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Hemolytic Disease of Newborn Follow-up

  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Ted Rosenkrantz, MD  more...
 
Updated: Jan 02, 2016
 

Further Inpatient Care

The following may be indicated in patients with hemolytic disease of newborn (HDN):

  • The stabilization of a hydropic newborn requires a high level of intensive coordinated management by a neonatal team well prepared for the possibly affected infant.
  • In general, immediate intubation followed by draining of pleural effusions and ascites results in immediate improvement in respiratory gas exchange.
  • A cautious correction of anemia with packed RBCs or by exchange transfusion is necessary to prevent circulatory overload.
  • These neonates have normal blood volume but elevated central venous pressure.
  • A close monitoring of metabolic status (eg, watching for hypoglycemia, hypocalcemia, hyperkalemia, acidosis, hyponatremia, renal failure) is absolutely essential to achieve a successful outcome.
  • Despite of the first use of phototherapy by Cremer and associates more than 40 years ago, no standard method for delivering phototherapy is yet available.
    • Phototherapy units differ widely with respect to the type and size of lamps used. The efficacy of phototherapy depends on the spectrum of light delivered, the blue-green region (425-490 nm) of visible light being the most effective; irradiance (µW/cm2/nm); and surface area of the infant exposed.
    • High-intensity phototherapy first described by Tan in 1977 uses irradiance greater than 25 µW/cm2/nm up to 40 µW/cm2/nm when a dose-response relationship to bilirubin degradation reaches a plateau.
    • Nonpolar bilirubin is converted into 2 types of water-soluble photoisomers as a result of phototherapy. The initial and most rapidly formed configurational isomer 4z, 15e bilirubin accounts for 20% of total serum bilirubin level in newborns undergoing phototherapy and is produced maximally at conventional levels of irradiance (6-9 µW/cm2/nm).
    • The structural isomer lumirubin is slowly formed, and its formation is irreversible and is directly proportional to the irradiance and surface area of skin exposed to phototherapy. Lumirubin is the predominant isomer formed during high-intensity phototherapy.[58] Decrease in bilirubin is mainly the result of excretion of these photoproducts in bile and removal via stool. In the absence of conjugation, these photoisomers can be reabsorbed by way of the enterohepatic circulation and diminish the effectiveness of phototherapy.
    • Phototherapy implementation guidelines were recently addressed in recent clinical practice guidelines published by the American Academy of Pediatrics.[59] The recommendations are as follows:
      • The guidelines are based on total serum bilirubin levels and the direct fraction should not be subtracted from the total unless it is more than 50% of the total serum bilirubin level.
      • Intensive phototherapy should be started for babies with hemolytic disease. This implies the use of irradiance in the 430-490 nm band of more than 30 µW/cm2/nm delivered to as much of the infant's surface area as possible. This can be accomplished using special blue fluorescent tubes that are labeled F20T12/BB (General Electric, Westinghouse, Sylvania) or TL52/20W (Phillips, Eindhoven, The Netherlands) and positioning them 10-15 cm above the infant. When fluorescent tubes are used, they should be brought as close to the infant as possible to increase irradiance. However, when halogen spotlights are used, the distance above the infant should be as per the manufacturer's instructions because spotlights can cause burns. Phototherapy lights emit minimal UV radiation that does not cause erythema and is completely absorbed by the acrylic Plexiglas covering of the tubes.
      • Irradiance should be measured using radiometers recommended by the manufacturers of phototherapy systems at multiple sites on the infant's body surface illuminated by the phototherapy lamp and the measurements averaged.
      • The infant should be in the bassinet, and the sides should be lined with white cloth or aluminum foil to expose more surface area. The exposed surface area is increased by the use of 1-2 fiberoptic pads that should be placed under the infant or by the use of BiliBed (Medela Inc; McHenry, Ill) or Bili-Bassinet (Olympic Medical; Seattle, Wash), which provides phototherapy from above and below. The diaper should be removed if bilirubin is approaching exchange levels.
      • The serum bilirubin declines by 0.5-1 mg/dL in the first 4-8 hours on intensive phototherapy and should be measured in 2-3 hours to document the effectiveness.
      • If the serum bilirubin level continues to rise despite intensive phototherapy or is within 2-3 mg/dL of exchange level, administer intravenous immunoglobulin (IVIG) at 0.5-1 g/kg over 2 hours and repeat every 12 hours if needed.
