You are in: eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology Hemolytic Disease of NewbornArticle Last Updated: Jan 10, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Sameer Wagle, MBBS, MD, Consulting Staff, Division of Neonatology, Northwest Medical Center of Washington County Sameer Wagle is a member of the following medical societies: American Academy of Pediatrics and American Medical Association Coauthor(s): Prashant G Deshpande, MD, Consulting Staff, Department of Pediatrics, Hope Children's Hospital Editors: Oussama Itani, MD, FAAP, FACN, Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David A Clark, MD, Chairman, Professor, Department of Pediatrics, Albany Medical College; Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina; Ted Rosenkrantz, MD, Head, Division of Neonatal-Perinatal Medicine, Professor, Departments of Pediatrics and Obstetrics/Gynecology, University of Connecticut School of Medicine Author and Editor Disclosure Synonyms and related keywords: hemolytic disease of the newborn, HDN, Hemolytic disease of fetus and newborn, HDFN, erythroblastosis fetalis, transplacental hemorrhage, fetomaternal hemorrhage, alloimmunization, hemolysis, hyperbilirubinemia, jaundice, kernicterus, nonimmune hydrops fetalis, fetal hydrops, anemia, erythroblasts, placental abruption, spontaneous abortion, therapeutic abortion, toxemia, fetal ascites, pleural effusion, hypoalbuminemia, fetal blood sampling, FBS, hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, triosephosphate isomerase deficiency, hemorrhages, hypothyroidism, gastrointestinal obstruction, syphilis, cytomegalovirus, CMV, parvovirus INTRODUCTIONSection 2 of 11
  BackgroundA French midwife was the first to report hemolytic disease of the newborn (HDN) in a set of twins in 1609. In 1932, Diamond and colleagues described the relationship among fetal hydrops, jaundice, anemia, and erythroblasts in the circulation, a condition later called erythroblastosis fetalis. Levine later determined the cause after Landsteiner and Weiner discovered the Rh blood group system in 1940. In 1953, Chown subsequently confirmed the pathogenesis of Rh alloimmunization to be the result of passage of Rh-positive fetal RBCs after transplacental hemorrhage into maternal circulation that lacked this antigen. In 1966, 2 groups from the United Kingdom and the United States demonstrated, in a combined study, that anti-D immunoglobulin G (IgG) prophylaxis soon after delivery prevented sensitization in Rh-negative women. The World Health Organization (WHO) technical report in 1971 recommended that a dose of 25 mcg (125 IU) of anti-D immunoglobulin G (IgG) should be given intramuscularly for every 1 mL of fetomaternal hemorrhage of Rh-positive packed RBCs or 2 mL of whole blood. In 1998, this recommendation was reinforced by the American Association of Blood Banks and the American College of Obstetrics and Gynecologists with inclusion of prophylaxis at 28 weeks' gestation. Routine use of Rh IgG prophylaxis resulted in a significant decline in the incidence of RhD alloimmunization, and erythroblastosis fetalis has become rare. The perinatal effects of maternal Rh alloimmunization are now referred to as hemolytic disease of the fetus and newborn, and fetal manifestations of the disease are more appreciated with newer technologies such as cordocentesis and fetal ultrasonography. PathophysiologyAlthough the Rh antibody was and still is the most common cause of severe HDN, other alloimmune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNSs (M, N, S, and s) systems do cause severe HDN. Rh blood group antigens are determined by at least 2 homologous but distinct membrane-associated proteins. Two separate genes located on the short arm of chromosome 1 encode Rh proteins. Each gene is 10 exons in length, and a 96% homology between these genes is observed. Production of 2 distinct proteins from the RHCE gene is due to alternative splicing of messenger RNA. Rh antigens exist in 3 loci: Cc, Dd, and Ee. Expression is limited to RBCs, with an increasing density during their maturation, unlike the ABH system, which exists in a wide variety of tissues. Rh antigen is not expressed on RBC progenitors. Individuals with partial- or weak-D phenotype express normal but reduced quantities of D antigen on the RBC surface, and most (90%) cannot be sensitized to produce anti-D. However, the remaining 10% that belong to partial-D phenotype can make anti-D and rarely experience fatal HDN. Most women with partial-D phenotype are classified as Rh negative on routine testing and are candidates for Rh immune globulin (RhIG). Currently, testing of all Rh-negative women for weak expression of D is not recommended. However, Rh-negative infants born to Rh-negative women should undergo testing to detect the partial-D phenotype so that RhIG can be administered in the event of weak expression. Procedures such as amniocentesis, chorionic villus sampling, and cordocentesis also increase the risk of alloimmunization. Because the transplacental hemorrhage is less than 0.1 mL in most pregnancies, most women are sensitized as a result of small, undetectable fetomaternal hemorrhage. After the initial exposure to a foreign antigen, B-lymphocyte clones that recognize the RBC antigen are established. The maternal immune system initially produces antibodies of the immunoglobulin M (IgM) isotype that do not cross the placenta and later produces antibodies of the IgG isotype that traverse the placental barrier. Predominant antibody subclass appears to be IgG1 in one third of individuals whereas a combination of IgG1 and IgG3 subclasses are found in the remaining individuals. The risk of Rh immunization after the delivery of the first child to a nulliparous Rh-negative mother is 16% if the Rh-positive fetus is ABO compatible with its mother, 2% if the fetus is ABO incompatible, and 2-5% after an abortion. The ABO-incompatible RBCs are rapidly destroyed in the maternal circulation, reducing the likelihood of exposure to the immune system. The degree of Rh sensitization of the mother is directly related to the amount of fetomaternal hemorrhage (ie, 3% with <0.1 mL compared with 22% with >0.1 mL). After sensitization, maternal anti-D antibodies cross the placenta into fetal circulation and attach to Rh antigen on fetal RBCs, which form rosettes on macrophages in the reticuloendothelial system, especially in the spleen. These antibody-coated RBCs are lysed by lysosomal enzymes released by macrophages and natural killer lymphocytes and are independent of the activation of the complement system. Prolonged hemolysis leads to severe anemia, which stimulates fetal erythropoiesis in the liver, spleen, bone marrow, and extramedullary sites, such as the skin and placenta. In severe cases, this can lead to displacement and destruction of hepatic parenchyma by erythroid cells, resulting in dysfunction and hypoproteinemia. Destruction of RBCs releases heme that is converted to unconjugated bilirubin. Hyperbilirubinemia becomes apparent only in the delivered newborn because the placenta effectively metabolizes bilirubin. HDN due to Kell sensitization results in hemolysis and suppression of erythropoiesis because the Kell antigen is expressed on the surface of erythroid progenitors. Hemolysis associated with ABO incompatibility exclusively occurs in type-O mothers with fetuses who have type A or type B blood, although it has rarely been documented in type-A mothers with type-B infants with a high titer of anti-B IgG. In mothers with type A or type B, naturally occurring antibodies are of the IgM class and do not cross the placenta, whereas 1% of type-O mothers have a high titer of the antibodies of IgG class against both A and B. They cross the placenta and cause hemolysis in fetus. FrequencyUnited StatesBefore the establishment of modern therapy, 1% of all pregnant women developed Rh alloimmunization. Since the advent of routine prophylaxis of at-risk women, incidence of Rh sensitization has declined from 45 cases per 10,000 births to 10.2 cases per 10,000 births, with less than 10% requiring intrauterine transfusion. Alloimmunization due to Kell antigen accounts for 10% of severely affected fetuses. Mortality/MorbidityNearly 50% of the affected newborns do not require treatment. Approximately 25% are born near term but become extremely jaundiced without treatment and either die (90%) or become severely affected by kernicterus (10%). The remaining 25% of affected newborns are severely affected in utero and become hydropic; about half of newborns are affected before 34 weeks' gestation, and the other half are affected between 34 weeks' gestation and term. RaceIncompatibility involving Rh antigens (anti-D or anti-c) occurs in about 10% of all pregnancies among Caucasians and African Americans; in contrast, it is very rare in Asian women. SexFetal sex plays a significant role in the degree of response to maternal antibodies. An apparent 13-fold increase is observed in fetal hydrops in RhD-positive male fetuses compared with female fetuses in similarly sensitized pregnancies. CLINICALSection 3 of 11
