Which clinical history findings are characteristic of hemolytic disease of the newborn (HDN)?

Updated: Dec 28, 2017
  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Muhammad Aslam, MD  more...
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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. [20] In the event of unclear ethnicity, quantitative polymerase chain reaction (PCR) of the RHD gene has been used to detect the heterozygous state. [21] Two such assays, one based on direct amplification of deletion and the other using RHD gene copy number with a reference gene, are available. Recent research revealed quantitative PCR to be highly accurate for detecting a paternal heterozygous state and now is preferred over serologic testing owing to the high frequency of interracial marriages. [22]

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 [23] or on cell-free DNA in maternal circulation. [24] 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. [25] 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. [26] 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 [27] 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). [28]

Modified Liley curve for gestation of less than 24 Modified 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). [29]

Queenan Curve: Modified Liley curve that shows del Queenan 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. [30] 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%. [31]

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