      • High-dose IVIG 1 g/kg given early in high-risk neonates with rapid rise of bilirubin level (>0.5 mg/kg/h) and worsening anemia (Hb < 12 g/dL) despite intensive phototherapy, is be able to eliminate the need for exchange transfusion and to reduce duration of phototherapy. The number needed to treat (NNT) is 6.[59]
    • Phototherapy is indicated in the term infant with hemolytic disease of the newborn immediately after birth due to Rh disease and due to ABO incompatibility as follows:[60]
      • Unborn (cord blood) - Total serum bilirubin level of more than 3.5 mg/dL
      • Age less than 12 hours - Total serum bilirubin level of more than 10 mg/dL
      • Age less than 18 hours - Total serum bilirubin level of more than 12 mg/dL
      • Age less than 24 hours - Total serum bilirubin level of more than 14 mg/dL
      • Age 2-3 days - Total serum bilirubin level of more than 15 mg/dL
      • Immediately after birth in all preterms who weigh less than 2500 g
  • Exchange transfusion removes circulating bilirubin and antibody-coated RBCs, replacing them with RBCs compatible with maternal serum and providing albumin with new bilirubin binding sites. The process is time consuming and labor intensive but remains the ultimate treatment to prevent kernicterus. The process involves the placement of a catheter via the umbilical vein into the inferior vena cava and removal and replacement of 5- to 10-mL aliquots of blood sequentially, until about twice the volume of the neonate's circulating blood volume is reached (ie, double-volume exchange).
  • This process removes approximately 70-90% of fetal RBCs. The amount of bilirubin removed directly varies with the pretransfusion bilirubin level and amount of blood exchanged. Because most of the bilirubin is in the extravascular space, only about 25% of the total bilirubin is removed by an exchange transfusion. A rapid rebound of serum bilirubin level is common after equilibration and frequently requires additional exchange transfusions.
  • The indications for exchange transfusion are controversial, except for the fact that severe anemia and the presence of a rapidly worsening jaundice despite optimal phototherapy in the first 12 hours of life indicate the need for exchange transfusion. In addition, the presence of conditions that increase the risk of bilirubin encephalopathy lowers the threshold of safe bilirubin levels.
  • Guidelines for exchange transfusion in neonates with hemolytic disease of the newborn are as follows:[61]
    • Total serum bilirubin level of more than 20 mg/dL - Weight more than 2500 g (healthy)
    • Total serum bilirubin level of more than 18 mg/dL - Weight more than 2500 g (septic)
    • Total serum bilirubin level of more than 17 mg/dL - Weight 2000-2499 g
    • Total serum bilirubin level of more than 15 mg/dL - Weight 1500-1999 g
    • Total serum bilirubin level of more than 13 mg/dL - Weight 1250-1499
    • Total serum bilirubin level of 9-12 mg/dL - Weight less than 1250
  • The following are indications for exchange transfusion:[62]
    • Severe anemia (Hb < 10 g/dL)
    • Cord bilirubin > 4 mg/dL.
    • Rate of bilirubin rises more than 0.5 mg/dL despite intensive phototherapy
    • Severe hyperbilirubinemia[59]
    • Serum bilirubin-to-albumin ratio exceeding levels that are considered safe
  • Exchange transfusion should be considered in newborns born at more than 38 weeks' gestation with a bilirubin-to-albumin ratio of 7.2 and in newborns born at 35-37 weeks' gestation with a bilirubin-to-albumin ratio of 6.8. Exchange transfusion is not free of risk, with the estimated morbidity rate at 5% and the mortality rate as high as 0.5%. Apnea, bradycardia, cyanosis, vasospasm, and hypothermia with metabolic abnormalities (eg, hypoglycemia, hypocalcemia) are the most common adverse effects.
  • IVIG has been shown to reduce the need for exchange transfusion in hemolytic disease of the newborn due to Rh or ABO incompatibility. The number needed to treat to prevent one exchange transfusion was noted to be 2.7 and was estimated to be 10, if all the infants with strongly positive direct Coombs test were to receive the medication.[63, 64] In addition, it also reduced the duration of hospital stay and phototherapy.[55] Although it was very effective as a single dose, multiple doses were more effective in stopping the ongoing hemolysis and reducing the incidence of late anemia.
  • A randomized, controlled trial by Smits-Wintjens et al, however, failed to show the benefit of prophylactic single-dose IVIG at 0.75 g/kg within 4 hours of life in severely sensitized neonates with prior IUT due to Rh alloimmunization.[56] While IVIG has been proven to be safe, a retrospective review reported almost 30-times increased risk of necrotizing enterocolitis (NEC) in late preterm and term infants.[65]
  • Tin-mesoporphyrin in a dose of 4.5 mg/kg (6 µmole/kg) was used in an infant with persistent hemolysis due to Rh alloimmunization to prevent need for further phototherapy, without any adverse effects.[66]
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Deterrence/Prevention

