Early
Human
Development,
29 (1992)
237
231-240
Elsevier Scientific Publishers Ireland Ltd. EHD 01283
Diagnosis and therapy in Rh-incompatibility J.W. Dudenhausen Free
University
Berlin,
Department
of Obstetrics,
Pulsstrasse
4, 1000 Berlin
19 (Germany)
suuuuary Direct access to the fetoplacental circulation improves diagnosis and therapy in immunized pregnancy Key words: anemia; fetus; Rh-incompatibility;
transfusion
Introduction In recent years, diagnostics and therapy of Rh-Incompatibility have been improved by the development of direct means of access to the fetus. These methods must be incorporated into the classical management schedule. Non-invasive diagnostics Non-invasive diagnostics consists of the antibody level, the blood group status of the partner and the fetal monitoring. Ultrasonography enables the detection of the severity of anemia, of a raised cardiac output, an increased hematopoiesis or a reduced protein synthesis. As indicators were found: the size of the liver, the diameter of the umbilical vein, the size of the heart. These indicators have subordinate significance for the appraisal of the fetal state. On the other hand, ascites, edema or indeed hydrops are very serious consequences of hemolysis and are moreover important diagnostic factors. Doppler ultrasonography allows an analysis of the flow profile to detect an increased cardiac output. In most cases, these non-invasive parameters are appropriate for detection of alterations in the course. However, they are not highly specific with regard to the detection and quantification of the anemia under consideration. Invasive measures to: J.W. Dudenhausen, Free University Berlin, Department of Obstetrics, Pulsstrasse 4, 1000 Berlin 19, Germany.
Correspondence
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
238
for diagnostics and therapy are of primary importance. The classical method is diagnosis from the amniotic fluid. The sampling of amniotic fluid enables determination of bilirubin as a degradation product of hemoglobin and thus as an indirect measure of hemolysis. Only modifications have been made since LILEY presented his diagram of spectrophotometric absorbance difference values at 450 nm. In principle, the therapeutic measures were based on this photometric determination of the bilirubin concentration with all its possibilities of error. In addition, several reports have suggested that amniotic fluid spectrophotometric measurements are unreliable in assessing the severity of Rh-incompatibility in fetuses during the mid-trimester; the results are uncertain mainly in the LILEY-zone 2. Transfusion therapy
Amniotic fluid diagnostic is to a certain extent indirect. Besides this, the direct withdrawal of blood from the fetus has recently become an established method. For the first time, this fetal blood sampling has enabled direct determination of blood parameters of the fetus which hitherto could only be established indirectly, with the known possible errors. Specificity of the measurement is thus no longer a problem. After ensuring that fetal blood was withdrawn (e.g. by means of the Kleihauer-Betke test), almost all conceivable hematological investigations can be carried out. Invasive diagnostics
Therapy of blood group incompatibility is concentrated on transfusion therapy for the already anemic fetus rather than alternative additional approaches to treatment such as plasmapheresis or enzyme induction by means of phenobarbital. Erythrocyte transfusion (0 Rh negative) is carried out in a pre-existent relevant anemia. The transfusate is an erythrocyte concentrate with a hematocrit of 80”% or more. It has been tested against syphilis, cytomegalovirus, hepatitis B and HIV. There are marked circulatory changes in transfusions. However, thanks to compensating mechanisms these have less direct and negative effects than would be expected on the basis of the initial volume load alone. The transfusion can be carried out both intra-abdominally and intravascularly. There has been much speculation on the appropriate site of needle biopsy. Besides classical intraperitoneal transfusion, centesis of the intra-abdominal umbilical vein and the heart are to be considered in fetuses. In centesis of the umbilical cord, three locations are discussed. The placental insertion, the free loop or the fetal insertion. Each of the methods with a direct access to the bloodstream has advantages and disadvantages. Up to now, cardiocentesis has been reserved for exceptional cases because of the possibility of interference with stimulus conduction. Depending on the position of the fetus, the intra-abdominal umbilical vein is accessible. It has recently undergone a renaissance, since feared reactions to umbilical centesis such as tamponade or vasospasm have not been observed; in addition, there is the possibility of simultaneously monitoring the cardiac circulation by means of the fetal heart rate and the QRWT-ECG analyser via the centesis needle. However movements of the fetus must be ruled out. This also applies to centesis of the um-
