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Prevention of rhesus isoimmunization
CORRESPONDENCE
Prevention of rhesus isoimmunization
To the Editors: Hensleigh's article (Hensleigh, P. A.: Preventing rhesus isoimmunization, AM. J. 0BSTET. GYNECOL. 146:749, 1983) in which he recommends against routine antepartum Rh prophylaxis because, in his belief, it is not cost-effective must be answered. The statistics and statements based upon government registry reports which are used by Hensleigh may not be accurate, if reporting to government agencies is no more accurate in the United States than it is in Canada. In his Table I, he compares Manitoba statistics for crude rates of hemolytic disease unfavorably, particularly with those of California, despite our use of antenatal Rh prophylaxis. The figures he reports from our province are the total rates for Rh immunization, over half of which are at the enzyme Rh-antibody level only and are not associated with Rh-hemolytic disease in the current pregnancies, but of course with hemolytic disease potential in subsequent pregnancies. In 1979, our true rate for Rh-hemolytic disease of the newborn was seven per 10,000 births, dropping to 5.5 per 10,000 births in 1982. In supporting the relative importance of Rh immunization during pregnancy as a major cause of persistent Rh immunization and the effectiveness of antepartum prophylaxis, we can only refer to the Manitoba statistics which have been reported elsewhere. 1- 3 Hensleigh admits that our ascertainment is very high. In our observations of Rh immunization during pregnancy from March, 1967, to December, 1974, and in an overlapping clinical trial of antenatal Rh prophylaxis encompassing treatment of primigravid women slated to deliver in one tertiary level and one urban community hospital from December, 1968, to July, 1975, we noted an incidence of Rh immunization during pregnancy of 1.8% in 62 of 3,533 women not treated antenatally versus only 0.06% in 1 of 1,358 women who were treated antenatally, a very significant difference. In the 3-year period ending October 31, 1976, during the antenatal prophylaxis clinical trial, just at the beginning of the institution of our antenatal prophylaxis service program, 68 of the 167 Rh-immunized pregnant women observed (41%) had become Rh immunized during pregnancy-32 in a previous pregnancy, 36 in the current pregnancy (12 per year). In 1982, seven of the 21 Rh-immunized pregnant women observed (33%) were Rh immunized during pregnancy-three in a previous pregnancy, four in the 1982 pregnancy. The persisting low incidence of Rh immunization during the current pregnancy represents Rh immunization by 28 weeks' gestation (antenatal Rh prophylaxis at 28 weeks' gestation is about 92% effective). A service program begun in 1975, in
which a single dose of 300 J.Lg of Rh-immune globulin was given at 28 weeks' gestation, was also highly effective. Of 8,422 women delivered of Rh-positive babies, treated at 28 weeks' gestation, we would have expected 136 to be Rh immunized by the time of delivery if antenatal prophylaxis was ineffective. In actual fact, only eight were immunized, and of the eight, four were multigravid women who had not been given antenatal prophylaxis in previous Rh-positive pregnancies. Many women who are Rh immunized during pregnancy subsequently have very severely affected babies. In this present era, a significant fraction of the women referred to our unit from outside of Manitoba for fetal transfusions is in difficulties because of the occurrence of Rh immunization during a past pregnancy. I can supply the Editors or Hensleigh with several pertinent examples of these tragedies if they desire. Using the Manitoba statistics and Hensleigh's cost of individual protection figure of $130 (which we think to be very high), we calculate that the drug cost of preventing one case of Rh immunization during pregnancy would be $11,500, not the $41,000 which he quotes. At the more reasonable figure of $40 (excluding the totally unnecessary cross-match charges, etc.), the drug cost would be $3,500. Hensleigh makes a big point about the possible adverse effect of exposing the fetus to the human gamma globulin present in