Consider the following in patients with hemolytic disease of the newborn:

  • Rh immune globin (RhIG) was licensed in 1968 in North America after several studies demonstrated its effectiveness in preventing Rh alloimmunization when administered to the mother within 72 hours of delivery. The current standard is to administer RhIG to all unsensitized Rh-negative women at 28 weeks' gestation with an additional dose administered soon after birth if the infant is Rh-positive, irrespective of the ABO status of the baby. RhIG is not indicated for mothers with weak or partial D status because most are not at risk for alloimmunization.[42]
  • The standard dose of RhIG is 300 mcg and is increased (300 mcg for every 25 mL of fetal blood in maternal circulation) based on the amount of fetomaternal hemorrhage, which can be quantified using the Kleihauer-Betke technique. Because only 50% of pregnancies with excess fetomaternal hemorrhage can be identified by clinical risk factors, routine screen for excess fetomaternal hemorrhage (FMH) is undertaken in all Rh negative women. However, if the incidence of excess FMH is 0.6%, the maximum risk of sensitization is 0.1%, suggesting routine assessment for excess FMH may not be justified.
  • Also administer RhIG to unsensitized Rh-negative women after any event known to be associated with transplacental hemorrhage such as spontaneous or elective abortion, ectopic pregnancy, amniocentesis, chorionic villous sampling, fetal blood sampling (FBS), hydatiform mole, fetal death in late gestation, blunt abdominal trauma, and external cephalic version. The indications for first trimester threatened abortion and ectopic pregnancy with no cardiac activity are not cost effective and are left to the clinician.[17]
  • No more than 5 units of RhIG should be given by intramuscular route in 24-hour period. An intravenous preparation is now available for administration of large doses. If RhIG was inadvertently omitted after delivery, the protection can still be offered if given within first 4 weeks. A repeat dose is not needed if delivery occurs within 3 weeks after administration of RhIG during antenatal period. The current incidence of Rh immunization stands at 0.1% with the above recommendations.
  • Most RhIG is derived from human plasma obtained from sensitized women or male donors sensitized with RhD positive cells. Because it is a blood product, it has risks of transmission of viral infections such as hepatitis C and may not be acceptable in some religious denomination. Hence 2 monoclonal anti-D antibodies derived from recombinant technology, BRAD-1 and BRAD-3, are being tested in clinical trials. A new novel polyclonal recombinant antibody, rozrolimupab has also been tested in phase I and II clinical trials with no adverse effects.[67]
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Complications

The 2 major complications of hemolytic disease of the newborn are bilirubin encephalopathy (kernicterus) and late anemia of infancy.

  • Bilirubin encephalopathy
    • Before the advent of exchange transfusion, kernicterus affected 15% of infants born with erythroblastosis. Approximately 75% of these neonates died within 1 week of life, and a small remainder died during the first year of life. Survivors had permanent neurologic sequelae and were thought to have accounted for 10% of all patients with cerebral palsy (CP).
    • The mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. Bilirubin enters the brain as lipophilic free bilirubin unbound to albumin, as supersaturated bilirubin acid that precipitates on lipid membrane in low pH, or as a bilirubin-albumin complex that transfers bilirubin to tissue by direct contact with cellular surface. The blood-brain barrier is comprised of ATP-dependent transport proteins and pumps free bilirubin from the brain back into plasma and maintains the concentration gradient of unconjugated bilirubin. A damaged blood-brain barrier enhances the entry and fails to remove all forms of bilirubin into the brain, which is especially important in preterm neonates with respiratory acidosis and vascular injury.
    • Bilirubin has been postulated to cause neurotoxicity via 4 distinct mechanisms:[58] (1) interruption of normal neurotransmission (inhibits phosphorylation of enzymes critical in release of neurotransmitters), (2) mitochondrial dysfunction, (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and precipitates on phospholipid membranes of mitochondria), and (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes).
    • The pathologic findings include characteristic staining and neuronal necrosis in basal ganglia (especially the globus pallidus and subthalamic nucleus), hippocampal cortex (especially the CA2 sector), brainstem nuclei (especially the auditory, vestibular, and oculomotor), and cerebellum (especially Purkinje cells). The cerebral cortex is generally spared. About half of these neonates also have extraneuronal lesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic cells.
    • Clinical signs of bilirubin encephalopathy typically evolve in 3 phases. Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and hypertonia are observed in phase 2, and, at times, the condition progresses to opisthotonus. Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor feeding, and athetosis.
    • Long-term sequelae include choreoathetoid CP, upward gaze palsy, sensorineural hearing loss, dental enamel hypoplasia of the deciduous teeth, and, less often, mental retardation. The abnormal or reduced auditory brainstem response of wave I (auditory nerve) and wave II and V (auditory brainstem nuclei), depicted as decreased amplitudes, and increased interval I-III and I-V characterize phase I of early, but reversible, encephalopathy. Subtle bilirubin encephalopathy that consists of either cognitive dysfunction, isolated hearing loss, or movement disorder has been described in absence of kernicterus and better correlates with free bilirubin levels.
    • Currently, the mortality rate stands at 50% in term newborns, but mortality is nearly universal in the preterm population who may simply appear ill without signs specific for kernicterus. Research has indicated that bilirubin production rates may be the critical piece of information identifying jaundiced infants at risk of neurotoxicity. A high bilirubin production rate is thought to result in rapid transfer of bilirubin to tissue, causing high tissue load, in which case any small further increase has great potential to enter the brain. Because the total serum bilirubin represents not only bilirubin production but also distribution and elimination, it is not an absolute indicator of risk of kernicterus. Techniques have been developed to measure the bilirubin production rates accurately and noninvasively using end-tidal carbon monoxide measurement and percutaneous measurement of carboxyhemoglobin.
  • Late anemia of infancy
    • Infants with significant hemolytic disease often develop anemia in the first month of life and frequently (50%) require packed RBC transfusion. The anemia appears to be due to several factors including suppression of fetal erythropoiesis from transfusion of adult Hb during intrauterine or exchange transfusion, resulting in low erythropoietin levels and reticulocyte count.
    • Continued destruction of neonatal RBCs by high titers of circulating maternal antibodies also contributes the development of anemia. Weekly Hcts and reticulocyte count need to be monitored after discharge until renewed erythropoiesis is noted. Administration of recombinant human erythropoietin (rh-EPO) has been shown to minimize the need for transfusion in these newborns.[68]

