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Changes in the management of severely Rh-immunized patients
Perkins
gradually increasing evidence that a great deal (far more than we have estimated) of perinatal brain damage occurs prior to the labor and delivery process, I think many of our academic efforts will be directed toward defining when perinatal brain damage occurs in order to exonerate the obstetrician from his responsibility for this while promoting educational techniques and patient care tools which will be available to everyone out there.
June I, 1984 Am. J. Obstet. Gynecol.
I do not like dogma, and I would hope that this would not be taken as dogma against fetal monitoring. REFERENCES 1. Sykes, G., Johnson, P., Ashworth, F., et al.: Do Apgar scores indicate asphyxia? Lancet 1:494, 1982. 2. Nelson, K. B., Ellenberg, J. H.: Apgar scores as predictors of chronic neurologic disability, Pediatrics 68:36, 1981.
Changes in the management of severely Rh-immunized patients James R. Scott, M.D., Neil K. Kochenour, M.D., Ronald M. Larkin, M.D., and Mary J. Scott Salt Lake City, Utah Since July 1, 1978, we have instituted the following changes in the management of severely Rh-immunized patients: (1) serial amniotic fluid optical density (1100450) values and real-time ultrasound scanning beginning at 21 weeks' gestation, (2) fetal transfusions as early as the twenty-third week, (3) ultrasound surveillance during and after intrauterine transfusions, and (4) planned premature delivery with neonatal exchange transfusions for selected cases between 29 to 32 weeks and for all patients after 32 weeks' gestation. The perinatal survival rate (83.8%) in 37 isoimmunized pregnancies managed with this regimen was significantly higher (p < 0.05) than in 34 such pregnancies (55.9%) managed according to the protocol utilized during the previous four years. (AM. J. OesTET. GVNECOL. 149:336, 1984.)
Standard guidelines for the use of intrauterine transfusion and preterm delivery in Rh-immunized patients have been based on serial amniotic fluid optical density (~OD450) values which were used to predict the severity of fetal erythroblastosis. Although some have questioned the value of intrauterine transfusion,l. 2 technical advances have improved the results obtainable with this procedure. At the same time, increased survival rates for low-birth weight infants in modern newborn intensive care units suggest that earlier delivery and neonatal exchange transfusion should also be considered for some cases traditionally treated with fetal transfusion. The purpose of this study was to assess the value of incorporating these technical advances into the obstetric management of severely Rh-immunized patients.
From the Department of Obstetrics and Gynecology, University of Utah Medical Center. Presented at the Fifty-first Annual Meeting of The Central Association rif Obstetricians and Gynecologists, Colorado Springs, Colorado, October 14-16, 1983. Reprint requests: James R. Scott, M.D., Professor and Chairman, Department of Obstetrics and Gynecology, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132.
336
Methods For the purpose of evaluation, all Rh-immunized patients whose ~OD450 values exceeded 2.0 mU or entered zone 3 on the Liley graph at any time were considered to be potentially severely affected. Seventy-one such cases were treated at the University of Utah Medical Center from July 1, 1974, to June 30, 1982, and form the basis for this report. The presumed causes of Rh immunization in these women are summarized in Fig. 1. In the first study period from July 1, 1974, to June 30, 1978, the first amniocentesis was performed during the twenty-third to the twenty-fourth week of gestation or as soon as the case was referred if that period of gestation had passed. Intrauterine transfusions aided by a fluoroscope with an image intensifier were utilized between 24 and 34 weeks' gestation if the ~OD450 value reached zone 3 on the Liley graph. High-hematocrit group 0 Rh-negative blood with plasma and buffy coat removed was cross matched against the mother's blood and transfused in volumes that were calculated by the formula (number of weeks' gestation - 20) x 10 m!. The fetal heart rate was continuously monitored throughout the procedure; the transfusion was termi-
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0.5 01974 -1978 (n= 34)
0.4
•
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C>---<>
Zone I BLOOD TYPED WRONG
TRANSFUSION
SENSITIZED DURING FIRST PREGNANCY
POSTPARTUM RH IMMUNE GLOBULIN NOT GIVEN
RH IMMUNE GLOBULIN FAILURE
Fig. 1. Presumed causes of Rh immunization. The first two bars indicate patients who were incorrectly typed as Rh positive and the second two bars indicate patients who had received Rh-positive blood transfusions. Sensitization during the first pregnancy is usually the result of antepartum fetomaternal hemorrhage, and Rh-immune globulin failures may be due to antepartum fetomaternal bleeding or to a fetomaternal hemorrhage at delivery too large to be protected by 300 ILg of postpartum Rh-immune globulin.