Rh-immune globulin (that is, the Rh antibody itself plus the other IgG in Rh-immune globulin). Surely, he is aware that all fetuses are exposed to much larger doses of human gamma globulin transplacentally acquired from their mothers from the twelfth week of gestation onward, and in the case of both Rh-negative and Rh-positive fetuses of Rh-immunized mothers, to much larger doses of anti-D which their mothers produce. Since maternal IgG is protective, not harmful to the fetus and newborn baby, all of whom receive it, and maternal anti-D if it produces any harm causes only hemolysis, we do not believe that the small amounts of passive anti-D (subsequent to maternal receipt of Rh-immune globulin) can harm the fetus or affect its immune competence in any way. We have seen no evidence of any harm in the tens of thousands of infants delivered after their mothers had received antenatal Rh prophylaxis. We have not studied their immune status in detail nor do we believe it necessary to do so. Finally, Hensleigh comments upon the health risks to volunteers immunized to produce Rh-immune globulin. In Canada, we greatly exceed the needs of the entire population (24,000,000), about one tenth that of the United States, for Rh-immune globulin given ante partum, post partum, and after abortion, by the plasmapheresis of 30 to 35 donors once per week. The 1151
1152 Correspondence
production of about 800 kg of Rh plasma from these donors per annum greatly exceeds our requirements. Indeed, more than half of the plasma produced is sent out of Canada. At present, all of our donors are highly naturally immunized, sterile, Rh-negative women who are hyperimmunized with 0. 7 ml of Rh-positive red cells every 6 months. Two hundred donors in the United States with similar Rh antibodies would produce about 6,000 kg of Rh plasma, an amount which should very adequately meet the United States' needs for Rh-immune globulin, including that required for antenatal prophylaxis. Be that as it may, we expect that, within 5 years, the production ofRh-immune globulin for Rh prophylaxis by means of tissue culture techniques4 will remove Hensleigh's third objection to antenatal prophylaxis. By materially reducing the cost of Rh immune globulin, it may also effectively remove his first objection. Rh immunization during pregnancy is as common as Rh immunization after spontaneous abortion. It is one half as common as Rh immunization after therapeutic abortion. It is almost 20 times as common as Rh immunization due to undiagnosed massive transplacental hemorrhage. It can only be prevented by universal antenatal Rh prophylaxis at 28 weeks' gestation, not by universal routine antepartum transplacental hemorrhage screening, which in itself will be very expensive. John M. Bowman, M.D. Rh Laboratory 735 Notre Dame Avenue Winnipeg, Manitoba, Canada RJE OLB REFERENCES I. Bowman,]. M., Chown, B., Lewis, M., and Pollock,]. M.: Rh isoimmunization during pregnancy: Antenatal prophylaxis, Can. Med. Assoc. J 118:623, 1978. 2. Bowman,]. M., and Pollock,]. M.: Antenatal prophylaxis of Rh isoimmunization: 28-weeks'-gestation service program, Can. Med. Assoc.]. 118:627, 1978. 3 .. Bowman, ]. M.: Suppression of Rh isoimmunization: A review, Obstet. Gynecol. 52:385, 1978. 4. Crawford, D. H., Harrison,]. F., Barlow, M.J., Winger, L., and Huehns, E. R.: Production of human monoclonal antibody to rhesus D antigen, Lancet 1:386, 1983.
To the Editors: I read with interest Hensleigh's article advising against the antepartum use ofRh-immune globulin but think his information is misleading and his conclusions unwarranted. The implication that Rh-immune globulin has been inadequately tested in human pregnancy is unfounded. Trials began in Canada in 1968, 1 and since then thousands have received either intramuscular or intravenous therapy. Despite widespread use, there is not one reported case of fetal morbidity due to antepartum Rh-immune globulin; Clearly, all physicians are concerned about potentially adverse effects from any substance administered antenatally. Does such fear preclude a treatment which reduces the risk of maternal Rh sensitization from 1.5% to 0.11%? By what theoreti-
April 15, 1984 Am. J. Obstet. Gynecol.
