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An Interview with Dr. Kenneth Moise
Conducted by Geff Klein, MD
Kenneth Moise, MDDR. KLEIN: I have with me today Dr. Kenneth Moise, professor of obstetrics gynecology from the University of North Carolina. He is considered one of the leading experts in the management of the Rh patient and we are going to talk today about the management of patients with Rh sensitization and prevention of the disease. Thank you, Dr. Moise.
DR. MOISE: Thank you for being here.
DR. KLEIN: Since RhoGAM is widely available, how often do we still see Rh disease?
DR. MOISE: Well, recently, the CDC went back and looked at some of their surveillance hospitals, and the incidence is about 1:1000 live births in the United States. It varies throughout the country. It is not seen as often in the Northeast. It is seen more commonly in the Southwest, in the Texas area for some reason; we are not sure why.
DR. KLEIN: How do these women get sensitized?
DR. MOISE: Well, as you know, RhoGAM is recommended to be used routinely at 28 weeks of gestation by the American College of OB/GYN and again after delivery. Some recent studies, one of the scout ones, showed about two-thirds of the cases involved antepartum sensitization prior to 28 weeks and about one third of the cases involved complete omission of Rh immune globulin. So people just forget to give it.
DR. KLEIN: What other antibodies can cause hemolytic disease in newborns?
DR. MOISE: Well, clearly D or anti-D antibody causes about 98% of cases. The others to remember would be Kell and c, which is also an Rh antibody which we don't have an immune globulin to prevent. There are about 43 others, but if one would remember D, Kell, and c, one would be dealing with most of the severe cases that require treatment in utero for severe fetal anemia.
DR. KLEIN: So, as far as management of the patient clinically, should we be giving RhoGAM for first trimester bleeding?
DR. MOISE: That is a good question, Geff. Basically, the American College of OB/GYN has not addressed that issue, but there are reports now of women who do get sensitized prior to this 28-week shot of Rh immune globulin, and therefore, I think it probably should be considered fairly strongly in the Rh negative patient who is not sensitized.
DR. KLEIN: And this also goes for ectopic pregnancy as well?
DR. MOISE: There are several of these situations; ectopic pregnancies, elective abortions are common reasons we see today for women to become sensitized. People forget to administer Rh immune globulin. The American College will say that you can give what you called micro Rho, which is only 50 ug, but in fact most of the time, we simply give a standard dose of 300 ug to these patients. The other incident when people forget to consider this is after motor vehicle accidents, particularly if they occur after 28 weeks. The basic premise is that at any time there might be a breakdown in the maternal/fetal barrier, then Rh immune globulin should be considered.
DR. KLEIN: Is it an expensive treatment?
DR. MOISE: Surely not. RhoGAMgam, as we know it, actually is made by several different companies. This is a misnomer. RhoGAM was first produced by Ortho and approved by the FDA in 1968. Three companies now make the product. It runs about $40 a vial. It is made from human plasma. We got questions all the time about its risk for AIDS and hepatitis, but those things have been worked through and it really does not have any risk for transmission of those viral agents.
DR. KLEIN: In a patient who is Rh negative, how do you follow that patient if she has been unsensitized while she is pregnant?
DR. MOISE: Well, as you know, all patients should have an antibody screen and blood typing at the first prenatal visit, and if your theoretical patient is found to be Rh negative and has no evidence of antibodies, she really does not need anything done until 28 weeks. At that point, she should have a repeat antibody screen to pick up the rare patient who becomes sensitized between the first visit and 28 weeks, and then she should receive a shot of Rh immune globulin. Now, I don't hold the patient in the office. I usually draw the blood sample, administer the Rh immune globulin and follow up with the blood sample. It is important you draw the blood sample before the shot because once you give someone Rh immune globulin, their antibody titer will in fact be positive, so that can be confusing, and so they recommend that it be done before we give a 28-week shot. If that's okay, they really don't need any further evaluation with antibody titers until delivery, when we evaluate them to see if they are a candidate for RhoGAM after delivery.
DR. KLEIN: Suppose that you did the antibody screening along with blood typing early in the pregnancy and you find the patient is Du-positive. Do you give them Rhogam?
