Special Feature: Current Management of Rh and Kell Sensitization

By John C. Hobbins, MD

Since the advent of anti d immune globulin, the incidence of Rh sensitization and, consequently, erythroblastosis fetalis has plummeted—but not to zero. We generally are following 2 or 3 patients a month who are either Kell or Rh sensitized as a result of insufficient or ill-timed delivery of anti-immune globulin or mismatched transfusions.

Some recent developments have allowed a kinder, less invasive approach to management of these patients. The "old" way, unfortunately still used by some clinicians in the United States, was to perform antibody testing monthly in all sensitized patients. If the antibody titer rose above 1:16, an amniocentesis was used to assess the optical density difference (DOD) in amniotic fluid. Since indirect bilirubin was absorbed at 450 mm, the difference between the actual absorbance and that expected (if no bilirubin were there) gave the clinician an indirect idea of how much hemoglobin was being broken down by maternal antibodies. The "DOD 450" was then plotted into a 3-zone curve according to gestational age, which was originally developed 4 decades ago by Liley and later modified by others such as Frigoletto and Queenan.

This type of assessment was reasonably good at predicting the unaffected or mildly affected fetus if the DOD 450 fell into Zone I or lower Zone II, but it was an inconsistent predictor of severe disease because of the inherently high false-positive rate. However, the biggest problem came from the invasive aspect of this approach. Many patients had amniocenteses every 2 weeks and, not infrequently, completely unnecessary cordocentesis based on an erroneously high DOD 450. Amniocentesis and cordocentesis have risks of their own that, although low for fetal death with amniocentesis, are not inconsequential when considering infection or need for emergency cesarean section—something that we have had to do on occasion for nonreassuring heart tones after an amniocentesis or cordocentesis in the third trimester. Also, when a needle strays near or into the placenta, the potential for worsening sensitization exists throughout pouring of antibody when fetal cells enter the maternal circulation.

Mari and colleagues first reported a relationship between peak velocity in the fetal middle cerebral artery (MCA) and the severity of fetal anemia.1 When the fetus is anemic, the oxygen delivery is diminished to most tissues, simply because there are fewer working red blood cells. The fetus then attempts to protect his or her brain by giving special circulatory attention to the cortex. Anemic blood has a low viscosity and, therefore, enters the middle cerebral arteries at high-peak velocities. With carefully angle-corrected Doppler measurements, the peak velocity can be accurately quantified.

Mari et al constructed a nomogram based on peak velocities at different gestational ages. The higher the peak velocities above 1.5 MoM, the greater the chance of severe fetal anemia. Levels below 1.5 MoM are indicative of a fetus that needs no special attention at the time of the test.

Large prospective studies by Mari et al, and now others, have suggested that the false-negative rate of a reassuring peak velocity (below 1.5 MoM) is extremely low (< 1%), and the false-positive rate of values above 1.5 MoM is about 12%. We have used this technique for the last 5 years in conjunction with other ultrasound signs of fetal anemia (spleen size, live size, pre-ascites, pericardial effusion, echogenic bowel) and have yet to encounter evidence of severe fetal anemia in the face of a reassuring MCA peak velocity. This approach has almost completely eliminated the need for invasive testing since in the overwhelming majority of cases the MCA peak velocity is reassuring.

The following represents our current approach to the Rh sensitized or Kell patient:

  • If the patient is Rh negative or Kell negative and has antibodies on first visit, we will encourage the father of the baby to have zygosity testing;
  • If he is negative for the antigens in question, no further testing is necessary (unless there is a question of paternity);
  • If he is heterozygous for the Rh or Kell factor, then in the second trimester we might suggest testing the Rh or Kell status of the fetus through amniocentesis;
  • If titers are consistently low, however, the amnio might be waived or postponed until there is an elevation above 1:16, or an amniocentesis planned for another reason (AMA);
  • If the fetus is Rh negative or Kell negative—a 50% likelihood when the father is heterozygous—then no further testing is needed;
  • If the father is homozygous or the fetus is found to be positive by amniocentesis, then Dopplers of the MCA are undertaken every 2 weeks.

The good news is that invasive procedures are rarely required. However, if the peak velocity is above 1.5 MoM and the pregnancy is less than 34 weeks, we will then book the patient for a cordocentesis and possible intra-uterine transfusion. Subsequent procedures will be predicated upon the gestational age, the hematocrit of the fetus at the end of the transfusion, and weekly MCA Doppler findings. (The peak velocities will drop dramatically immediately after an intra-uterine transfusion.)

This protocol represents a safe and effective way to save potentially risky procedures for only those few patients who really need them.

References

1. Detti L, et al. Am J Obstet Gynecol. 2001;185(5): 1048-1051.

2. Mari G, et al. N Engl J Med. 2000;342(1):9-14.