HistoryWomen at risk for alloimmunization should undergo an indirect Coombs test and antibody titers at their first prenatal visit. If positive, obtain a paternal blood type and genotype with serologic testing for other Rh antigens (C, c, E, e). The paternal zygosity for the D allele is determined from race-specific gene frequency tables that take into account the serology results of Rh antigen expression, ethnicity, and number of previous Rh-positive children. In the event of unclear ethnicity, quantitative polymerase chain reaction (PCR) for number of copies of the RhD gene has been used to detect heterozygous state. PhysicalThe infant born to an alloimmunized mother shows clinical signs based on the severity of the disease. The typical diagnostic findings are jaundice, pallor, hepatosplenomegaly, and fetal hydrops in severe cases. The jaundice typically manifests at birth or in the first 24 hours after birth with rapidly rising unconjugated bilirubin level. Occasionally, conjugated hyperbilirubinemia is present because of placental or hepatic dysfunction in those infants with severe hemolytic disease. Anemia is most often due to destruction of antibody-coated RBCs by the reticuloendothelial system, and, in some infants, anemia is due to intravascular destruction. The suppression of erythropoiesis by IVT of adult Hb to an anemic fetus can also cause anemia. Extramedullary hematopoiesis can lead to hepatosplenomegaly, portal hypertension, and ascites. Anemia is not the only cause of hydrops. Excessive hepatic extramedullary hematopoiesis causes portal and umbilical venous obstruction and diminished placental perfusion because of edema. Increased placental weight and edema of chorionic villi interfere with placental transport. Fetal hydrops results from fetal hypoxia, anemia, congestive cardiac failure, and hypoproteinemia secondary to hepatic dysfunction. Commonly, hydrops is not observed until Hb drops below approximately 4 g/dL (Hct <15%). Clinically significant jaundice occurs in as many as 20% of ABO-incompatible infants. CausesIn the absence of a positive direct Coombs test result, other causes of pathologic jaundice should be considered, including intrauterine congenital infections; erythrocyte membrane defects (eg, hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis); RBC enzyme deficiencies (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency, pyruvate kinase deficiency, triosephosphate isomerase deficiency); and nonhemolytic causes (eg, enclosed hemorrhages, hypothyroidism, gastrointestinal obstruction, and metabolic diseases).
DIFFERENTIALSSection 4 of 11
Anemia, Acute Atrial Flutter Cardiac Tumors Cytomegalovirus Infection Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia) Hydrops Fetalis Hypothyroidism Parvovirus B19 Infection Syphilis Toxoplasmosis Tyrosinemia
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| Characteristics | Rh | ABO | |
|---|---|---|---|
| Clinical aspects | First born | 5% | 50% |
| Later pregnancies | More severe | No increased severity | |
| Stillborn/hydrops | Frequent | Rare | |
| Severe anemia | Frequent | Rare | |
| Jaundice | Moderate to severe, frequent | Mild | |
| Late anemia | Frequent | Rare | |
| Laboratory findings | Direct antibody test | Positive | Weakly positive |
| Indirect Coombs test | Positive | Usually positive | |
| Spherocytosis | Rare | Frequent | |
High-resolution ultrasonography has been a major advance in detection of early hydrops and has also reduced the fetal trauma and morbidity rate to less than 2% during percutaneous umbilical blood sampling (PUBS) and placental trauma during amniocentesis. High-resolution ultrasonography has been extremely helpful in directing the needle with intraperitoneal transfusion (IPT) and IVT in fetal location.
Management of maternal alloimmunization
As a rule, serial maternal antibody titers are monitored until a critical titer of 1:32, which indicates that a high risk of fetal hydrops has been reached. At this point, the fetus requires very intense monitoring for signs of anemia and fetal hydrops. In Kell alloimmunization, hydrops can occur at low maternal titers because of suppressed erythropoiesis, and, thus, a titer of 1:8 has been suggested as critical. Hence, delta-OD 450 values are also unreliable in predicting disease severity in Kell alloimmunization.
Maternal titers are not useful in predicting the onset of fetal anemia after the first affected gestation. Large differences in titer can be seen in the same patient between different laboratories, and a newer gel technique produces higher titer results than the older tube method. Therefore, standard tube methodology should be used to determine critical titer, and a change of more than 1 dilution represents a true increase in maternal antibody titer. For all the antibodies responsible for hemolytic disease of the newborn (HDN), a 4-fold increase in any antibody titer is typically considered a significant change that requires fetal evaluation.
When indicated, amniocentesis can be performed as early as 15 weeks' gestation (rarely needed in first affected pregnancy before 24 weeks' gestation) to determine fetal genotype and to assess the severity. Maternal and paternal blood samples should be sent to the reference laboratory with amniotic fluid sample to eliminate false-positive results (from maternal pseudogene or Ccde gene) and false-negative results (from a rearrangement at the RHD gene locus in the father).
