Transfusion support during childbirth for a woman with anti-U and the RHD*weak D type 4.0 allele

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VOLUME 37 , ISSUE 1 (March 2021) > List of articles

Transfusion support during childbirth for a woman with anti-U and the RHD*weak D type 4.0 allele

Q. Yin / K. Srivastava / D.G. Brust / W.A. Flegel *

Keywords : RHD*weak D type 4.0 allele, RhIG, pregnancy

Citation Information : Immunohematology. Volume 37, Issue 1, Pages 1-4, DOI: https://doi.org/10.21307/immunohematology-2021-001

License : (Transfer of Copyright)

Published Online: 31-March-2021

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ABSTRACT

D– red blood cells (RBCs), always in short supply, and Rh immune globulin (RhIG) are not needed for patient care if D+ RBCs can safely be transfused. According to a recent work group recommendation, patients with the RHD*weak D type 4.0 allele can be considered D+. We report an African American woman who presented for delivery at the end of the third trimester, at which time anti-U and a serologic weak D phenotype were recognized, requiring U–, D– RBC units. We obtained 3 U– RBC units, including 1 D– unit. Later, the RHD*weak D type 4.0 allele was determined by RHD genotyping, only 6 days before delivery. The patient had an uneventful vaginal delivery of a D+ baby. No transfusion was needed for mother or baby. In this case, a pregnant woman with the RHD*weak D type 4.0 allele can safely be managed as D+, relaxing the unnecessary D– restriction for the limited U– RBC supply. The procured U–, D– RBC unit was frozen with 14 days of shelf-life remaining. To conserve D– RBC units, not limited to U–, for patients with a definite need, we recommend molecular analysis of a serologic weak D phenotype before a transfusion becomes imminent. The best time to resolve a serologic weak D phenotype with RHD genotyping is early in a pregnancy. Immunohematology 2021;37:1–4.

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Hemolytic disease of the fetus and newborn is reliably prevented by proper management, based on antenatal D typing and screening for red blood cell (RBC) antibodies. Many hospital laboratories do not determine the RHD genotype of pregnant women with a serologic weak D phenotype, because these women are often managed as D–.1 However, Rh immune globulin (RhIG) and provision of D– RBC units are unnecessary if D+ RBCs can safely be transfused. An Interorganizational Work Group on RHD Genotyping recommended in 20152 to phase-in RHD genotyping for patients with a serologic weak D phenotype. The same authors3 specified their recommendation in 2020 to phase-out the reporting of a “serologic weak D phenotype” and resolve all weak D types with RHD genotyping.

We report a pregnant woman with anti-U and a serologic weak D phenotype. The clinical workup in this case illustrated the importance of molecular analysis of serologic weak D phenotypes early in the pregnancy to preserve rare D– RBC units and to eliminate the unnecessary administration of RhIG.

Case Report and Results

A 23-year-old African American woman (gravida 2, para 1) presented for childbirth. The woman had no history of blood transfusion. Testing of her blood sample showed her RBCs to be group B with a serologic weak D phenotype; anti-U was identified by the antibody screening process (Table 1). Without any molecular information for her RHD genotype, the woman was initially considered to be managed as D–. We decided to obtain 3 U– RBC units; however, only 1 was D–.

Table 1.

Clinical laboratory results for mother and neonate

10.21307_immunohematology-2021-001-tbl1.jpg

In the week before delivery, nucleotide sequencing of the RHD gene was performed on the mother and, later, on the neonate.4 Based on the three amino acid substitutions (Table 2), we concluded that the mother carried the RHD*weak D type 4.0 allele (Table 2) and was hemizygous for the RHD gene. The neonate was a compound heterozygote for the RHD gene with a RHD*weak D type 4.0 allele from the mother in trans to a normal RHD allele from the father. A total of 12 and 13 nucleotide changes were confirmed in the mother and neonate, respectively (Table 2).

Table 2.