.03 23 24 25 26 27 28 29 30 31 32 33 34 35 WEEKS GESTATION
Fig. 2. Comparison of amniotic fluid dOD.5o mIL values in severely Rh-immunized patients in study groups 1 and 2. N signifies the total number of dOD.5o values obtained in each group.
Table I. Clinical characteristics of the two groups of severely Rh-immunized patients studied Patients
nated if there was any evidence of fetal cardiac irregularity or bradycardia. Patients not treated with intrauterine transfusions included those with fetal deaths before the transfusion could be performed and those with falling amniotic fluid dOD 45o values. Any patient treated with betamethasone for fetal lung immaturity was given 12 mg intramuscularly 48 and 24 hours before delivery. Except for one case of premature labor and one of cervical effacement and dilatation at the predetermined time for delivery, all patients with live fetuses were delivered by cesarean section between 32 and 36 weeks' gestation. During study period 2 (July I, 1978, to June 30, 1982), the first amniocentesis was performed as early as 21 weeks' gestation. A rising dOD 45o value that reached high zone 2 or above on the Liley graph or sonographic evidence for the development of fetal hydrops have been the indications to begin fetal transfusions. Intrauterine transfusions were performed as early as 23 weeks' gestation, but no fetuses were transfused after the thirty-first week. During this period of time, ultrasound examinations were used to search for fetal hydrops and to aid in the performance of intrauterine transfusions as previously described. 3 The standard betamethasone regimen was usually utilized prior to delivery if the amniotic fluid lecithin/sphingomyelin ratio was <2.0. Seven patients were delivered before 32 weeks' gestation for the following reasons; premature labor (1), refusal of intrauterine transfusion (1), technical inability to perform an intrauterine transfusion (1), and severe hydrops or fetal distress (4). The route of
Total No. Mean age (yr) Mean gravidity Mean parity Previous pregnancies Intrauterine transfusion required Exchange transfusion required Perinatal deaths
1974-1978
1978-1982
34 28.6 4.3 2.4
37 29.3 4.7 3.2*
3
5
18
22
16
18
*p < 0.05.
delivery at 32 to 36 weeks was vaginal in five instances and by cesarean section in the remaining 25 cases. The infant outcome for the 34 severely Rh-immunized patients managed from July I, 1974, to June 30, 1978, was compared with that from the 37 patients treated between July I, 1978, to June 30, 1982. The statistical significance of the data was evaluated by the Students' t test and by tests.
x:
Results
The clinical characteristics of the patients in both groups were comparable, as shown in Table I, and the mean amniotic fluid dOD 45o values for the two groups were similar, as shown in Fig. 2. During the first 4 years, two infants died in utero before an intrauterine transfusion could be accomplished, and eight fetal deaths occurred despite the use of intrauterine transfusions. Of the 24 live-born infants, one was delivered for fetal distress, one was de-
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J.
June 1, 1984 Obstet. Gynecol.
