Modern Rhesus (Rh) typing in transfusion and pregnancy

Willy Albert Flegel

doi:10.1503/cmaj.201212

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What constitutes “the most cautious approach” for a pregnant woman with weak D type 4.0 and her baby?
Willy Albert Flegel [MD], Melanie Bodnar [MD FRCPC], Gwen Clarke [MD FRCPC], Judith Hannon [MD FRCPC] and Lani Lieberman [MD FRCPC]

Posted on: 28 April 2021
RE: Modern Rhesus (Rh) typing in transfusion and pregnancy
Melanie Bodnar [MD FRCPC], Judith Hannon [MD FRCPC] and Lani Lieberman [MD FRCPC]

Posted on: 06 April 2021

Posted on: (28 April 2021)
Page navigation anchor for What constitutes “the most cautious approach” for a pregnant woman with weak D type 4.0 and her baby?
What constitutes “the most cautious approach” for a pregnant woman with weak D type 4.0 and her baby?
Willy Albert Flegel [MD], Transfusion Medicine Specialist, Chief of Laboratory Services Section, NIH Clinical Center, National Institutes of Health
Other Contributors:
Melanie Bodnar, Hematopathologist, Transfusion Medicine Specialist

Gwen Clarke, Hematopathologist, Transfusion Medicine Specialist, Associate Medical Director of Donor and Clinical Services

Judith Hannon, Hematopathologist, Transfusion Medicine Specialist, Chair of Perinatal Advisory Council

Lani Lieberman, Pediatric Hematologist, Transfusion Medicine Specialist, Chair of Canadian Obstetric and Pediatric Transfusion Network
A recent Practice article(1) on “Five Things to Know about…Modern Rhesus (Rh) typing in transfusion and pregnancy” and its associated correspondence(2) prompted a productive discussion on safe recommendations for pregnancies in women with a weak D type 4.0 allele, originally described in 2000.(3) The differing approaches(1,2) represent the personal views of the respective authors. The brief format of the original article did, of course, not allow to present much evidence in support of the modern Rh typing strategy. Based on the review of 20 years’ worth of literature on this specialized topic, the undersigned authors have agreed on the following 5 statements:
1. There are no published case reports that any pregnant women with weak D type 4.0 have experienced an adverse clinical effect caused by an (allo- or auto-) anti-D (for instance, hemolysis).
2. There are no published case reports that a fetus or newborn have experienced an adverse clinical effect caused by such a mother’s (allo- or auto-) anti-D (for instance, anemia or jaundice).
3. There is no published evidence that RhIg is clinically effective in an individual with weak D type 4.0 (for instance, prevention of an anti-D formation). In such individuals, RhIg can cause a positive direct antiglobulin test, which does not imply clinical harm (for instance, hemolysis).
4. The weak D type 4.0 phenotype may be associated with a proportionately larger number of anti-D than most other weak D types.(...
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A recent Practice article(1) on “Five Things to Know about…Modern Rhesus (Rh) typing in transfusion and pregnancy” and its associated correspondence(2) prompted a productive discussion on safe recommendations for pregnancies in women with a weak D type 4.0 allele, originally described in 2000.(3) The differing approaches(1,2) represent the personal views of the respective authors. The brief format of the original article did, of course, not allow to present much evidence in support of the modern Rh typing strategy. Based on the review of 20 years’ worth of literature on this specialized topic, the undersigned authors have agreed on the following 5 statements:
1. There are no published case reports that any pregnant women with weak D type 4.0 have experienced an adverse clinical effect caused by an (allo- or auto-) anti-D (for instance, hemolysis).
2. There are no published case reports that a fetus or newborn have experienced an adverse clinical effect caused by such a mother’s (allo- or auto-) anti-D (for instance, anemia or jaundice).
3. There is no published evidence that RhIg is clinically effective in an individual with weak D type 4.0 (for instance, prevention of an anti-D formation). In such individuals, RhIg can cause a positive direct antiglobulin test, which does not imply clinical harm (for instance, hemolysis).
4. The weak D type 4.0 phenotype may be associated with a proportionately larger number of anti-D than most other weak D types.(4-6) The nature of these anti-D has not been well characterized (allo- vs. auto-antibody).(6) A fraction of all individuals with a weak D type 4.0 are routinely typed as normal RhD-positive and do not receive RhIg.(3,7,8)
5. The decision, whether or not to use RhIg and RhD-negative transfusion in such mothers, should be based on national guidelines.(9) Both approaches have been adopted by expert groups(2,6,8-10) and are considered safe. The individual decision may still depend on a patient’s circumstances.(11) If providers are unsure, consultation with a transfusion medicine physician or perinatal immunohematology reference lab is recommended.(1,10)

