Hemolytic Disease of Newborn Clinical Presentation

  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Ted Rosenkrantz, MD   more...
 
Updated: May 18, 2011
 

History

Two usual patterns of Rh isoimmunization severity are noted. The disease may remain at the same degree of severity or may become progressively worst with each pregnancy. A history of hydropic birth increases the risk of fetal hydrops in the next pregnancy to 90%; the fetal hydrops occurs at about the same time or earlier in gestation in the subsequent pregnancy. Women at risk for alloimmunization should undergo an indirect Coombs test and antibody titers at their first prenatal visit. If results are 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.[11] In the event of unclear ethnicity, quantitative polymerase chain reaction (PCR) of the RHD gene has been used to detect the heterozygous state.[12] Two such assays, one based on direct amplification of deletion and the other using RHD gene copy number with a reference gene, are available.

Obtaining serial maternal titers is suggested if the father is homozygous. If the father is heterozygous, determine fetal Rh genotype using PCR for the RHD gene on fetal cells obtained at amniocentesis[13] or on cell-free DNA in maternal circulation.[14] The sensitivity and specificity of PCR typing on amniotic fluid is 98.7% and 100%, respectively. However, obtaining maternal blood to rule out a maternal RHD pseudogene (in a Rh-positive fetus) and obtaining paternal blood to rule out RHD gene locus rearrangement (in a Rh-negative fetus) is important to improve the accuracy.[15] Determining fetal Rh genotype is also possible by performing cordocentesis, which is also called fetal blood sampling (FBS). FBS is associated with a more than 4-fold increase in perinatal loss compared with amniocentesis.

Indicators for severe hemolytic disease of the newborn (HDN) include mothers who have had previous children with hemolytic disease, rising maternal antibody titers, rising amniotic fluid bilirubin concentration, and ultrasonographic evidence of fetal hydrops (eg, ascites, edema, pleural and pericardial effusions, worsening biophysical profile, decreasing hemoglobin [Hb] levels). The major advance in predicting the severity of hemolytic disease was the delta-OD 450 reported by Liley in 1961.[16] The serial values of deviation from baseline at 450 nm, the wavelength at which bilirubin absorbs light, are plotted on a Liley curve (see the image below) against the gestational weeks. The values above 65% on zone 2 indicate direct fetal monitoring by cordocentesis. Hematocrit (Hct) levels below 30% or a single value in zone 3 are indications for intrauterine transfusion.

Liley curve. This graph illustrates an example of 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.

The modification of Liley chart was developed by extrapolating the Liley curve[17] and is used to correct for gestations of less than 27 weeks because bilirubin levels normally peak at 23-25 weeks' gestation in unaffected fetuses (see the image below).[18]

Modified Liley curve for gestation of less than 24Modified Liley curve for gestation of less than 24 weeks showing that bilirubin levels in amniotic fluid peak at 23-24 weeks' gestation.

Another curve was developed by Queenan for management of pregnancies before 27 weeks' gestation (see the image below).[19]

Queenan Curve: Modified Liley curve that shows delQueenan Curve: Modified Liley curve that shows delta-OD 450 values at 14-40 weeks' gestation.

In a recent prospective evaluation, the Queenan curve predicted moderate anemia with a sensitivity of 83% and a specificity of 94%, whereas the sensitivity and specificity for severe anemia were 100% and 79%, respectively.[20] The delta-OD 450 value that plots out in the intrauterine death risk zone of Queenan curve indicates the need for FBS. A recent comparison of the curves found the Queenan curve to be superior to the Liley curve in overall sensitivity, specificity, and accuracy; when limited to less than 27 weeks' gestation, its sensitivity was higher by 10%, with both having a specificity of 40%.[21]

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Physical

An 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 intravascular transfusion (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 the Hb level drops below approximately 4 g/dL (Hct < 15%)[5] . Clinically significant jaundice occurs in as many as 20% of ABO-incompatible infants.

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Causes

In the absence of a positive direct Coombs test result, other causes of pathologic jaundice should be considered,[22] 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, GI obstruction, and metabolic diseases).

Similarly, hydrops can occur from nonimmune hematologic disorders that cause anemia, such as hemoglobinopathies (eg, α-thalassemia major), cardiac failure due to dysrhythmia, congenital heart defects, and infections (eg, syphilis, cytomegalovirus [CMV], parvovirus).

  • Common causes of hemolytic disease of the newborn
    • Rh system antibodies
    • ABO system antibodies
  • Uncommon causes - Kell system antibodies
  • Rare causes
    • Duffy system antibodies
    • MNS and s system antibodies
  • No occurrence in hemolytic disease of the newborn
    • Lewis system antibodies
    • P system antibodies
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Contributor Information and Disclosures
Author

Sameer Wagle, MBBS, MD  Consulting Staff, Division of Neonatology, Northwest Medical Center of Washington County

Sameer Wagle, MBBS, MD is a member of the following medical societies: American Academy of Pediatrics and 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, Oak Lawn, Illinois; Assistant Clinical Professor of Pediatrics, Midwestern University, Downers Grove, IL

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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 College of Nutrition, American College of Physician Executives, and American Heart Association

Disclosure: Nothing to disclose.

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 & Dental Society, Medical Society of the State of New York, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Carol L Wagner, MD  Professor of Pediatrics, Medical University of South Carolina

Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and 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 Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

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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