Table II. Patients purposely delivered prior to 32 weeks' gestation
Patient
2 3
4
5
6
Reason for delivery
Sudden fetal bradycardia 4 hr after intrauterine transfusion Refused intrauterine transfusion, fetal hydrops Late referral, severe fetal hydrops Fetal distress I week after intrauterine transfusion, fetal hydrops Unsuccessful intrauterine transfusion with persistent transverse lie with back up Persistent severe fetal bradycardia after intrauterine transfusion
Delivery (weeks' gestation)
No. of exchange transfusions
29
Infant complications
Infant outcome
Lacerated intra-abdominal vessel and fetal exsanguination
Stillborn
29
8
Respiratory distress syndrome
Survived
30
II
Respiratory distress syndrome, congestive heart failure
Survived
30
5
31
9
Mild respiratory distress syndrome
Survived
29
3
Respiratory distress syndrome, pneumothorax
Survived
livered because of premature spontaneous labor, and an amniotic fluid lecithin/sphingomyelin ratio was not obtained in one other case. Sixteen of the remaining 21 had lecithin/sphingomyelin ratios >2.0 prior to delivery; four whose mothers were not treated with betamethasone had a lecithin/sphingomyelin ratios <2.0, and one had a lecithin/sphingomyelin ratio <2.0, but the mother had received betamethasone. Five infants died after delivery, primarily from respiratory distress syndrome. Three of these were from the group with lecithin/sphingomyelin ratios <2.0 whose mothers had not received betamethasone, and two had lecithin/ sphingomyelin ratios >2.0. During the second 4-year period, one fetus died before an intrauterine transfusion could be carried out, and four fetal deaths occurred in the group treated with intrauterine transfusions. Six of 32 patients who were delivered of living children had unknown lecithin/ sphingomyelin ratios and/or were delivered prematurely for fetal distress or spontaneous labor. Of the remaining 26, 10 had lecithin/sphingomyelin ratios >2.0, one had a lecithin/sphingomyelin ratio <2.0 (not treated with betamethasone), and 15 had lecithin/ sphingomyelin ratios <2.0 (treated with betamethasone). The only neonatal death was a result of severe respiratory distress and intracranial hemorrhage following spontaneous premature labor and delivery at 27 weeks' gestation. The six patients in this group who were deliberately delivered before 32 weeks' gestation are listed in Table II. All five surviving infants are developing normally at the present time. As summarized in Table III, infant outcome improved in all categories in the groups both treated and not treated with intrauterine transfusions during the
Survived
last four years, with an overall perinatal survival rate of 55.9% during study period 1 and 83.8% during study period 2 (p < 0.05). In addition to reducing the amount of radiation exposure, the use of ultrasound after July 1, 1978, decreased the incidence of traumatic deaths and improved the prognosis for hydropic fetuses. Comment
Intrauterine transfusions have been recommended for severely Rh-immunized patients when a rising amniotic fluid ~OD450 value reaches high zone 2 or zone 3 on the Liley graph between 22 and 24 and 32 and 34 weeks' gestation. 4. 5 Because we have observed fetal ascites as early as 21 weeks' gestation, we believe that ultrasound examinations and amniocenteses should be started by that time. Recent technical advances in performing intrauterine transfusions have resulted in perinatal survival rates of 69% to 92%.6-8 In addition to amniotic fluid ~OD450 values, serial ultrasound examinations are helpful in deciding when and for which patient an intrauterine transfusion is necessary. Since there is no consistent correlation between amniotic fluid ~OD450 values and ultrasound findings, the two should be used in conjunction when the severity of fetal involvement is assessed and proper management is decided. We and others 9 have observed patients with no sonographic evidence of fetal ascites, subcutaneous edema, or pericardial effusion whose initial ~OD450 values in low zone 3 of the Liley curve gradually decreased without intrauterine transfusion. Conversely, we have seen other patients with severe fetal hydrops by sonography who required intrauterine transfusion before the
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Table III. Data on clinical management, intrauterine transfusions, and infant outcome of severely Rh-immunized patients from July 1, 1974, to June 30, 1982 Data