Single nucleotide variants detected in the RHD gene

10.21307_immunohematology-2021-001-tbl2.jpg

Zygosity testing for the RHD gene was done by a quantitative fluorescence–polymerase chain reaction (QF-PCR) assay.5 The mother was hemizygous (one copy) and the neonate was homozygous (two copies) for the RHD gene. The QF-PCR is the preferred method for RHD zygosity testing in individuals of African descent, although it is known to have limitations in white individuals where a restriction fragment– length polymorphism (RFLP) assay may be the more reliable method.6–8

We still applied an RFLP assay that is designed to detect the standard downstream Rhesus box, indicative of the presence of an RHD gene (i.e., lack of the RHD deletion).7 However, the mother who carried an RHD gene tested negative (seemingly no copies) in this RFLP assay, and the neonate who carried two copies of the RHD gene tested hemizygous for the RHD gene (seemingly only one copy). These discrepancies are explained by variations in the downstream Rhesus box of individuals of African ancestry and are a known limitation of the RFLP assay in these individuals.6,8,9

The mother, with an unexplained hemoglobin (Hb) concentration of 9.8 g/dL prepartum, had an uneventful vaginal delivery. Her Hb dropped by 0.9 g/dL, and she did not require transfusion (Table 1). The neonate’s blood sample typed as group B, D+ with normal clinical laboratory results (Table 1), and no treatment was required. The 2 U–, D+ RBC units were returned and used in the care of another pregnant woman with anti-U. The unnecessarily procured U–, D– RBC unit had to be frozen, however, with only 14 days of shelf-life remaining.

Discussion

The present clinical report exemplifies the advantage of RHD genotyping in expectant mothers to identify RHD alleles that allow the mothers to be safely treated as D+.3 The molecular analysis should be performed early in a pregnancy. This approach, which was missed at the first-time maternity visit in our patient, would have allowed for an efficient organization of RBC genotyping with or without antibody identification. Most hospitals would typically send samples to an immunohematology reference laboratory. In our case, while birth was imminent, the shipping and testing was accomplished within 5 days, including a weekend. The extra cost inflicted by this time constraint could surely have been avoided with better planning of the required tests during the pregnancy. Complex serologic and molecular testing in immunohematology are more prone to errors when performed under extreme time constraints and thus should be avoided.

The blood supply in transfusion service is often limited, especially for patients with the D– phenotype, and more so if antibodies to high-prevalence RBC antigens are also present.10 For the expectant mother in our study, a compatible donor with a U–, D– phenotype is extremely rare, representing <0.1 percent of the African American population.11 U–, D+ RBC units are also very rare, but there are five to ten times more donors if the D– restriction can be removed.

Supporting every patient who is D+ due to RHD*weak D type 4.0 with D– RBC units to prevent anti-D would be a burden and is discouraged.3,12 D– RBC transfusion and RhIG administration may be considered during pregnancy in an abundance of caution, although several health care systems are considering moving to an exclusively D+ transfusion management policy.3,13,14 Pregnant women with the RHD*weak D type 4.0 allele, who were never shown to produce an alloanti-D with adverse clinical outcome, could falsely be diagnosed of carrying an alloanti-D that is actually due to RhIG administration.13,14 This passively acquired anti-D can mislead the results of compatibility testing, when RBC units are crossmatched in preparation for delivery. Pitfalls of mistaking passive anti-D for active immunization can be avoided by obtaining a history and performing an anti-D titer.15 In summary, we decided to treat the current patient as D+ for transfusion purposes and recommended against RhIG administration during pregnancy and after the birth of the D+ baby boy.

Studies on cost and financial implications explored the economic aspect of RHD genotyping for pregnant women with a weak D phenotype.16,17 If the personal health information is properly maintained and shared, particularly in highly developed countries like the United States, RHD genotyping would add only a one-time testing cost for each pregnant woman with a weak D phenotype, while providing a rationale for the transfusion strategy during the rest of a woman’s life.18 This strategy could prevent unnecessary costs and risks associated with RhIG administration and follow-up scheduling during the current and every subsequent pregnancy.3 The best time to resolve a serologic weak D phenotype with RHD genotyping is early in the first pregnancy.2

Acknowledgments

We thank Marina U. Bueno in the Immunohematology Reference Laboratory and Traci D. Paige in the Transfusion Services Laboratory in the Department of Transfusion Medicine, NIH Clinical Center at the National Institutes of Health (NIH), for support. This case report was presented by Martin S. Ongkeko, MD, at the Clinical Vignette session of the Virtual 10th Annual Red Cell Genotyping 20/20 Symposium: Visionary Solutions, held on 9 September 2020 at the NIH Clinical Center. This work was supported in part by the Intramural Research Program (project ID ZIC CL002128) of the NIH Clinical Center at the National Institutes of Health.