cal mechanism(s) does passive globulin administration adversely affect adult antigen processing? There is no clinical or even direct laboratory evidence to support such a direct relationship between antibody and subsequent immune response. Since the report cited pointing out the hazards of administration of immune globulin dealt with different globulins, no valid comparison can be made with Rh-immune globulin. Even in the study mentioned, there was no documented adverse effect, except for lymphocyte mitogenic responses, which may not be clinically relevant. In my location, 300 JLg of Rh-immune globulin costs $30. Therefore, I consider its antepartum use to be cost-effective, especially since the current regimen eliminates the need for two antibody titers. It has been clearly shown that no clinical parameter predicts subsequent antepartum Rh sensitization. 2 In the absence of more direct evidence to the contrary, I will continue to view the development of the antepartum immune globulin therapy as a significant advancement in Rh prophylaxis. Michael R. Caudle, M.D. Department of Obstetrics and Gynecology 415 Devonia Street Harriman, Tennessee 37748 REFERENCES I. Bowman, ]. M.: Suppression of Rh isoimmunization,
Obstet. Gynecol. 52:385, 1978. 2. Scott,]. R., Beer, A. E., Guy, R., and Elbert, G.: Pathogenesis of Rh immunization in primigravidas, Obstet. Gynecol. 49:9, 1977.
Reply to Bowman and Caudle To th1? Editors: Bowman's field trials in Manitoba have been prominent in the literature on antepartum use of Rh-immune globulin. However, in answering questions about small increments of benefit, it is essential to compare treatment and nontreatment groups which are randomly selected. In his reports, the "controls" are neither contemporary nor matched. My response to his comments and those of Caudle is the same: Further discussion in regard to published or unpublished data for which there are not proper controls will neither establish the precise benefits nor convince the skeptics that the fetal exposure is without risk. The sample size needed to document actual benefit of antepartum Rh-immune globulin administration in a controlled study can be predicted statistically. I have assumed results similar to those obtained in Davey's trial in which treated and "control" subjects are contemporaries (although not matched or randomly selected).1 Davey's results were shown in my previous report as Table II and they demonstrate that 0.6% fewer of the treated patients had Rh antibody at 6 months postpartum and during the next pregnancy. To show that this difference is statistically significant at the 5% level with power 80% would require a controlled study of 2,600 randomly treated patients compared to the
Prevention of rhesus isoimmunization
To the Editors: Hensleigh's article (Hensleigh, P. A.: Preventing rhesus isoimmunization, AM. J. 0BSTET. GYNECOL. 146:749, 1983) in which he recommends against routine antepartum Rh prophylaxis because, in his belief, it is not cost-effective must be answered. The statistics and statements based upon government registry reports which are used by Hensleigh may not be accurate, if reporting to government agencies is no more accurate in the United States than it is in Canada. In his Table I, he compares Manitoba statistics for crude rates of hemolytic disease unfavorably, particularly with those of California, despite our use of antenatal Rh prophylaxis. The figures he reports from our province are the total rates for Rh immunization, over half of which are at the enzyme Rh-antibody level only and are not associated with Rh-hemolytic disease in the current pregnancies, but of course with hemolytic disease potential in subsequent pregnancies. In 1979, our true rate for Rh-hemolytic disease of the newborn was seven per 10,000 births, dropping to 5.5 per 10,000 births in 1982. In supporting the relative importance of Rh immunization during pregnancy as a major cause of persistent Rh immunization and the effectiveness of antepartum prophylaxis, we can only refer to the Manitoba statistics which have been reported elsewhere. 1- 3 Hensleigh admits that our ascertainment is very high. In our observations of Rh immunization during pregnancy from March, 1967, to December, 1974, and in an overlapping clinical trial of antenatal Rh prophylaxis encompassing treatment of primigravid women slated to deliver in one tertiary level and one urban community hospital from December, 1968, to July, 1975, we noted an incidence of Rh immunization during pregnancy of 1.8% in 62 of 3,533 women not treated antenatally versus only 0.06% in 1 of 1,358 women who were treated antenatally, a very significant difference. In the 3-year period ending October 31, 1976, during the antenatal prophylaxis clinical trial, just at the beginning of the institution of our antenatal prophylaxis service program, 68 of the 167 Rh-immunized pregnant women observed (41%) had become Rh immunized during pregnancy-32 in a previous pregnancy, 36 in the current pregnancy (12 per year). In 1982, seven of the 21 Rh-immunized pregnant women observed (33%) were Rh immunized during pregnancy-three in a previous pregnancy, four in the 1982 pregnancy. The persisting low incidence of Rh immunization during the current pregnancy represents Rh immunization by 28 weeks' gestation (antenatal Rh prophylaxis at 28 weeks' gestation is about 92% effective). A service program begun in 1975, in