239
bilical cord near to the fetal insertion, to a lesser extent to centesis of free umbilical cord loops and not at all to centesis of the placental umbilical cord insertion irrespective of whether this is diaplacental or via the amniotic cavity. Centesis of the free loop has the advantage that a dislocation can occur less readily owing to unsteadiness of the needle either due to a manipulation or to a movement of the mother. The methods of transfusion differ in various respects. The intraperitoneal method allows an administration of relatively large volumes. However, these only have to be absorbed gradually via the subdiaphragmatic lymphatics. Accordingly, the uptake capacity of the lymphatic system is a prerequisite for success. The additional administration of glucocorticoids is intended to eliminate possibly obstructive swelling in the region of the lymphatics. It is apparent, however, that intraperitoneal blood transfusions are ineffective when the fetus is already hydropic, Furthermore, large intraperitoneally deposited blood volumes can increase the intraabdominal pressure to the extent, that venous return is impaired. The amount to be transfused is calculated according to the gestational age. The formula applied is: week of pregnancy minus 10 x 10 ml. With the intraperitoneal method it is not possible to evaluate the degree of anemia, nor the effect of treatment. The intervals between transfusions are calculated in accordance with the estimated fall in the hematocrit and are as a rule between one and three weeks. Intravascular transfusion In the intravascular methods, bolus and exchange transfusion are used. Most authors prefer bolus transfusion. The amount transfused depends on the fetoplacental blood volume V, which is 100 ml/kg estimated body weight for the gestational age, as well as on the initial hematocrit, the target hematocrit and the hematocrit of the transfusate. According to clinical experience, the rate of transfusion may be 5-15 ml/mm and the frequency of transfusion can be extended to weekly intervals after the second transfusion. Nicolaides et al. have suggested that the fetal hematocrit usually decreases by lg % per day. In accordance with the special situation of hydropic fetuses with initially raised central venous pressure, exchange transfusion must be considered in this situation, especially in extreme cases. Finally, some complications should be mentioned synoptically. The most severe complications are acute reactions in the fetoplacental circulation such as vasospasm or umbilical tamponade in which any life-saving measure is too late. As a rule, venous hemorrhages do not constitute a major problem. Besides this, complications must be mentioned such as amnionitis and rupture of the fetal membranes. An undesired boosting of antibodies was demonstrated especially with diaplacental access. The success of the therapy diverges greatly at different centers, of which a voluntary selection was made here (Table I). They range from 20 to 100%. There are multifarious reasons for this. One of the crucial factors is the gestational age and the condition of the fetus on commencement of therapy. To summarize, direct access to the fetoplacental circulation substantially improves diagnosis in fetomatemal group intolerance owing to the higher specificity, so that
240 TABLE I Method and successof transfusion therapy. Reference
Method
Patient (4
IUT’s (4
Success m
Hansmann, 1979-858 Mackenzie et al. 1987 Voto and Margulies, 1988 Lemery et al. 1989 Rodeck et al. 1984 Grannum et al. 1988 Poissonnier et al. 1989 Bars et al. 1988 Hansmann, 1986-8.91a
Intraperitoneal Fetoscopy Intravascular Exchange Fetoscopy and other Intravascular Exchange Intravascular Intravascular
48 10 33 15 25 26 107 23 209
183 17 90 30 71 12 200 61 956
65 20 64 61 12 81 86 87 94
aPersonal communication.