Not treated with intrauterine transfusion No. of patients Live-born infants (No. and %) Week delivered (mean and range) Surviving neonatal period (No. and %) Treated with intrauterine transfusion No. of patients All fetal transfusions (No.) Week of first intrauterine transfusion (mean and range) Hydrops, transfused (No. and %) Hydrops, surviving neonatal period (No. and %) Traumatic deaths (No. and %) Traumatic death rate per transfusion (%) Total live-born infants (No. and %) Week delivered (mean and range) Surviving neonatal period (No. and %) Total patients in both groups Week delivered (mean and range) Live-born infants (No. and %) Surviving neonatal period (No. and %)
1974-1978
1978-1982
18 16 (88.9%) 34.3 (32-36) 11 (61.1 %)
17 16 (94.1%) 32.9 (27-36)* 15 (88.2%)
16 25 27.6 (24-32) 5 (31.3%) 1 (20.0%) 2 (11.1%) 8.0 8 (50.0%) 33.8 (30-36) 8 (50.0%)
20 43 26.6 (23-31) 6 (30.0%) 4 (66.7%) 1 (5.9%) 2.3 16 (80.0%) 32.8 (29-35) 16 (80.0%)
34.1 (30-36) 24 (70.6%) 19 (55.9%)
32.9 (27-36) 32 (86.5%) 31 (83.8%)*
*p < 0.05. dOD45o value reached zone 3. Once the infant has been transfused, frequent ultrasound examinations are extremely useful for timing the next intrauterine transfusion. Specifically, ultrasound evidence of increasing or decreasing fetal peritoneal fluid accumulation can be used to determine whether transfusion intervals should be decreased or increased. 9 However, even with the use of ultrasound examinations, the risk of traumatic fetal death exists with each intrauterine transfusion. During the last 4 years of our study, one fetus died at 29 weeks' gestation from intra-abdominal bleeding after the procedure. Moreover, severe anemia and hydrops can be more reliably and rapidly corrected by an exchange transfusion, the use of digitalis, and diuretic therapy after delivery. The successful management of markedly premature infants requires all the resources of a tertiary intensive care nursery; lengthy hospitalizations for these infants are not uncommon. Nevertheless, the survival rate of very low-birth weight infants has steadily improved and long-term morbidity has decreased with the introd uction of sophisticated life-support systems. lO • 11 Since the perinatal survival rate for all infants born at the University of Utah Medical Center at 32 weeks' gestation is now 97%, we no longer employ intrauterine transfusions after that time. After 28 weeks' gestation, the infant survival rate is 90% and after 30 weeks it is 96%. For these reasons, we believe that consideration should be given to the delivery of severely Rhimmunized patients who are past these stages of gestation if: (1) the placental and/or fetal position remains unfavorable for intrauterine transfusion, (2) attempts at intrauterine transfusion are unsuccessful, or (3) se-
vere fetal hydrops is present. This view is supported by our data which include the death of one fetus in 1977 at 34 weeks' gestation after an intrauterine transfusion and the absence of any neonatal deaths of erythroblastotic infants delivered after 29 weeks' gestation from 1978 to 1982. In our series two fetuses exhibited severe hydrops by 22 weeks and both died in utero. Should these women attempt another pregnancy, or in any case in which the severity of fetal involvement can be predicted from the prior obstetric history, experimental regimens may be indicated. Two such regimens are plasmapheresis and/or immunosuppression beginning after 12 weeks' gestation and continuing until the first intrauterine transfusion can be accomplished. 12 In summary, both the antepartum management and neonatal care of the erythroblastotic infant are improving. Regular surveillance is necessary to determine the risk of infant morbidity and mortality as a consequence of allowing the pregnancy to continue versus that of premature delivery. Aggressive and early use of new diagnostic techniques and of advances in fetal therapy, the proper timing of delivery, and modern changes in neonatal care have all contributed to the improved perinatal outcome for severely Rh-immunized patients.
REFERENCES 1. Palmer, A., Gordon, R. R.: A critical review of intrauterine transfusion, Br. J. Obstet. Gynaecol. 83:688, 1976. 2. Robertson, E. G., Brown, A., Ellis, M. I., et al.: Intrauterine transfusion in the management of severe rhesus isoimmunization, Br. J. Obstet. Gynaecol. 83:694, 1976. 3. Larkin, R. M., Knochel, J. Q., and Lee, T. G.: In-
340
4. 5. 6. 7. 8. 9.