which a single dose of 300 J.Lg of Rh-immune globulin was given at 28 weeks' gestation, was also highly effective. Of 8,422 women delivered of Rh-positive babies, treated at 28 weeks' gestation, we would have expected 136 to be Rh immunized by the time of delivery if antenatal prophylaxis was ineffective. In actual fact, only eight were immunized, and of the eight, four were multigravid women who had not been given antenatal prophylaxis in previous Rh-positive pregnancies. Many women who are Rh immunized during pregnancy subsequently have very severely affected babies. In this present era, a significant fraction of the women referred to our unit from outside of Manitoba for fetal transfusions is in difficulties because of the occurrence of Rh immunization during a past pregnancy. I can supply the Editors or Hensleigh with several pertinent examples of these tragedies if they desire. Using the Manitoba statistics and Hensleigh's cost of individual protection figure of $130 (which we think to be very high), we calculate that the drug cost of preventing one case of Rh immunization during pregnancy would be $11,500, not the $41,000 which he quotes. At the more reasonable figure of $40 (excluding the totally unnecessary cross-match charges, etc.), the drug cost would be $3,500. Hensleigh makes a big point about the possible adverse effect of exposing the fetus to the human gamma globulin present in Rh-immune globulin (that is, the Rh antibody itself plus the other IgG in Rh-immune globulin). Surely, he is aware that all fetuses are exposed to much larger doses of human gamma globulin transplacentally acquired from their mothers from the twelfth week of gestation onward, and in the case of both Rh-negative and Rh-positive fetuses of Rh-immunized mothers, to much larger doses of anti-D which their mothers produce. Since maternal IgG is protective, not harmful to the fetus and newborn baby, all of whom receive it, and maternal anti-D if it produces any harm causes only hemolysis, we do not believe that the small amounts of passive anti-D (subsequent to maternal receipt of Rh-immune globulin) can harm the fetus or affect its immune competence in any way. We have seen no evidence of any harm in the tens of thousands of infants delivered after their mothers had received antenatal Rh prophylaxis. We have not studied their immune status in detail nor do we believe it necessary to do so. Finally, Hensleigh comments upon the health risks to volunteers immunized to produce Rh-immune globulin. In Canada, we greatly exceed the needs of the entire population (24,000,000), about one tenth that of the United States, for Rh-immune globulin given ante partum, post partum, and after abortion, by the plasmapheresis of 30 to 35 donors once per week. The 1151
1152 Correspondence
production of about 800 kg of Rh plasma from these donors per annum greatly exceeds our requirements. Indeed, more than half of the plasma produced is sent out of Canada. At present, all of our donors are highly naturally immunized, sterile, Rh-negative women who are hyperimmunized with 0. 7 ml of Rh-positive red cells every 6 months. Two hundred donors in the United States with similar Rh antibodies would produce about 6,000 kg of Rh plasma, an amount which should very adequately meet the United States' needs for Rh-immune globulin, including that required for antenatal prophylaxis. Be that as it may, we expect that, within 5 years, the production ofRh-immune globulin for Rh prophylaxis by means of tissue culture techniques4 will remove Hensleigh's third objection to antenatal prophylaxis. By materially reducing the cost of Rh immune globulin, it may also effectively remove his first objection. Rh immunization during pregnancy is as common as Rh immunization after spontaneous abortion. It is one half as common as Rh immunization after therapeutic abortion. It is almost 20 times as common as Rh immunization due to undiagnosed massive transplacental hemorrhage. It can only be prevented by universal antenatal Rh prophylaxis at 28 weeks' gestation, not by universal routine antepartum transplacental hemorrhage screening, which in itself will be very expensive. John M. Bowman, M.D. Rh Laboratory 735 Notre Dame Avenue Winnipeg, Manitoba, Canada RJE OLB REFERENCES I. Bowman,]. M., Chown, B., Lewis, M., and Pollock,]. M.: Rh isoimmunization during pregnancy: Antenatal prophylaxis, Can. Med. Assoc. J 118:623, 1978. 2. Bowman,]. M., and Pollock,]. M.: Antenatal prophylaxis of Rh isoimmunization: 28-weeks'-gestation service program, Can. Med. Assoc.]. 118:627, 1978. 3 .. Bowman, ]. M.: Suppression of Rh isoimmunization: A review, Obstet. Gynecol. 52:385, 1978. 4. Crawford, D. H., Harrison,]. F., Barlow, M.J., Winger, L., and Huehns, E. R.: Production of human monoclonal antibody to rhesus D antigen, Lancet 1:386, 1983.