DR. MOISE: No, we really don't. The Du-positive should be considered a weak Rh positive individual, and so in essence, these women cannot become sensitized. So, if we do it at the first prenatal visit and let's say the patient comes back O-negative, Du-positive, we see this more commonly in the black race, then they really are not candidates for Rhesus immune globulin. They really cannot become sensitized. Now, there is some controversy if this occurs at the end of pregnancy. Let's say the patient had no good prenatal care, and she comes in at delivery and your test shows that she is Du-positive; that can be somewhat confusing for the following reason. If the patient had a large fetal/maternal bleed, then in fact she could have a Du-positive result that was in fact incorrect. So, that's one of the controversial area. The American College of OB/GYN says that you should go ahead and give Rh immune globulin to the Du-positive patient at delivery whom you did not have a blood type on earlier in the pregnancy. The American Association of Blood Banks, however, says that all patients at delivery should be screened for fetal/maternal hemorrhage. In that situation, if you identify a patient that's positive, you go ahead and give her Rh immune globulin.
DR. KLEIN: As for the patients who were sensitized already, do you give them RhoGAM after delivery?
DR. MOISE: That's a good question. A lot of people say if I give them RhoGAM at delivery, perhaps I can keep their sensitization from getting worse, and the answer is it just doesn't work. It has been tested, and clearly if someone is already sensitized, the Rh immune globulin does not work. These patients have this disease for the rest of their lives.
DR. KLEIN: How do I know if I'm giving enough RhoGAM after delivery?
DR. MOISE: That's a good question. It's one of the other reasons that women do in fact fail Rh immune globulin. At any hospital associated with the American Association of Blood Banks, their blood bank will set a series of events in motions that is undetected by you. They'll do what you call a RhoGAM work-up. You don't have to order this. It's done automatically. The first test that'll do is look at the baby's blood type to see if in fact the baby is Rh positive. If the baby is Rh negative like the mother, then there is no indication to administer Rhesus immune globulin. If, however, the baby is positive, then you go on to check the maternal serum for antibody. If she has a large amount of antibody present, she is sensitized and she doesn't need Rh immune globulin. If there isn't a lot of antibody in the mother's system, there will be two tests. The first test is called the rosette test, and it's a test to see if there is any evidence of fetal/maternal bleed, and that test is read as positive or negative. If the test is negative, then they're probably wasn't a bleed or it was very small, they will recommend treatment with one ampule or 300 ug Rh immune globulin. On the other hand, if the rosette test is positive, meaning that there was a bleed, they go on to do a Kleihauer-Betke stain, and that stain is done to determine the volume of the bleed. Then they would make recommendations to you as to whether you need to give additional units of Rh immune globulin. Remember one unit will only cover about 30 cc of fetal/maternal bleed. So, if there is 50 cc bleed, you would have to administer two units of Rh immune globulin.
DR. KLEIN: Let's switch gears here and talk about patients who have already been sensitized and now in a subsequent pregnancy. Would you identify the first thing you should do in that situation?
DR. MOISE: Obviously, the first thing you want to do is check her titer. That just indicates the amount of antibody in the patient's serum. A critical titer is a titer at which we are first concerned about fetal disease. It varies from center to center, but we typically use the titer around 16 in most U.S. centers. So any titer below 16 can be repeated at monthly intervals, and once the titer 16 is reached, then we began to look at additional tests that might be necessary. Most centers in the U.S. would use amniocentesis for delta OD450; that is cast on the amniotic fluid to measure bilirubin, and would consider beginning those tests once you've reached that critical value. So I would say that you would follow the antibody test every month or so. When you hit the critical value, switch over to amniocentesis to check the delta OD450. If the delta OD450 value rises into the upper zone 2 of a lightly curve, then that patient is probably a candidate for a procedure known as cordocentesis. In that procedure we actually, under ultrasound guidance, obtain blood directly from the umbilical cord in utero and check the baby's blood count. If that count is low, we of course then administer blood in the form of an intrauterine transfusion.
DR. KLEIN: This is all very sophisticated for the general OB/GYN physician to be performing. At what point does the patient need to be referred to a specialist?
DR. MOISE: I have done this in two different ways. That would depend on the comfort level of the primary care obstetrician. Usually, they'll call for advice once they identify an antibody and I'll have them just keep on following their patient with titers until they reach that critical value, and then we have two ways we can go. We can either have them do the amniocentesis and do the delta ODs and plot them out and work in conjunction with the perinatologist, or more likely at that point, they would refer the patient to an experienced perinatologist who deals with Rh disease and let him do the amniocentesis. On many occasions I have allowed the patient to deliver with the primary care obstetrician and simply have managed the Rh disease portion of the pregnancy, giving advice to the primary care obstetrician. I don't think that all of these babies require delivery in a tertiary care center.