therapy has undergone a hitherto inconceivable improvement in formerly almost hopeless cases. However, this progress was not possible without an additional risk, as documented by the centesis incidents with lethal outcome for the fetus. These are rare and occur with an incidence of 2-5%. References Bars, V.A., Benacerraf, B.R., Frigoletto, F.D., Greene, M.F., Penso, C., Saltzmann, D.H., Nadel, A., Heffner, L.J., Scherl, J.E. and Doubilet, P.M. (1988): Management of isoimmunized pregnancy by use of intravascular techniques. Am. J. Obstet. Gynecol., 158, 932-937. Grannum, P.A.T., Copel, J.A., Moya, F.R., Scioscia, A.L., Robert, J.A., Winn, H.N., Coster, B.C., Burdine, C.B. and Hobbins, J.C. (1988): The reversal of hydrops fetalis by intravascular intrauterine transfusion in severe isoimmune fetal anemia. Am. J. Obstet. Gynecol., 158, 914-919. Lemery, D., Urbain, M.F., Van Lieferinghen, P., Mivorek, J.C. and Jacquetin, B. (1989): Intra-uterine exchange transfusion under ultrasound guidance. Eur. J. Obstet. Gynecol. Reprod. Biol., 33, 161-168. Mackenzie, I.Z., Bowell, P.J., Ferguson, J., Castle, B.M. and Entwisle, C.C. (1987): In-utero intravascular transfusion of the fetus for the management of severe rhesus isoimmunization - a reappraisal. Br. J. Obstet. Gynaecol., 94, 1068-1073. Poissonnier, M.-H., Brossard, Y., Demedeiros, N., Vassileva, J., Pamet, F., Larsen, M., Gosset, M., Chavinie, J. and Huchet, J. (1989): Two hundred intrauterine exchange transfusion in severe blood incompatibilities. Am. J. Obstet. Gynecol., 161, 709-713. Rodeck, C.H., Nicolaides, K.H., Warsof, S.L., Fysh, W.J., Gamsu, H.R. and Kemp, J.R. (1984): The management of severe rhesus isoimmunization by fetoscopic intravascular transfusion. Am. J. Obstet. Gynecol., 150, 769-774. Voto, L.S. and Margulies, M. (1988): Severe Rh-isoimmunisation: intravenous immunoglobulin versus intravascular transfusion. 8th Annual Meeting of the International Fetal Medicine and Surgery Society. Monterey, California.
Human
Development,
29 (1992)
237
231-240
Elsevier Scientific Publishers Ireland Ltd. EHD 01283
Diagnosis and therapy in Rh-incompatibility J.W. Dudenhausen Free
University
Berlin,
Department
of Obstetrics,
Pulsstrasse
4, 1000 Berlin
19 (Germany)
suuuuary Direct access to the fetoplacental circulation improves diagnosis and therapy in immunized pregnancy Key words: anemia; fetus; Rh-incompatibility;
transfusion
Introduction In recent years, diagnostics and therapy of Rh-Incompatibility have been improved by the development of direct means of access to the fetus. These methods must be incorporated into the classical management schedule. Non-invasive diagnostics Non-invasive diagnostics consists of the antibody level, the blood group status of the partner and the fetal monitoring. Ultrasonography enables the detection of the severity of anemia, of a raised cardiac output, an increased hematopoiesis or a reduced protein synthesis. As indicators were found: the size of the liver, the diameter of the umbilical vein, the size of the heart. These indicators have subordinate significance for the appraisal of the fetal state. On the other hand, ascites, edema or indeed hydrops are very serious consequences of hemolysis and are moreover important diagnostic factors. Doppler ultrasonography allows an analysis of the flow profile to detect an increased cardiac output. In most cases, these non-invasive parameters are appropriate for detection of alterations in the course. However, they are not highly specific with regard to the detection and quantification of the anemia under consideration. Invasive measures to: J.W. Dudenhausen, Free University Berlin, Department of Obstetrics, Pulsstrasse 4, 1000 Berlin 19, Germany.
