CLINICAL ACTIONS:

The care of patients with sensitization to antigens other than D, that are known to cause hemolytic disease, should be the same as that for patients with D alloimmunization. ACOG provides guidance that includes the following recommendations:

In a center with trained personnel and when the fetus is at an appropriate gestational age, Doppler measurement of peak systolic velocity in the fetal middle cerebral artery is an appropriate noninvasive means to monitor pregnancies complicated by red cell alloimmunization

The initial management of a pregnancy involving an alloimmunized patient is determination of the paternal erythrocyte antigen status

Serial titers are not useful for monitoring fetal status when the mother has had a previously affected fetus or neonate

Antibody titers are not appropriate for monitoring Kell-sensitized patients because Kell antibodies do not correlate with fetal status

Anti-D immune globulin is indicated only in Rh-negative women who are not previously sensitized to D

In addition, The AABB working group addressed the work up and management of ‘weak D’ (formerly D^u) in their joint statement that included representatives from ACOG, CAP, American Red Cross, Armed Services Blood Program

Persons with a weak D type 1, 2 or 3 can be managed safely as Rh-positive and such women, if pregnant, do not require Rh immune globulin. For more than 50 years, the recommended practice in the United States has been to Rh type patients using laboratory methods that interpret weak D phenotypes as Rh-negative. The intent of this practice has been to protect Rh-negative persons, particularly Rh-negative women of childbearing potential, from inadvertent exposure and alloimmunization to Rh-positive red blood cells. RHD genotyping methods are now available that can identify those persons with a weak D phenotype who can be managed as Rh-positive (weak D types 1, 2 or 3).

ACOG has responded to the AABB working group above and advises that for weak D (previously known as D^u)

An attractive solution to this problem is to perform molecular genetic RHD typing in weak D phenotype individuals as suggested by the Work Group on RHD Genotyping.

Currently, there is a lack of comprehensive cost-benefit analysis for this clinical approach. Clinicians are advised to administer Rh D immune globulin to patients with weak D blood type in appropriate clinical situations, by the same rationale as that for Rh D typing blood donors, until further scientific and economic studies are available. 

SYNOPSIS:

Antepartum or intrapartum fetal-maternal bleeding may stimulate an immune response in the mother when any fetal blood group factor inherited from the father is not possessed by the mother. Maternal antibodies may form (alloimmunization) and there may be transplacental passage of these antibodies into the fetal circulation. This transplacental passage of antibodies into the fetal circulation may lead to hemolytic disease in the fetus and newborn. The risk of hemolytic disease is determined by the degree of antigenicity and the amount and type of antibody involved.  The AABB recommends that patients should undergo repeat screening before receiving anti-D immune globulin at 28 weeks, postpartum and at the time of any event in pregnancy.

KEY POINTS:

Determination of Paternal Genotype in Pregnant Patients with Rh-D Alloimmunization

• If the father or sperm donor (certain biologic paternity) is negative for Rh-D
  • No further assessment and intervention are unnecessary
• If father or sperm donor is homozygous
  • All pregnancies with alloimmunized patient are at risk
• If father or sperm donor is heterozygous
  • 50% of pregnancies with alloimmunized patient are at risk
• ACOG recommends

Paternal RHD zygosity testing using genotypic analysis is recommended for Rh-D alloimmunization risk assessment. It may be reasonable to defer or discontinue fetal surveillance for anemia in the setting of paternal genotyping that is RHD homozygous negative

Determination of Fetal Genotype in Pregnant Patients with Rh-D alloimmunization

• Perform fetal antigen genotyping if paternal genotype is heterozygous or unknown
  • If fetus negative for Rh antigen of interest, no further surveillance is necessary
• Invasive testing
  • Amniocentesis is recommended
  • CVS is not recommended as it may cause maternal-fetal hemorrhage
• Noninvasive testing
  • Cell-free DNA (cfDNA) isolated from maternal plasma is a reliable alternative to amniocentesis and “it is reasonable to use it as an alternative tool for fetal RHD testing”

Determination of Paternal and Fetal Genotyping in Pregnant Patients with non–Rh-D alloimmunization

• Paternal
  • Molecular testing exists for other red blood cell antigens
  • Consultation advised to determine optimal approach for paternal status
• Fetal
  • Amniocentesis remains the primary modality for determining fetal blood type if paternal genotype is thought to be heterozygous or is unknown
  • Noninvasive testing is not considered first line for determination of fetal status but “may be considered for pregnant patients declining amniocentesis, after weighing cost, access, and the encouraging-yet-limited data supporting its use”

Red Cell Antigen Groups and Risk for Hemolytic Disease

• Five major antigens can be identified for the Rh (C,D,E) blood group system, these are:
  • C,c,D,E,e
  • In addition to the 5 antigens of the Rh system, there are more than 30 red cell antigen groups that have been described and many of these can can cause hemolytic disease in the newborn and fetus
• Most cases of Rh alloimmunization causing hemolytic disease are the result of incompatibility with respect to the D antigen
• The red cell antigen groups and their association with hemolytic disease:

Blood Group System	Antigen	Hemolytic Disease Severity
Lewis		No proven risk
I		No proven risk
Xg	Xga	Mild
Lutheran	LuaLub	Mild
Kell	K	Severe including hydrops
	kK0KpaKpb Jsa Jsb	Mild
Rh E and c (non-D)	cECe	Mild to severe (c and E canlead to hydrops); e and C are rare
Duffy	Fya	Mild to severe including hydrops
	Fyb	Not a known cause of HDN
	Fy3	Mild
Kidd	Jka	Mild to severe
	JkbJk3	Mild
MNSs	MUSs	Mild to severe
	Mia	Moderate
	N	Mild
MSSs	Mta	Moderate
	MtaVwMurHil Hut	Mild
P	PP1pk(Tja)	Mild to severe
Diego	D1aD1b	Mild to severe
Xg	Xga	Mild
Lutheran	LuaLub	Mild

Note: Mild only, with no risk to advance to a higher risk category, can be treated with routine obstetric care.  Any risk of moderate or above requires referral for fetal assessment

Learn More – Primary Sources:

ACOG Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy

ACOG Clinical Practice Update: Paternal and Fetal Genotyping in the Management of Alloimmunization in Pregnancy

ACOG Practice Bulletin No. 181: Prevention of Rh D Alloimmunization

Dean L (NCBI): Blood Groups and Red Cell Antigens

AABB: Joint Statement on Phasing-In RHD Genotyping for Pregnant Women and Other Females of Childbearing Potential with a Serologic Weak D Phenotype

Locate a Maternal Fetal Medicine Specialist:

• Maternal-Fetal Medicine Specialist Locator-SMFM

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