References
1. Flegel WA. Modern Rhesus (Rh) typing in transfusion and pregnancy. CMAJ 2021;193: E124.
2. Bodnar M, Hannon J, Lieberman L. RE: Modern Rhesus (Rh) typing in transfusion and pregnancy. CMAJ 6 Apr 2021;193:www.cmaj.ca/content/193/4/E124/tab-e-letters#re-modern-rhesus-rh-typing-...
3. Wagner FF, Frohmajer A, Ladewig B, et al. Weak D alleles express distinct phenotypes. Blood 2000;95:2699-708.
4. Flegel WA. How I manage donors and patients with a weak D phenotype. Curr. Opin. Hematol. 2006;13:476-83.
5. Pham BN, Roussel M, Gien D, et al. Molecular analysis of patients with weak D and serologic analysis of those with anti-D (excluding type 1 and type 2). Immunohematology 2013;29:55-62.
6. Westhoff CM, Nance S, Lomas-Francis C, et al. Experience with RHD*weak D type 4.0 in the USA. Blood Transfus 2019;17:91-3.
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Competing Interests: None declared.
References
7. Yu X, Wagner FF, Witter B, et al. Outliers in RhD membrane integration are explained by variant RH haplotypes. Transfusion 2006;46: 1343-51.
8. Ouchari M, Srivastava K, Romdhane H, et al. Transfusion strategy for weak D Type 4.0 based on RHD alleles and RH haplotypes in Tunisia. Transfusion 2018;58: 306-12.
9. Flegel WA, Peyrard T, Chiaroni J, et al. 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.
10. 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.
11. Yin Q, Srivastava K, Brust DG, et al. Transfusion support during childbirth for a woman with anti-U and the RHD*weak D type 4.0 allele. Immunohematology 2021;37: 1-4.
Posted on: (6 April 2021)
Page navigation anchor for RE: Modern Rhesus (Rh) typing in transfusion and pregnancy
RE: Modern Rhesus (Rh) typing in transfusion and pregnancy
Melanie Bodnar [MD FRCPC], Hematopathologist and Transfusion Medicine Specialist, Canadian Blood Services, 8249 114 Street, Edmonton, Alberta T6G-2R8
Other Contributors:
Judith Hannon, Hematopathologist and Transfusion Medicine Specialist, Chair of the Perinatal Advisory Council

Lani Lieberman, Pediatric Hematologist and Transfusion Medicine Specialist, Chair of the Canadian Obstetric and Pediatric Transfusion Network
Dr. Flegel’s recent publication highlights the importance of molecular testing for patients with serologic weak D.(1) We think there is currently insufficient evidence to consider weak D 4.0 as D positive and feel these individuals should receive Rh immune globulin (RhIg) prophylaxis during pregnancy and D negative red blood cells (RBC) for transfusion.

Although no clinically significant transfusion reactions or pregnancy complications have been reported for this weak D subtype, we feel caution is warranted as the risk of D alloimmunization has not been fully resolved in the literature. Indeed, a recent commentary by Dr. Flegel and other experts in the field acknowledge that for pregnant women with weak D type 4.0 RhIg may be indicated along with D negative transfusions. (2)

Observations from large reference laboratories in the United States note several cases of anti-D in women of childbearing age and patients with sickle cell disease who carry the weak D 4.0 allele: the distinction between auto-anti-D and allo-anti-D was not determined for the majority of these cases. (3) Alloantibodies may lead to delayed serologic and/or hemolytic transfusion reactions or hemolytic disease of the fetus and newborn. Weak D 4.0 is more common in individuals of African descent and given the heightened risk of transfusion associated hemolytic complications in the sickle cell population, this distinction is especially important. Westhoff et al. highlight the need for further...
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Dr. Flegel’s recent publication highlights the importance of molecular testing for patients with serologic weak D.(1) We think there is currently insufficient evidence to consider weak D 4.0 as D positive and feel these individuals should receive Rh immune globulin (RhIg) prophylaxis during pregnancy and D negative red blood cells (RBC) for transfusion.

Although no clinically significant transfusion reactions or pregnancy complications have been reported for this weak D subtype, we feel caution is warranted as the risk of D alloimmunization has not been fully resolved in the literature. Indeed, a recent commentary by Dr. Flegel and other experts in the field acknowledge that for pregnant women with weak D type 4.0 RhIg may be indicated along with D negative transfusions. (2)

Observations from large reference laboratories in the United States note several cases of anti-D in women of childbearing age and patients with sickle cell disease who carry the weak D 4.0 allele: the distinction between auto-anti-D and allo-anti-D was not determined for the majority of these cases. (3) Alloantibodies may lead to delayed serologic and/or hemolytic transfusion reactions or hemolytic disease of the fetus and newborn. Weak D 4.0 is more common in individuals of African descent and given the heightened risk of transfusion associated hemolytic complications in the sickle cell population, this distinction is especially important. Westhoff et al. highlight the need for further systematic study of anti-D in individuals who carry these variant RHD alleles before they can safely be considered D positive.

The national reference laboratory in France reported anti-D in 9/47 (19.1%) referred in cases with weak D 4.0. One alloantibody, 2 autoantibodies and 6 unresolved cases were reported. (4) By contrast, when this same group published on the significance of anti-D in patients with weak D type 1 and 2 (routinely considered D positive in Canada), they noted 12/220 (5.5%) anti-D with all cases demonstrating laboratory features of an autoantibody.(5)

Molecular typing for pregnant women with serologic weak D has been the practice in Canada for several years. Women of childbearing age and patients with sickle cell disease comprise most of the cases referred for RHD genotyping in Canada with the bulk of testing performed at two reference laboratories. An audit of 2843 RHD genotyping samples at Canadian Blood Services (2018-2020) noted that weak D type 4.0 represents a small proportion (6.5%) of samples tested (personal observation). Providing weak D 4.0 individuals with RhIg prophylaxis during pregnancy and D negative RBCs for transfusion is the most cautious approach until additional data is available.
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Competing Interests: None declared.
References
1. Flegel WA. Modern Rhesus (Rh) typing in transfusion and pregnancy. CMAJ 2021; 193:E124.
2. Flegel WA, Denomme FA, 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; 60:885-9.
3. Westhoff CM, Nance S, Lomas-Francis C, et al. Experience with RHD*weak D type 4.0 in the USA. Blood Transfusion 2019;17:91-3.
4. Pham BN, Roussel M, Gien D, et al., Molecular analysis of patients with weak D and serologic analysis of those with anti-D (excluding type 1 and type 2). Immunohematology 2013; 29(2):56-62.
5. Pham N, Roussel M, Peyrard GT, et al. Anti-D investigations in individuals expressing weak D Type 1 or weak D Type 2: allo- or autoantibodies? Transfusion 2011;51:2679-85.