery is usually planned between weeks of gestation. No benefits are gained by continuing the pregnancy beyond this time frame, and continuation of the pregnancy can actually be detrimental to the fetus. Once born, the neonate should be carefully examined and monitored in order to determine the need for therapy. Providers should be prepared to manage anemia and hyperbilirubinemia in the newborn period; however, postnatally the main goal of therapy is to prevent kernicterus and permanent neurologic damage. 3
9 HEMOLYTIC DISEASE 9 Hemolytic anemia in the newborn period is most likely associated with Rh incompatibility, although ABO and minor blood group incompatibilities can also result in serious hemolysis. A low cord hemoglobin at birth is present in approximately 50% of affected cases and reflects the severity of the intrauterine hemolysis the infant experienced. The newborn infant s cardiovascular status should be carefully monitored for tachycardia, hypotension, pallor, and hepatosplenomegally suggestive of hemolysis, decreased RBC volume, and impaired oxygen carrying capacity. Initial postnatal evaluation for anemia should include a complete blood count (CBC) with RBC indices, a reticulocyte count, and evaluation of the peripheral blood smear. 7 The infant is considered to be anemic when the hemoglobin or the hematocrit value is more than two standard deviations below the mean for their age. Along with anemia, there will also be accompanying reticulocytosis. Elevated reticulocyte levels reflect the infant s degree of compensation, and help support a diagnosis of ongoing hemolysis. Reticulocyte levels will vary according to gestational age. Term infants will have a normal range of 4-5%. Preterm infants between weeks will have values ranging between 6-10%. In symptomatic Rh disease, values can be as high as 10-40%. The peripheral blood smear in Rh disease will usually reveal polychromasia, normoblastosis that is proportionate to the reticulocyte count, absence of spherocytes, and often a nucleated RBC count greater than 10. In ABO hemolytic disease, microspherocytes on the peripheral blood smear are a hallmark of the disease. 7 Red blood cell transfusion may be indicated if anemia has diminished the oxygen carrying capacity of the blood and compromised tissue oxygenation. The decision to transfuse should be individually based on symptoms and severity of illness. Blood from cytomegalovirus negative donors should be used. Packed RBCs should be filtered and irradiated. RBCs should be transfused in aliquots of 10 to 20 cc/kg. The blood used should be from a single donor so that
10 HEMOLYTIC DISEASE 10 subsequent transfusions will be drawn from the same unit, helping to minimize the infant s exposure to multiple donors and reduce the risk of transfusion complications. 8 Infants with hemolytic disease will also develop pathologic unconjugated hyperbilirubinemia, with rapidly rising Total Serum Bilirubin (TSB) within the first 24 hours of life. Serial testing of bilirubin levels helps determine the rate of increase in unconjugated bilirubin levels. This in turn provides an index of the severity of hemolysis and the need for exchange transfusion. Physical exam will reveal jaundice of the skin due to accumulation of bilirubin in the body s tissues. A careful neurologic exam should also be conducted, as severe hyperbilirubinemia can be toxic to the central nervous system. Infants should be monitored for signs of early onset bilirubin encephalopathy including lethargy, poor feeding, vomiting, hypotonia, and seizures. 9 Phototherapy can be employed as a means to reduce bilirubin levels. Phototherapy reduces or slows the rise of serum bilirubin. It converts bilirubin to an excretable form through photoisomerization and photooxidation. In severe hemolytic disease, it is used as an adjunct to exchange transfusion in efforts to decrease bilirubin levels and reduce the number of exchange transfusions needed. In those infants that demonstrate ongoing hemolysis and rapidly rising bilirubin levels, exchange transfusion will likely be indicated. In hemolytic disease of the newborn, conducting an exchange transfusion removes antibody coated RBCs and replaces them with donor RBCs that lack the sensitizing antigen, thereby prolonging RBC survival. Exchange transfusions also reduce potentially toxic bilirubin levels and are indicated when there is significant risk for kernicterus. Exchange transfusions should be considered when: there is evidence of ongoing hemolysis and TSB has failed to decline by 1-2 mg/dl after 4-6 hours of phototherapy; the
