Fetal blood group genotype for managing hemolytic disease of fetus and newborn


A systematic review and meta-analysis on the benefits of non-invasive prenatal testing (NIPT) for detecting hemolytic disease of fetus and newborn (HDNF) validates routing anti-D prophylaxis.

The review in the journal Transfusion Medicine Reviews also concluded that NIPT is highly sensitive and specific for RHD genotyping beyond 11-week gestation and that the test can estimate potential fetal risks for guiding further interventions.

The authors noted that HDFN poses a tremendous healthcare burden linked to maternal alloimmunization against parental-inherited fetal red blood cell antigens that cause fetal anemia and death.

“We were inspired to undertake the review to investigate the use of NIPT for fetal RHD genotyping and its application to other blood group systems to identify HDFN,” said co-author Denise Jackson, PhD, a professor of hematology at the Royal Melbourne Institute of Technology (RMIT) University in Melbourne, Australia.

Only relevant English-written studies that reported reference tests and accuracy data for NIPT were searched in PubMed/Medline, Scopus and Ovid for published articles from January 2006 to April 2020.

The 24 geographically diverse eligible studies from 13 countries revealed that routine cord blood serology was adopted by all studies in conjunction with fetal genotyping by NIPT.

Fetal RHD genotyping was performed through targeting several RHD exons; 4, 5, 7 and/or 10, as triplicates for increasing NIPT sensitivity.But 3 studies targeted only a singlet RHD exon: 4 or 10.

The studies showed that amplifications from ≥2 exons are optimum to increase accuracy.

In addition, NIPT is cost-effective and precious resources sparing, along with low emotional stress for the patient.

However, knowledge of parental ethnicity is critical for correct NIPT result interpretations and quantitative screening.

Cut-off titers of ≥8 and up to 32 impact anti-D alloantibodies, while a lower titer is applicable for anti-K antibodies.

Alloimmunization is influenced by maternal RHD status, gravida status and history of adverse obstetrics.

“The use of NIPT genotyping for RHD will be extremely useful to determine early in pregnancy which ones are at risk of alloimmunization to RHD antigen and the need for Rh immune globulin (RhIg),” Jackson told Contemporary OB/GYN®. “NIPT canalso be used to determine the need for RhIg.If the fetus is a true RHD negative, then RhIg would not be required”.

NIPT provides safe genotyping, according to the authors, and it is a more convenient source of fetal circulating free DNA (cfDNA) than traditional invasive testing, such as cordocentesis, amniocentesis or chorionic villus sampling, which causes a higher risk of fetal loss.

“NIPT can be used to detect other blood group system genotypes as well,” Jackson said.“For instance, both anti-c and anti-Kell (anti-K) antibodies are associated with severe HDFN.”

NIPT testing also can be used for determining fetal c or K antigen status. “This is important for management of pregnancies affected by anti c or anti K antibodies where the titer does not correlate with disease severity,” Jackson said.

However, mothers with weak/partial-D phenotypes increase the risk of obtaining false-positive and inconclusive results during NIPT testing.

Furthermore, fetal RHD genotyping by NIPT cannot completely prevent RHD-negative pregnancies from HDFN risk because other blood groups can result in maternal alloimmunization.

Ethnicity impacts those non-RHD-related HDFN cases as well.

Therefore, large-scale studies of NIPT for non-RHD genotyping within different ethnic groups and in the presence of clinically significant alloantibodies are needed, according to the authors.



Jackson reports no relevant financial disclosures.


  1. Alshehri AA, Jackson DE.Non-invasive prenatal fetal blood group genotype and its application in the management of hemolytic disease of fetus and newborn: systematic review and meta-analysis.Transfus Med Rev. Published online March 1, 2021. doi:10.1016/j.tmrv.2021.02.001
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