To the Editors: I read with interest Hensleigh's article advising against the antepartum use ofRh-immune globulin but think his information is misleading and his conclusions unwarranted. The implication that Rh-immune globulin has been inadequately tested in human pregnancy is unfounded. Trials began in Canada in 1968, 1 and since then thousands have received either intramuscular or intravenous therapy. Despite widespread use, there is not one reported case of fetal morbidity due to antepartum Rh-immune globulin; Clearly, all physicians are concerned about potentially adverse effects from any substance administered antenatally. Does such fear preclude a treatment which reduces the risk of maternal Rh sensitization from 1.5% to 0.11%? By what theoreti-
April 15, 1984 Am. J. Obstet. Gynecol.
cal mechanism(s) does passive globulin administration adversely affect adult antigen processing? There is no clinical or even direct laboratory evidence to support such a direct relationship between antibody and subsequent immune response. Since the report cited pointing out the hazards of administration of immune globulin dealt with different globulins, no valid comparison can be made with Rh-immune globulin. Even in the study mentioned, there was no documented adverse effect, except for lymphocyte mitogenic responses, which may not be clinically relevant. In my location, 300 JLg of Rh-immune globulin costs $30. Therefore, I consider its antepartum use to be cost-effective, especially since the current regimen eliminates the need for two antibody titers. It has been clearly shown that no clinical parameter predicts subsequent antepartum Rh sensitization. 2 In the absence of more direct evidence to the contrary, I will continue to view the development of the antepartum immune globulin therapy as a significant advancement in Rh prophylaxis. Michael R. Caudle, M.D. Department of Obstetrics and Gynecology 415 Devonia Street Harriman, Tennessee 37748 REFERENCES I. Bowman, ]. M.: Suppression of Rh isoimmunization,
Obstet. Gynecol. 52:385, 1978. 2. Scott,]. R., Beer, A. E., Guy, R., and Elbert, G.: Pathogenesis of Rh immunization in primigravidas, Obstet. Gynecol. 49:9, 1977.
Reply to Bowman and Caudle To th1? Editors: Bowman's field trials in Manitoba have been prominent in the literature on antepartum use of Rh-immune globulin. However, in answering questions about small increments of benefit, it is essential to compare treatment and nontreatment groups which are randomly selected. In his reports, the "controls" are neither contemporary nor matched. My response to his comments and those of Caudle is the same: Further discussion in regard to published or unpublished data for which there are not proper controls will neither establish the precise benefits nor convince the skeptics that the fetal exposure is without risk. The sample size needed to document actual benefit of antepartum Rh-immune globulin administration in a controlled study can be predicted statistically. I have assumed results similar to those obtained in Davey's trial in which treated and "control" subjects are contemporaries (although not matched or randomly selected).1 Davey's results were shown in my previous report as Table II and they demonstrate that 0.6% fewer of the treated patients had Rh antibody at 6 months postpartum and during the next pregnancy. To show that this difference is statistically significant at the 5% level with power 80% would require a controlled study of 2,600 randomly treated patients compared to the