DR. KLEIN: For the patient who requires intrauterine transfusion, how do you counsel that patient?
DR. MOISE: Well, we tell her that we can do a pretty good job of saving most of the babies. The overall survival rate, if the baby not hydropic, is on the order of 85%. If the baby is hydropic, which means he is fairly sick when we first see him, survival probably drops to about 75%. So, we tell them we do pretty well, but we still loose about 15% of babies. These are typically the babies who presented at, say, 20 weeks of gestation with severe fetal anemia. In those situations we have some limitation technically on how well we can get into the umbilical cord to infuse red blood cells.
DR. KLEIN: For the patient with this disease, are there any long-term consequences?
DR. MOISE: Generally we would tell patient that if the fetus survives the anemia through the use of intrauterine infusion, then it probably could be normal. At least that's what preliminary data would say. Now, there is a more sophisticated technique of intravascular intrauterine transfusion; that's when we put blood directly into the fetal umbilical cord, fairly new, probably about ten years of age. We really don't have any good follow-up data on those babies. There has only been one study published on Canada. It showed that the rate of cerebral palsy is slightly higher in those babies. So some of our concern is that we are saving sicker babies and that we may see some consequences in those particular babies, but we say that generally, these babies will be fairly normal. Interestingly enough, if intraperitoneal transfusions are used , female babies seem to have a higher incidence of umbilical hernias and male babies seem to have a higher incidence of inguinal hernia. We think this is because we are increasing the intraperitoneal pressure by doing this procedure. So I counseled patients that these children may need some surgical correction of those hernias later in life.
DR. KLEIN: As for the prevention of this disease, is there anything in the horizon?
DR. MOISE: Well, I think a couple of things are coming down the pike. We had our center of development animal model for this disease, and we feel that we sort of looked for only one a sign of disease, that of the fetal anemia. We really are interested in trying to get rid of the maternal antibody, that's the problem. If we could get a mother to drop her titers before she became pregnant through some sort of immunomodulation, we think that would ultimately be the correct way to treat this disease. Studies are early. The model is clearly a representative of human disease, and we are encouraged that we may one day be able to treat these mothers in essence and not have to do intrauterine transfusions. In some situations even today, through genetic engineering, we are now able to offer some unique therapies to the father or to the couple that are in fact heterozygous. Just for a second, let me explain that. If the father is heterozygous, that means that although he is Rh positive, he has a 50-50 chance of in fact fathering an affected offspring, and if that offspring happens to be Rh negative, of course, then that offspring has no effects of the disease and he'll be fine. If in fact the offspring is Rh positive, he obviously will be affected. We are now able to do genetic engineering with in vitro fertilization with the egg cells and test those embryos to see if they're Rh negative or Rh positive. We would then only put back the Rh negative embryos and guarantee this couple an uneventful pregnancy. To my knowledge, no one has done that in the world. It was really only tried once and were not successful. We currently are talking to three different couples who have very bad Rh disease, a heterozygous paternal genotype, and they are considering this therapy. So, I think there are some exciting new things out on the horizon.
DR. KLEIN: I believe a recent article was published about identifying the Rh negative/Rh positive status of baby in utero.
DR. MOISE: That's right. We can use the technique we just mentioned to do an amniocentesis in the case of a heterozygous paternal genotype and tell us in fact if we should continue to do other tests on the baby. At the time of the first delta OD450 determination, we could take a small sample of fluid, send it for DNA analysis, and if the fetus happens to be Rh negative, we would be finished with that pregnancy. We would refer that pregnancy back to the primary care obstetrician because we would have in fact found an unaffected infant in utero. If, however, that test is positive, we would continue doing serial amniocentesis. So, that is an exciting test that enables us to pick up the Rh negative fetus in utero fairly easily now.
DR. KLEIN: Well, thank you very much for the time. We appreciate this opportunity.Dr. Kenneth Moise Curriculum Vitae
For a consultation with Dr. Moise call 1-800-RHDISEASE
Email: kmoisejr@med.unc.edu