10.
11. 12.
Scott et al.
trauterine transfusions: New techniques and results, Clin. Obstet. Gynecol. 25:303, 1982. Queenan,J. T.: Modern Management of the Rh Problem, ed. 2, Hagerstown, Maryland, 1977, Harper & Row, Publishers, p. 154. Bowman, J. M.: The management of Rh-isoimmunization, Obstet. Gynecol. 52: I, 1978. Berkowitz, R. L., and Hobbins, J. c.: Intrauterine transfusion utilizing ultrasound, Obstet. Gynecol. 57:33,1981. Clewell, W. H., Dunne, M. G., Johnson, M. L., et al.: Fetal transfusion with real-time ultrasound guidance, Obstet. Gynecol. 57:516, 1981. Bowman, J. M., and Manning, F. A.: Intrauterine transfusions: Winnipeg 1982, Obstet. Gynecol. 61:203, 1983. Frigoletto, F. D., Greene, M. F., Acker, D., et al.: Management of severe Rh isoimmune disease without intrauterine transfusion, presented at the Third Annual Meeting of the Society of Perinatal Obstetricians, San Antonio, Texas, January 27-29, 1983. Hack, M., Merkatz, I. R., Jones, P. K., et al.: Changing trends of neonatal and postneonatal deaths in very-lowbirth-weight infants, AM. J. OBSTET. GYNECOL. 137:797, 1980. Fairweather, D. V. I.: Obstetric management and followup of the very-low-birth-weight infant, J. Reprod. Med. 26:387, 1982. Caudle, M. R., and Scott, J. R.: The potential role of immunosuppression, plasmapheresis, and desensitization as treatment modalities for ·Rh immunization, Clin. Obstet. Gynecol. 25:313, 1982.
Discussion DR. L. A. AARO, Rochester, Minnesota. In their current management of severely Rh-immunized patients, the authors have recognized and employed two very significant recent advances in the care of the obstetric patient and the premature infant. The first of these advances has been the use of diagnostic ultrasound for the intrauterine evaluation of the fetus. With serial intrauterine ultrasound examinations, the development, progression, and treatment of erythroblastosis fetalis may be closely followed before, during, and after intrauterine transfusions. This useful tool has greatly increased the effectiveness of the management of the Rh-sensitized pregnant patient. The other significant recent advance in caring for the erythroblastotic infant has been the development of excellent neonatal care as provided by our pediatric colleagues in modern neonatal intensive care units. As the authors have pointed out, the perinatal survival rate for all infants born at their medical center is 97% at 32 weeks, 96% at 30 weeks, and 90% at 28 weeks' gestation. These survival rates reveal spectacular improvement when compared with the survival rates of similar low-birth weight infants born only a decade ago.! Modern neonatal care has markedly improved the outlook for the infant with severe hemolytic disease. The authors have recommended early amniotic fluid studies, fetal transfusions as early as the twenty-third week, ultrasound surveillance, and planned delivery of all patients after 32 weeks' gestation. These recommendations are already accepted practices at most tertiary care centers. Bowman and Manning2 have reported a large series of patients and recommended
June I, 1984 Am. J. Obstet. Gynecol.