Correspondence
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
238
for diagnostics and therapy are of primary importance. The classical method is diagnosis from the amniotic fluid. The sampling of amniotic fluid enables determination of bilirubin as a degradation product of hemoglobin and thus as an indirect measure of hemolysis. Only modifications have been made since LILEY presented his diagram of spectrophotometric absorbance difference values at 450 nm. In principle, the therapeutic measures were based on this photometric determination of the bilirubin concentration with all its possibilities of error. In addition, several reports have suggested that amniotic fluid spectrophotometric measurements are unreliable in assessing the severity of Rh-incompatibility in fetuses during the mid-trimester; the results are uncertain mainly in the LILEY-zone 2. Transfusion therapy
Amniotic fluid diagnostic is to a certain extent indirect. Besides this, the direct withdrawal of blood from the fetus has recently become an established method. For the first time, this fetal blood sampling has enabled direct determination of blood parameters of the fetus which hitherto could only be established indirectly, with the known possible errors. Specificity of the measurement is thus no longer a problem. After ensuring that fetal blood was withdrawn (e.g. by means of the Kleihauer-Betke test), almost all conceivable hematological investigations can be carried out. Invasive diagnostics
Therapy of blood group incompatibility is concentrated on transfusion therapy for the already anemic fetus rather than alternative additional approaches to treatment such as plasmapheresis or enzyme induction by means of phenobarbital. Erythrocyte transfusion (0 Rh negative) is carried out in a pre-existent relevant anemia. The transfusate is an erythrocyte concentrate with a hematocrit of 80”% or more. It has been tested against syphilis, cytomegalovirus, hepatitis B and HIV. There are marked circulatory changes in transfusions. However, thanks to compensating mechanisms these have less direct and negative effects than would be expected on the basis of the initial volume load alone. The transfusion can be carried out both intra-abdominally and intravascularly. There has been much speculation on the appropriate site of needle biopsy. Besides classical intraperitoneal transfusion, centesis of the intra-abdominal umbilical vein and the heart are to be considered in fetuses. In centesis of the umbilical cord, three locations are discussed. The placental insertion, the free loop or the fetal insertion. Each of the methods with a direct access to the bloodstream has advantages and disadvantages. Up to now, cardiocentesis has been reserved for exceptional cases because of the possibility of interference with stimulus conduction. Depending on the position of the fetus, the intra-abdominal umbilical vein is accessible. It has recently undergone a renaissance, since feared reactions to umbilical centesis such as tamponade or vasospasm have not been observed; in addition, there is the possibility of simultaneously monitoring the cardiac circulation by means of the fetal heart rate and the QRWT-ECG analyser via the centesis needle. However movements of the fetus must be ruled out. This also applies to centesis of the um-
239
bilical cord near to the fetal insertion, to a lesser extent to centesis of free umbilical cord loops and not at all to centesis of the placental umbilical cord insertion irrespective of whether this is diaplacental or via the amniotic cavity. Centesis of the free loop has the advantage that a dislocation can occur less readily owing to unsteadiness of the needle either due to a manipulation or to a movement of the mother. The methods of transfusion differ in various respects. The intraperitoneal method allows an administration of relatively large volumes. However, these only have to be absorbed gradually via the subdiaphragmatic lymphatics. Accordingly, the uptake capacity of the lymphatic system is a prerequisite for success. The additional administration of glucocorticoids is intended to eliminate possibly obstructive swelling in the region of the lymphatics. It is apparent, however, that intraperitoneal blood transfusions are ineffective when the fetus is already hydropic, Furthermore, large intraperitoneally deposited blood volumes can increase the intraabdominal pressure to the extent, that venous return is impaired. The amount to be transfused is calculated according to the gestational age. The formula applied is: week of pregnancy minus 10 x 10 ml. With