References


  1. Sandler SG, Roseff SD, Domen RE, Shaz B, Gottschall JL. Policies and procedures related to testing for weak D phenotypes and administration of Rh immune globulin: results and recommendations related to supplemental questions in the Comprehensive Transfusion Medicine survey of the College of American Pathologists. Arch Pathol Lab Med 2014;138:620–5.
    [PUBMED] [CROSSREF]
  2. Sandler SG, Flegel WA, Westhoff CM, et al. It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group. Transfusion 2015;55:680–9.
    [PUBMED] [CROSSREF]
  3. Flegel WA, Denomme GA, Queenan JT, et al. It’s time to phase out “serologic weak D phenotype” and resolve D types with RHD genotyping including weak D type 4. Transfusion 2020;60:855–9.
    [PUBMED] [CROSSREF]
  4. Wagner FF, Gassner C, Müller TH, Schönitzer D, Schunter F, Flegel WA. Molecular basis of weak D phenotypes. Blood 1999;93:385–93.
    [PUBMED] [CROSSREF]
  5. Pirelli KJ, Pietz BC, Johnson ST, Pinder HL, Bellissimo DB. Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D. Prenat Diagn 2010;30:1207–12.
    [PUBMED] [CROSSREF]
  6. Grootkerk-Tax MG, Maaskant-van Wijk PA, van Drunen J, van der Schoot CE. The highly variable RH locus in nonwhite persons hampers RHD zygosity determination but yields more insight into RH-related evolutionary events. Transfusion 2005;45:327–37.
    [PUBMED] [CROSSREF]
  7. Wagner FF, Flegel WA. RHD gene deletion occurred in the Rhesus box. Blood 2000;95:3662–8.
    [PUBMED] [CROSSREF]
  8. Wagner FF, Moulds JM, Flegel WA. Genetic mechanisms of Rhesus box variation. Transfusion 2005;45:338–44.
    [PUBMED] [CROSSREF]
  9. Wagner FF, Moulds JM, Tounkara A, Kouriba B, Flegel WA. RHD allele distribution in Africans of Mali. BMC Genet 2003;4:14.
    [PUBMED] [CROSSREF]
  10. Seltsam A, Wagner FF, Salama A, Flegel WA. Antibodies to high-frequency antigens may decrease the quality of transfusion support: an observational study. Transfusion 2003;43:1563–6.
    [PUBMED] [CROSSREF]
  11. Beadling W, Cooling L. Immunohematology. In: McPherson R, Pincus M, Eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. Philadelphia, PA: Elsevier, 2007: 617–36.
  12. Westhoff CM, Nance S, Lomas-Francis C, Keller M, Chou ST. Experience with RHD*weak D type 4.0 in the USA. Blood Transfus 2019;17:91–3.
    [PUBMED]
  13. Ouchari M, Srivastava K, Romdhane H, Jemni Yacoub S, Flegel WA. Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia. Transfusion 2018;58:306–12.
    [PUBMED] [CROSSREF]
  14. Flegel WA, Peyrard T, Chiaroni J, Tournamille C, Jamet D, Pirenne F. A proposal for a rational transfusion strategy in patients of European and North African descent with weak D type 4.0 and 4.1 phenotypes. Blood Transfus 2019;17:89–90.
    [PUBMED]
  15. Evans ML, Holmes B, Dowling K, et al. Evaluating automated titre score as an alternative to continuous flow analysis for the prediction of passive anti-D in pregnancy. Transfus Med 2021;31:36–42.
    [PUBMED] [CROSSREF]
  16. Kacker S, Vassallo R, Keller MA, et al. Financial implications of RHD genotyping of pregnant women with a serologic weak D phenotype. Transfusion 2015;55:2095–103.
    [PUBMED] [CROSSREF]
  17. Laget L, Izard C, Durieux-Roussel E, et al. Relevance and costs of RHD genotyping in women with a weak D phenotype. Transfus Clin Biol 2019;26:27–31.
    [PUBMED] [CROSSREF]
  18. Flegel WA. How I manage donors and patients with a weak D phenotype. Curr Opin Hematol 2006;13:476–83.
    [PUBMED] [CROSSREF]
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REFERENCES