Potential complications of exchange transfusion include the following (despite declining frequency of exchange transfusion, adverse events and complications have remained stable in most recent reports)[69, 70] :

  • Cardiac - Arrhythmia, volume overload, congestive failure, and arrest
  • Hematologic - Overheparinization, neutropenia, thrombocytopenia, and graft versus host disease
  • Infectious - Bacterial, viral (cytomegalovirus [CMV], human immunodeficiency virus [HIV], hepatitis), and malarial
  • Metabolic - Acidosis, hypocalcemia, hypoglycemia, hyperkalemia, and hypernatremia
  • Vascular - Embolization, thrombosis, necrotizing enterocolitis, and perforation of umbilical vessel
  • Systemic - Hypothermia
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Prognosis

Overall survival is 85-90% but reduced for hydropic fetuses by 15%. Most survivors of alloimmunized gestation are intact neurologically. Fetal hydrops does not seem to affect long-term outcome.[71] However, neurologic abnormality has been reported to be closely associated with severity of anemia and perinatal asphyxia. Sensorineural hearing loss may be slightly increased.

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Contributor Information and Disclosures
Author

Sameer Wagle, MBBS, MD Consulting Staff, Division of Neonatology, Northwest Medical Center of Springdale and Willow Creek Women’s Hospital

Sameer Wagle, MBBS, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Prashant G Deshpande, MD Attending Pediatrician, Department of Pediatrics, Christ Hospital Medical Center and Hope Children's Hospital; Assistant Clinical Professor of Pediatrics, Midwestern University

Prashant G Deshpande, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Telemedicine Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David A Clark, MD Chairman, Professor, Department of Pediatrics, Albany Medical College

David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical and Dental Associations, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Oussama Itani, MD, FAAP, FACN Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center

Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American Association for Physician Leadership, American Heart Association, American College of Nutrition

Disclosure: Nothing to disclose.

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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.
Modified Liley curve for gestation of less than 24 weeks showing that bilirubin levels in amniotic fluid peak at 23-24 weeks' gestation.
Queenan Curve: Modified Liley curve that shows delta-OD 450 values at 14-40 weeks' gestation.
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).
Management of first affected pregnancy.
Management of pregnant women with previously affected fetus.
Table. Comparison of Rh and ABO Incompatibility
CharacteristicsRhABO
Clinical aspectsFirst born5%50%
Later pregnanciesMore severeNo increased severity
Stillborn/hydropsFrequentRare
Severe anemiaFrequentRare
JaundiceModerate to severe, frequentMild
Late anemiaFrequentRare
Laboratory findingsDirect antibody testPositiveWeakly positive
Indirect Coombs testPositiveUsually positive
SpherocytosisRareFrequent
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