For Physicians. By Physicians.™

ObGFirst: Get guideline notifications, fast. First month free!Click here
Practical obstetrics info for your women's healthcare practice

Alloimmunization and Red Cell Antibodies – Time to be Concerned?


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 has provided updated guidance (March 2018) 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 Du) 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 Du)

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. 


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.


  • 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





 Rh E and c (non-D) cE



 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



 Mild to severe
Mia  Moderate
N  Mild
 MSSs Mta  Moderate




 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 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: