Peter S. Bernstein, MD, MPH, FACOG; David Scott Cole, MD


October 16, 2002


Kindly let me know whether there are any reports/research into incidences or relative risks of Rh alloimmunization in subsequent pregnancies (especially third) in an Rh D-negative G3P2002 with 2 previous Rh D-positive healthy babies and negative Coombs test postpartum. Mother received 2 recommended doses of RhoGAM (rhesus immune globulin) during 28th and 34th week in both pregnancies. How safe is this third pregnancy?

Response from Peter S. Bernstein, MD, MPH, FACOG and David Scott Cole, MD

Fetal red blood cells that escape into the mother's bloodstream are recognized as foreign if they are a different blood type from the mother. A natural rejection process -- alloimmunization -- will ensue with the formation of antibodies. In most cases, the red blood cell incompatibility involves the Rhesus, or Rh D, antigen. The pregnancy in which the alloimmunization first occurs results in an unaffected child; however, during subsequent pregnancies, antibodies in the mother can cross to the fetus causing anemia and sometimes fetal death. In general, the fetus of each subsequent pregnancy exhibits more severe effects than in the previous pregnancy.

Many clinical scenarios can cause an Rh D-negative woman to become alloimmunized. Of Rh D-negative women who do not receive RhoGAM during pregnancy, 17% will become alloimmunized; 90% of these cases can result from fetomaternal hemorrhage at delivery; 10% can result from antenatal fetomaternal hemorrhage. The amount of blood needed to become alloimmunized is tiny; a fetomaternal hemorrhage of less than 0.1 mL is all that is needed.[1]

What Are Other Risks for Alloimmunization?

Spontaneous abortions are associated with a 1.5% to 2% risk of alloimmunization, and therapeutic abortions are associated with a 4% to 5% risk of alloimmunization in Rh D-negative women. Threatened abortions, ectopic pregnancies, chorionic villus sampling (CVS), amniocentesis, cordocentesis, blunt abdominal trauma, hydatiform mole, an intrauterine fetal demise in the second or third trimester, and external cephalic version all have risks of fetomaternal hemorrhage.[1] Therefore, they all can cause Rh D alloimmunization. Possibly the most significant risk for many Rh D-negative women is the risk of spontaneous abortion. Many women have miscarriages before they even know that they are pregnant.

What Are the Current Recommendations for Rh D-Negative Women?

An antibody screen should be performed on every pregnant patient at her first prenatal visit. Although there is some debate, the antibody screen should be repeated at 28 weeks in the Rh D-negative woman. At the same visit at 28 weeks, 300 microg of RhoGAM should be given, unless the father is known to be Rh D negative. A fetomaternal hemorrhage of 30 cc can be treated with 300 microg of RhoGAM. This dose has reduced the incidence of antenatal alloimmunization from 2% to 0.1%. Furthermore, some experts argue that a second dose of RhoGAM be given at 40 weeks gestation if the patient is not yet delivered.[2] RhoGAM should again be given within 72 hours of delivery of an Rh D-positive infant.

In addition, RhoGAM should be given after a first-trimester pregnancy loss and after CVS, amniocentesis, and fetal blood sampling. RhoGAM should also be considered after a threatened abortion, second or third trimester antenatal bleeding, external cephalic version, and blunt abdominal trauma.

In England, the management is slightly different. Rh D-negative women receive 100 microg of RhoGAM at 28 and 34 weeks and after delivery. There is an extra dose of RhoGAM given, but the cumulative dosage is smaller than in the United States.[1]

Should Screening Be Done for Excessive Fetomaternal Hemorrhage?

The American College of Obstetricians and Gynecologists has only recommended that a Kleihauer-Betke or rosette test be done on Rh D-negative women who deliver an Rh D-positive infant and have abdominal trauma, abruption, previa, intrauterine manipulation, multiple gestation, or manual removal of placenta. However, the American Association of Blood Banks believes that all Rh D-negative women who deliver an Rh D-positive infant should receive a screening test for excessive fetomaternal hemorrhage.[3]

How Likely Is Alloimmunization After Receiving RhoGAM in Prior Pregnancies?

A patient's main risk of alloimmunization would be excessive fetomaternal hemorrhage with her last delivery that was not appreciated. Other risks would include a spontaneous abortion between this pregnancy and the prior one that was unknown and not treated with RhoGAM. Most likely, a pregnancy is unaffected, especially if the initial antibody screen is negative. If the initial antibody screen is positive, then maternal titers should be assessed, and consultation with a maternal-fetal medicine specialist is indicated.


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