Fetal Rh-genotype determination in maternal plasma has become routine in other countries and will soon be offered in the United States. Fetal cell free DNA accounts for 3% of the total circulating maternal plasma DNA. It is subjected to real-time PCR for the presence of RHD gene-specific sequences and has been found to be accurate in 99.5% of cases. The SRY gene (in the male fetus) and DNA polymorphisms in the general population (in the female fetus) are used as internal controls to confirm the fetal origin of the cell-free DNA.
Serial amniocentesis is begun at 10-14 day intervals to monitor the severity of the disease in the fetus. All attempts should be made to avoid transplacental passage of needle which can lead to fetomaternal hemorrhage (FMH) and a further rise in antibody titer. Serial delta-OD 450 values are plotted on the Queenan chart (see Media file 3) to evaluate the risk of fetal hydrops. Early ultrasonography is performed to establish correct gestational age. Frequent ultrasonographic monitoring is also performed to assess fetal well-being and to detect moderate anemia and early signs of hydrops.
Recently, the peak systolic middle cerebral artery (MCA) Doppler velocity has proved to be a reliable screening tool to detect fetal anemia. The MCA is easily visualized with color-flow Doppler; pulsed Doppler is then used to measure the peak systolic velocity just distal to its bifurcation from the internal carotid artery. Because the MCA velocity increases with advancing gestational age, the result is reported in multiples of median (MOMs). In recent studies, the sensitivity for detection of moderate and severe fetal anemia has been proven to be 100%, with a false-positive rate of 10% at 1.5 MOM.4 It has been shown to reduce the need for invasive diagnostic procedures such as amniocentesis and cordocentesis by more than 70%.
MCA Doppler studies can be started as early as 18 weeks' gestation but are not reliable after 35 weeks' gestation. It has also been used to time the subsequent fetal transfusion and to diagnose anemia from multiple causes, such as in twin-twin transfusion. The MCA slope from 3-weekly readings is now used to predict fetal risk for severe anemia (see Media file 4).
During the period when intrauterine peritoneal transfusion was the only means of treatment, newborns were routinely delivered at 32 weeks' gestation. This approach resulted in a high incidence of hyaline membrane disease and exchange transfusions. With the advent of IVT in utero, the general approach to the severely affected fetus is to perform IVT as required until 35 weeks' gestation, with delivery planned at term. Establishment of lung maturity is difficult in these fetuses because of contamination of amniotic fluid with residual blood during transfusion.
In addition, excess amniotic fluid bilirubin levels cause false elevation on the fluorescence depolarization TDx fetal lung maturity test, version II (TDX-FLMII); therefore, other tests to determine fetal lung maturity should be used, such as infrared spectroscopy, lamellar body count, phosphatidylglycerol quantitation or lecithin/sphingomyelin (L/S) ratio.
Liley first described IPT in 1963. A Tuohy needle is introduced into the fetal peritoneal cavity under ultrasonographic guidance. An epidural catheter is threaded through the needle. A radiopaque medium is injected into the fetal peritoneum. The proper placement is confirmed by delineation outside of bowel or under the diaphragm or by diffusion in fetal ascites. Packed RBCs at Hct of 75-80% that are CMV-negative, less than 4-days-old, group O, Rh-negative, Kell-negative, leukoreduced, irradiated with 25 Gy to prevent graft versus host disease, and cross-matched with maternal serum are injected in 10-mL aliquots to a volume calculated by the following formula:
IPT volume = (gestation in wk - 20) X 10 mL
Residual Hb in the fetus is estimated to allow for proper spacing of IPT and selection of gestation of delivery by the following formula:
Hb g/dL = 0.85/125 X a/b X 120 - c/120
In the formula, a is the amount of donor RBC Hb transfused, b is the estimated fetal body weight, and c is the interval in days from the time of transfusion to the time of donor Hb estimation.
IPT is repeated when the fetal Hb is estimated to have dropped to 10 g/dL. Usually, a second IPT is performed 10 days after the first transfusion in order to raise the Hb above 10 g/dL. Then another transfusion is performed every 4 weeks until the time of planned delivery at 34-35 weeks' gestation. Fetal diaphragmatic movements are necessary in order for absorption of RBC to occur. This approach is of no value for a moribund nonbreathing fetus. Maternal complications include infection and transplacental hemorrhage, whereas fetal complications are overtransfusion, exsanguination, cardiac tamponade, infection, preterm labor, and graft versus host disease. Survival rates after IPT approached approximately 75% with the help of ultrasonography.
Direct IVT has become a preferred route of fetal intervention because of the higher rate of complications and limited effectiveness of IPT in a hydropic fetus. Rodeck first successfully performed IVT in 1981. With ultrasonographic guidance, a needle is introduced into an umbilical vein at the cord insertion into the placenta or into its intrahepatic portion, and a fetal blood sample is obtained. The blood sample is confirmed to be of fetal origin by rapid alkaline denaturation test. All the relevant fetal tests (eg, blood type, direct antibody test, reticulocyte count, platelet count, Hb level, Hct level, serum albumin level, erythropoietin level) are performed. If the Hb level is less than 11 g/dL or if the Hct level is less than 30%, an IVT is started. The position of the needle is confirmed by noting the turbulence in the fetal vessel on injection of saline. The fetus is frequently paralyzed with pancuronium in order to prevent the displacement of the needle by fetal movements.
The transfusion is performed in 10-mL aliquots to a volume of approximately 50 mL/kg estimated body weight using ultrasonography or until an Hct level of 40% is reached. The procedure is promptly discontinued if cardiac decompensation is noted on ultrasonography findings. Severely anemic fetuses do not tolerate acute correction of their Hct to normal values, and the initial Hct should not be increased by more than 4-fold at the time of first IVT. They should then be monitored every 2-7 days. The IVT is repeated when it reaches a value that reflects critical anemia in the fetus. A loss of 1% of transfused cells per day can be anticipated.
In addition to the complications of IPT, transient fetal bradycardia, cord hematoma, umbilical vein compression, and fetal death have been reported during IVT. However, IVT has many advantages, including immediate correction of anemia and resolution of fetal hydrops, reduced rate of hemolysis and subsequent hyperinsulinemia, and acceleration of fetal growth for nonhydropic fetuses who are often growth retarded. IVT is the only intervention available for moribund hydropic fetuses and those with anterior placenta. The risk of fetal loss is about 0.8% with IVT versus 3.5% per procedure for IPT, and the overall survival rate is 88%.
Recently washed maternal RBCs have been successfully used as a source of antigen-negative RBCs in the event of rare incompatibility but also have been routinely used because of benefits such as decreased risk for sensitization to new red cell antigens, a longer circulating half-life being fresh, and decreased risk of transmission of viral agents. Mother can donate a unit of red cells after the first trimester.
In the event of pulmonary immaturity and delta-OD 450 in the affected zone of the Queenan curve, oral administration of 30 mg of phenobarbital to the mother 3 times per day, followed by induction in one week, reduces the need for exchange transfusion in the affected neonate. Excellent algorithms for management of the first affected pregnancy and the pregnancy in a mother with previously affected fetus are outlined in a review by Gest et al.5 (See Media files 5 and 6).
Initial attempts to suppress Rh antibody production with Rh hapten, Rh-positive RBC stroma, and administration of promethazine were unsuccessful. Extensive plasmapheresis with partial replacement using 5% albumin and intravenous immunoglobulin (IVIG) or the administration of IVIG at 1 g/kg body weight weekly has been shown to be moderately effective. The mechanism of action appears to be blockage of Fc receptors in the placenta, reducing antibody transport across to the fetus, Fc receptors on the phagocytes in the fetal reticuloendothelial system, and feedback inhibition of maternal antibody synthesis.
However, these techniques only postpone the need for PUBS and IVT until 20-22 weeks' gestation, when these procedures can be performed at a more acceptable risk. A recent review of IVIG use shows its usefulness in preventing the onset of fetal hydrops and in delaying the need for IUT.6 Thus, a combined approach of plasmapheresis that starts at 12 weeks' gestation 3 times in that week, followed by IVIG at a loading dose of 2 g/kg after the third plasmapheresis, and then continued IVIG 1 g/kg/wk until 20 weeks' gestation has been suggested for at-risk fetuses prior to 20 weeks' gestation and can also be used later in gestation if IVT cannot be performed or if hydrops is unresponsive to IVT.
Maternal alloantibodies to paternal leukocytes have been shown to result in Fc blockade and to reduce the severity of fetal hemolytic anemia. This may be used in the future.