the intraperitoneal method it is not possible to evaluate the degree of anemia, nor the effect of treatment. The intervals between transfusions are calculated in accordance with the estimated fall in the hematocrit and are as a rule between one and three weeks. Intravascular transfusion In the intravascular methods, bolus and exchange transfusion are used. Most authors prefer bolus transfusion. The amount transfused depends on the fetoplacental blood volume V, which is 100 ml/kg estimated body weight for the gestational age, as well as on the initial hematocrit, the target hematocrit and the hematocrit of the transfusate. According to clinical experience, the rate of transfusion may be 5-15 ml/mm and the frequency of transfusion can be extended to weekly intervals after the second transfusion. Nicolaides et al. have suggested that the fetal hematocrit usually decreases by lg % per day. In accordance with the special situation of hydropic fetuses with initially raised central venous pressure, exchange transfusion must be considered in this situation, especially in extreme cases. Finally, some complications should be mentioned synoptically. The most severe complications are acute reactions in the fetoplacental circulation such as vasospasm or umbilical tamponade in which any life-saving measure is too late. As a rule, venous hemorrhages do not constitute a major problem. Besides this, complications must be mentioned such as amnionitis and rupture of the fetal membranes. An undesired boosting of antibodies was demonstrated especially with diaplacental access. The success of the therapy diverges greatly at different centers, of which a voluntary selection was made here (Table I). They range from 20 to 100%. There are multifarious reasons for this. One of the crucial factors is the gestational age and the condition of the fetus on commencement of therapy. To summarize, direct access to the fetoplacental circulation substantially improves diagnosis in fetomatemal group intolerance owing to the higher specificity, so that
240 TABLE I Method and successof transfusion therapy. Reference
Method
Patient (4
IUT’s (4
Success m
Hansmann, 1979-858 Mackenzie et al. 1987 Voto and Margulies, 1988 Lemery et al. 1989 Rodeck et al. 1984 Grannum et al. 1988 Poissonnier et al. 1989 Bars et al. 1988 Hansmann, 1986-8.91a
Intraperitoneal Fetoscopy Intravascular Exchange Fetoscopy and other Intravascular Exchange Intravascular Intravascular
48 10 33 15 25 26 107 23 209
183 17 90 30 71 12 200 61 956
65 20 64 61 12 81 86 87 94
aPersonal communication.
therapy has undergone a hitherto inconceivable improvement in formerly almost hopeless cases. However, this progress was not possible without an additional risk, as documented by the centesis incidents with lethal outcome for the fetus. These are rare and occur with an incidence of 2-5%. References Bars, V.A., Benacerraf, B.R., Frigoletto, F.D., Greene, M.F., Penso, C., Saltzmann, D.H., Nadel, A., Heffner, L.J., Scherl, J.E. and Doubilet, P.M. (1988): Management of isoimmunized pregnancy by use of intravascular techniques. Am. J. Obstet. Gynecol., 158, 932-937. Grannum, P.A.T., Copel, J.A., Moya, F.R., Scioscia, A.L., Robert, J.A., Winn, H.N., Coster, B.C., Burdine, C.B. and Hobbins, J.C. (1988): The reversal of hydrops fetalis by intravascular intrauterine transfusion in severe isoimmune fetal anemia. Am. J. Obstet. Gynecol., 158, 914-919. Lemery, D., Urbain, M.F., Van Lieferinghen, P., Mivorek, J.C. and Jacquetin, B. (1989): Intra-uterine exchange transfusion under ultrasound guidance. Eur. J. Obstet. Gynecol. Reprod. Biol., 33, 161-168. Mackenzie, I.Z., Bowell, P.J., Ferguson, J., Castle, B.M. and Entwisle, C.C. (1987): In-utero intravascular transfusion of the fetus for the management of severe rhesus isoimmunization - a reappraisal. Br. J. Obstet. Gynaecol., 94, 1068-1073. Poissonnier, M.-H., Brossard, Y., Demedeiros, N., Vassileva, J., Pamet, F., Larsen, M., Gosset, M., Chavinie, J. and Huchet, J. (1989): Two hundred intrauterine exchange transfusion in severe blood incompatibilities. Am. J. Obstet. Gynecol., 161, 709-713. Rodeck, C.H., Nicolaides, K.H., Warsof, S.L., Fysh, W.J., Gamsu, H.R. and Kemp, J.R. (1984): The management of severe rhesus isoimmunization by fetoscopic intravascular transfusion. Am. J. Obstet. Gynecol., 150, 769-774. Voto, L.S. and Margulies, M. (1988): Severe Rh-isoimmunisation: intravenous immunoglobulin versus intravascular transfusion. 8th Annual Meeting of the International Fetal Medicine and Surgery Society. Monterey, California.
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