11 HEMOLYTIC DISEASE 11 bilirubin rate of rise indicates that the level will be 25 mg/dl within 48 hours; early signs of encephalopathy are present with high concentrations of TSB; and when hemolysis causes severe anemia and hydrops. After exchange, TSB can be decreased by 50%, but a rebound can be expected once the bilirubin in tissues migrates back into the circulation. Moreover, it should be noted that exchange transfusions are not risk free and have reported mortality rates of 0.5-2%. They should be performed only after intensive phototherapy has failed and the risk for kernicterus outweighs the risk of the exchange transfusion. 10 Some studies have shown that intravenous immunoglobulin (IVIG) has reduced the need for exchange transfusion. IVIG works by blocking the Fc antibody binding receptor sites in the neonate s reticuloendothelial system. This prevents further hemolysis by competing with sensitized neonatal RBCs. Its use is recommended in isoimmune hemolytic disease if TSB continues to rise despite phototherapy, or if the TSB is within 2-3 mg/dl of the exchange level. It is also recommended for use in other types of Rh hemolytic disease, including anti-c and anti- E. However, efficacy has been brought into question by recent studies indicating that when administered to infants with severe Rh hemolytic disease, the need for exchange transfusion was not reduced. Furthermore, an increased incidence of necrotizing enterocolitis (NEC) has been found in infants with hemolytic disease who have been treated with IVIG. 9 Thus, the use of IVIG in hemolytic disease should be carefully weighed. In summary, improved screening and administration of RhoGAM have succeeded in reducing the incidence and severity of Rh hemolytic disease. However, cases can still be encountered among women without access to care, those who did not receive prophylaxis after abortion or invasive procedures, or in those with a history of IV drug abuse. An estimated 6.8 cases for every 1000 live births still occur. 3 Additionally, severe hemolysis can also result from
12 HEMOLYTIC DISEASE 12 incompatibilities due to ABO and atypical antigens. Efforts should continue to focus on prevention thru maternal prophylaxis, as well as early detection of affected pregnancies and appropriate treatment of newborns in order to achieve the best possible outcomes.
13 HEMOLYTIC DISEASE 13 References 1. Kaplan, M., Wong, R. J., Sibley, E., & Stevenson, D. K. (2011). Neonatal jaundice and liver disease. In A. Fanaroff, J. Martin, & C. Walsh (Eds), Neonatal perianal medicine: Diseases of the fetus and infant (9 th ed., ). Saint Louis, MI: Elsevier Mosby. 2. Dean, L. (2005a). Blood group antigens are surface markers on the red blood cell membrane. In Blood groups and red cell antigens (Chapter 2). Retrieved from 3. Gruslin, A. M. & Moore, T. R. (2011). Erythroblastosis fetalis. In A. Fanaroff, J. Martin, & C. Walsh (Eds), Neonatal perianal medicine: Diseases of the fetus and infant (9 th ed., ). Saint Louis, MI: Elsevier Mosby. 4. Dean, L. (2005b). Hemolytic disease of the newborn. In Blood groups and red cell antigens (Chapter 4). Retrieved from 5. Ramin, S. M. (2013). Fetal acid-base physiology. Retrieved from 6. Luchtman-Jones, L. & Wilson, D. B. (2011). The blood and hematopoietic system. Part One: Hematologic problems in the fetus and neonate. In A. Fanaroff, J. Martin, & C. Walsh (Eds), Neonatal perianal medicine: Diseases of the fetus and infant (9 th ed., ). Saint Louis, MI: Elsevier Mosby. 7. Whitehurst, R. M. Rh incompatibility. In T. L. Gomella, M. D. Cunningham, & F. G. Eyal (Eds), Neonatology: Management, procedures, on-call problems, diseases, and drugs (7 th ed, ). New York, NY: McGraw Hill.
14 HEMOLYTIC DISEASE Paul, D. A. (2013). Perinatal anemia. Retrieved from l_anemia.html#v Gomella, T. L. (2013). Hyperbilirubinemia, unconjugated. In T. L. Gomella, M. D. Cunningham, & F. G. Eyal (Eds), Neonatology: Management, procedures, on-call problems, diseases, and drugs (7 th ed, ). New York, NY: McGraw Hill. 10. Uy, C. (2013). Hyperbilirubinemia, indirect. In T. L. Gomella, M. D. Cunningham, & F. G. Eyal (Eds), Neonatology: Management, procedures, on-call problems, diseases, and drugs (7 th ed, ). New York, NY: McGraw Hill.