Management of the sensitized neonate
Mild hemolytic disease accounts for 50% of newborns with positive direct antibody test results. Most of these newborns are not anemic (cord Hb >14 g/dL) and have minimal hemolysis (cord bilirubin <4 mg/dL). Apart from early phototherapy, they require no transfusions. However, these newborns are at risk of developing severe late anemia by 3-6 weeks of life. Therefore, monitoring their Hb levels after hospital discharge is important.
Moderate hemolytic disease accounts for approximately 25% of affected neonates. Moderate HDN is characterized by moderate anemia and increased cord bilirubin levels. These infants are not clinically jaundiced at birth but rapidly develop unconjugated hyperbilirubinemia in the first 24 hours of life. Peripheral smear shows numerous nucleated RBCs, decreased platelets, and, occasionally, a large number of immature granulocytes. These newborns often have hepatosplenomegaly and are at risk of developing bilirubin encephalopathy without adequate treatment. Early exchange transfusion with type-O Rh-negative fresh RBCs with intensive phototherapy is usually required. Use of IVIG in doses of 0.5-1 gm/kg in a single or multiple dose regimen have been able to effectively reduce need for exchange transfusion. These newborns are also at risk of developing late hyporegenerative anemia of infancy at 4-6 weeks of life.
Severe hemolytic disease accounts for the remaining 25% of the alloimmunized newborns who are either stillborn or hydropic at birth. The fetal hydrops is predominantly caused by a capillary leak syndrome due to tissue hypoxia, hypoalbuminemia secondary to hepatic dysfunction, and high-output cardiac failure from anemia. About half of these fetuses become hydropic before 34 weeks' gestation and need intensive monitoring and management of alloimmunized gestation as described earlier. Mild hydrops involving ascites reverses with IVTs in only 88% of cases with improved survival but severe hydrops causing scalp edema and severe ascites and pleural effusions reverse in 39% of cases and are associated with poor survival.
Management of ABO incompatibility
Management of hyperbilirubinemia is a major concern in newborns with ABO incompatibility. The criteria for exchange transfusion and phototherapy are similar to those used in Rh alloimmunization. IVIG has also been very effective when administered early in the course. Tin (Sn) porphyrin a potent inhibitor of heme oxygenase, the enzyme that catalyzes the rate-limiting step in the production of bilirubin from heme, has been shown to reduce the production of bilirubin and reduce the need for exchange transfusion and the duration of phototherapy in neonates with ABO incompatibility.
Tin or zinc protoporphyrin or mesoporphyrins have been studied in newborns. They must be administered intramuscularly in a dose based on body weight, and their effectiveness appears to be dose related in all gestations. Their possible toxic effects include skin photosensitization, iron deficiency, and possible inhibition of carbon monoxide production. Their use in Rh HDN has not been reported. Their routine use cannot be recommended yet because of lack of long-term safety data.
These agents normalize antibody levels in patients with primary defective antibody synthesis. They prevent and treat certain bacterial and viral infections and reduce the immune-mediated hemolysis and phagocytosis.
| Drug Name | Intravenous immunoglobulin (Gamimune, Gammagard, Sandoglobulin, Gammar-P) |
|---|---|
| Description | Several studies have reported success in minimizing the need for exchange transfusion in severe HDN with IVIG. Effective adjunct to phototherapy. Mechanism of action appears to be related to blockage of Fc receptors in the neonatal reticuloendothelial system. Studies have also documented decreased hemolysis after administration of IVIG using carboxyhemoglobin levels. Administration in doses of 500-1000 mg/kg in the first few hours of life to a newborn with severe hemolysis should be considered. However, efficacy depends on timing of administration, duration of treatment, and severity of hemolysis. Should be prepared by and dispensed from pharmacy and should not be mixed with normal saline. Dispensed as either 3% or 6% solution. |
| Adult Dose | 1 g/kg IV qwk for maternal alloimmunization |
| Pediatric Dose | 0.5-1 g/kg IV in first few h following birth for severe hemolysis in newborn; start infusion at rate of 0.5 mL/kg/hour for 15 min, then increase q15-30min; not to exceed rate of 4 mL/kg/hour; if adverse reactions occur, reduce rate to a previously well-tolerated rate |
| Contraindications | Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies |
| Interactions | Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine) |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Ensure that patient is not volume depleted before initiation of therapy; periodic monitoring of renal function and urine output should be undertaken in those at increased risk for developing acute renal failure (eg, preexisting renal insufficiency, diabetes mellitus, age >65 y, hypovolemia, sepsis, paraproteinemia, those on nephrotoxic drugs); in such patients, reduce rate of infusion and discontinue if renal function deteriorates; patients with agammaglobulinemia or extreme hypogammaglobulinemia who have never received IVIG before or have not received IVIG within preceding 8 wk are at increased risk of developing inflammatory reaction after IVIG infusion (these reactions are manifested by fever, chills, nausea, and vomiting and appear to be related to rate of infusion) |
These agents may be required to correct anemia.