  1. Sandler SG, Roseff SD, Domen RE, Shaz B, Gottschall JL. Policies and procedures related to testing for weak D phenotypes and administration of Rh immune globulin: results and recommendations related to supplemental questions in the Comprehensive Transfusion Medicine survey of the College of American Pathologists. Arch Pathol Lab Med 2014;138:620–5.
    [PUBMED] [CROSSREF]
  2. Sandler SG, Flegel WA, Westhoff CM, et al. It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group. Transfusion 2015;55:680–9.
    [PUBMED] [CROSSREF]
  3. Flegel WA, Denomme GA, Queenan JT, et al. It’s time to phase out “serologic weak D phenotype” and resolve D types with RHD genotyping including weak D type 4. Transfusion 2020;60:855–9.
    [PUBMED] [CROSSREF]
  4. Wagner FF, Gassner C, Müller TH, Schönitzer D, Schunter F, Flegel WA. Molecular basis of weak D phenotypes. Blood 1999;93:385–93.
    [PUBMED] [CROSSREF]
  5. Pirelli KJ, Pietz BC, Johnson ST, Pinder HL, Bellissimo DB. Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D. Prenat Diagn 2010;30:1207–12.
    [PUBMED] [CROSSREF]
  6. Grootkerk-Tax MG, Maaskant-van Wijk PA, van Drunen J, van der Schoot CE. The highly variable RH locus in nonwhite persons hampers RHD zygosity determination but yields more insight into RH-related evolutionary events. Transfusion 2005;45:327–37.
    [PUBMED] [CROSSREF]
  7. Wagner FF, Flegel WA. RHD gene deletion occurred in the Rhesus box. Blood 2000;95:3662–8.
    [PUBMED] [CROSSREF]
  8. Wagner FF, Moulds JM, Flegel WA. Genetic mechanisms of Rhesus box variation. Transfusion 2005;45:338–44.
    [PUBMED] [CROSSREF]
  9. Wagner FF, Moulds JM, Tounkara A, Kouriba B, Flegel WA. RHD allele distribution in Africans of Mali. BMC Genet 2003;4:14.
    [PUBMED] [CROSSREF]
  10. Seltsam A, Wagner FF, Salama A, Flegel WA. Antibodies to high-frequency antigens may decrease the quality of transfusion support: an observational study. Transfusion 2003;43:1563–6.
    [PUBMED] [CROSSREF]
  11. Beadling W, Cooling L. Immunohematology. In: McPherson R, Pincus M, Eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. Philadelphia, PA: Elsevier, 2007: 617–36.
  12. Westhoff CM, Nance S, Lomas-Francis C, Keller M, Chou ST. Experience with RHD*weak D type 4.0 in the USA. Blood Transfus 2019;17:91–3.
    [PUBMED]
  13. Ouchari M, Srivastava K, Romdhane H, Jemni Yacoub S, Flegel WA. Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia. Transfusion 2018;58:306–12.
    [PUBMED] [CROSSREF]
  14. Flegel WA, Peyrard T, Chiaroni J, Tournamille C, Jamet D, Pirenne F. A proposal for a rational transfusion strategy in patients of European and North African descent with weak D type 4.0 and 4.1 phenotypes. Blood Transfus 2019;17:89–90.
    [PUBMED]
  15. Evans ML, Holmes B, Dowling K, et al. Evaluating automated titre score as an alternative to continuous flow analysis for the prediction of passive anti-D in pregnancy. Transfus Med 2021;31:36–42.
    [PUBMED] [CROSSREF]
  16. Kacker S, Vassallo R, Keller MA, et al. Financial implications of RHD genotyping of pregnant women with a serologic weak D phenotype. Transfusion 2015;55:2095–103.
    [PUBMED] [CROSSREF]
  17. Laget L, Izard C, Durieux-Roussel E, et al. Relevance and costs of RHD genotyping in women with a weak D phenotype. Transfus Clin Biol 2019;26:27–31.
    [PUBMED] [CROSSREF]
  18. Flegel WA. How I manage donors and patients with a weak D phenotype. Curr Opin Hematol 2006;13:476–83.
    [PUBMED] [CROSSREF]

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