| Drug Name | Epoetin alfa, recombinant (Epogen, Procrit) |
|---|---|
| Description | Purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Amino acid sequence is identical to that of endogenous EPO. Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces release of reticulocytes from bone marrow into the blood stream. |
| Adult Dose | 50-150 U/kg IV/SC 3 times/wk |
| Pediatric Dose | 200 U/kg SC 3 times a wk starting at day 14 of life and lasting for 6 wk |
| Contraindications | Documented hypersensitivity; uncontrolled hypertension |
| Interactions | None reported |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Caution in porphyria, hypertension, history of seizures; decrease dose if hematocrit increase exceeds 4 U in any 2-wk period; the multidose preserved formulation contains benzyl alcohol and may increase risk of neurologic toxicity in infants (use preservative-free formulation); treatment results depend on adequate iron supplementation |
Phase III clinical trials have been completed in the
| Drug Name | Stannsoporfin (SnMP, Stanate) |
|---|---|
| Description | Also known as tin-mesoporphyrin. Investigational in the United States. Phase III clinical trials completed. Structural analog of heme that blocks heme oxygenase (HO-1), a rate-limiting enzyme in bilirubin production, thereby preventing the conversion of heme to bilirubin. Heme is excreted unchanged in bile and is not stored in tissue. It is inert and does not enter the brain or interact with DNA. It does not affect previously formed bilirubin conjugation or excretion in liver. Several randomized, controlled and, when possible, blinded studies over the last decade that involved >700 neonates with all principle forms of neonatal jaundice have shown SnMP to be effective in preventing and blocking jaundice progression. Phototherapy was eliminated in 97% of treated infants. Also inhibits nitric oxide synthase and soluble guanylyl cyclase. Repeated doses lead to inhibition of intestinal heme oxygenase involved in iron absorption and may lead to anemia. It also stimulates HO-1 transcription and protein levels. The half-life as measured in healthy adult volunteers is 3.8 h. Available under the rules of a compassionate use protocol by WellSpring Pharmaceutical and InfaCare Pharmaceutical Corporations. For details, contact Dr Benjamin Levinson (732) 938-5885 ext 224, or by email at blevin@wellsringpharm.com. |
| Adult Dose | Not indicated |
| Pediatric Dose | 6 µmol/kg IM as a single dose administered within 24 h of birth with severe hemolytic process |
| Contraindications | Photosensitivity conditions (eg, congenital porphyria) |
| Interactions | Data limited; none known |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Transient cutaneous photosensitivity may occur, prophylax with inorganic based sunscreens (eg, titanium oxide, zinc oxide); repeated doses may cause anemia |
Most survivors of alloimmunized gestation are intact neurologically. Fetal hydrops does not seem to affect long-term outcome. However, neurologic abnormality has been reported to be closely associated with severity of anemia and perinatal asphyxia.
| Media file 1: Liley curve. This graph illustrates an example of amniotic fluid spectrophotometric reading of 0.206, which when plotted at 35 weeks' gestation falls into zone 3, indicating severe hemolytic disease. | |
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| Media file 2: Modified Liley curve for gestation of less than 24 weeks showing that bilirubin levels in amniotic fluid peak at 23-24 weeks' gestation. | |
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| Media file 3: Queenan Curve: Modified Liley curve that shows delta-OD 450 values at 14-40 weeks' gestation. | |
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| Media file 4: Slopes for peak systolic velocity in middle cerebral artery (MCA) for normal fetuses (dotted line), mildly anemic fetuses (thin line), and severely anemia fetuses (thick line). | |
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| Media file 5: Management of first affected pregnancy. | |
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| Media file 6: Management of pregnant women with previously affected fetus. | |
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