amniotic fluid studies beginning at 20Y2 weeks and intrauterine transfusions, carried out under ultrasound guidance, beginning as early as 22Y2 weeks gestation. These same Canadian authors 2 have also reported the survival of up to 92% of fetuses that received intrauterine transfusions. Although Dr. Scott and co-workers have advocated early intrauterine transfusions and early delivery of transfused fetuses, their actual data reveal only a mean difference of 1 weeks' gestation between the times of transfusion and delivery of their two study groups, yet the results, as measured by neonatal survival, are much better in their latest group that received intrauterine transfusions. I would like to ask the authors if they believe the improved results are due to early intervention or to improved transfusion techniques and neonatal care. In terms of future technologies that may become available to deal with intrauterine transfusions, the most promising techniques seem to be associated with fetoscopy. The British, in particular, have taken the lead in utilizing fetoscopy for direct intrauterine transfusions via the umbilical vein. With this technique, direct measurements of fetal hemoglobin and hematocrit may be made from the umbilical vein and direct intravenous fetal transfusions may be accomplished. Another advantage claimed for this new technique is that drugs may also be administered to the fetus by the intravenous route. This paper reminds many obstetricians of the days, only 15 years ago, when Rh immunization was common among pregnant patients. In 1968, the Food and Drug Administration granted approval for the postpartum administration of Rh-immune globulin and since then its widespread usage has almost eliminated severe Rh immunization. The authors have outlined an excellent plan to follow when obstetricians encounter the rare unfortunate pregnant patient who has developed a severe Rh immunity. REFERENCES
1. Stewart, A. L., and Reynolds, E. R.: Improved prognosis for infants of very low birth weight, Pediatrics 54:724, 1974. 2. Bowman, J. M., and Manning, F. A.: Intrauterine fetal transfusions: Winnipeg, 1982, Obstet. Gynecol. 61:203, 1983.
DR. REBECCA D. SHAW, Des Moines, Iowa. This paper is an excellent demonstration of how the improvement in techniques for intrauterine transfusions and the advances in the management of low-birth weight infants by the neonatologists have had an additive if not a synergistic effect on the increased survival rates of infants of severely Rh-sensitized women. Dr. Scott and associates mention that ultrasound is used to search for fetal hydrops which is characterized by universal edema and extreme ascites. The development of fetal hydrops is not totally understood. A
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number of authors, including Dr. Bowman! from Winnipeg, describe the process as stemming from severe hemolysis followed by extensive hepatic erythropoiesis, causing marked distortion and enlargement of hepatic parenchyma. The development of portal and umbilical venous hypertension results in ascites. Perhaps the authors could comment on whether they have had any success in detecting hepatomegaly with ultrasound, since this may have a direct role in the development of hydrops. White et al.,2 from the University of Iowa, published a study, in 1978, which evaluated 15 intrauterine transfusion survivors over the age of 3 years, comparing them with two control groups matched for birth weight, gestational age, and mode of delivery. The only significant differences among the intrauterine transfusion survivors were an increased incidence of inguinal and umbilical hernias and an increased number of dental caries. Intellectual, academic, and behavioral studies were normal in the study and the control groups. No significant differences were found between groups in height, weight, immune competence, and renal and hepatic function. Although sufficient time has not elapsed to study the group of intrauterine transfusion survivors from 1978 to 1982 from the University of Utah, I would be interested if the authors are seeing any notable differences compared with control patients in their group from 1974 to 1978. In a report from London in 1981, the authors3 described their experience with intravascular transfusions via fetoscopy for management of Rh isoimmunization. Although the risks of fetal intravascular transfusion are not known, the authors suggest that fetal intravascular and intraperitoneal transfusions may ultimately have a complementary role in managing severely Rh-sensitized patients. I would appreciate the authors' thoughts about the roles of fetoscopy and intravascular transfusions in the future management of these patients. REFERENCES 1. Bowman, J.: The management of Rh-isoimmunization, Obstet. Gynecol. 52: 1, 1978. 2. White, C. A., Goplerud, C. P., Kisker, C. T., et al.: Intrauterine fetal transfusion, 1965-1976, with an assessment of the surviving children, AM. J. OBSTET. GYNECOL. 130:933, 1978. 3. Rodeck, C. H., et al.: Direct intravascular fetal blood transfusion by fetoscopy in severe rhesus isoimmunization, Lancet 1:625, 1981. DR. RICHARD P. PERKINS, Albuquerque, New Mexico. I want to congratulate the authors on their results, particularly in regard to the results that they have achieved with hydropic babies.
Management of severely Rh-immunized patients
341
My question is: Have they had sufficient opportunity to anticipate the development of hydrops in order to be able to avoid some of the morbidity which seems irreducible in dealing with the hydropic fetus. DeVore and others have reported that the development of pericardial fluid on M-mode echocardiography has been a useful tool in anticipating the development of hydrops, and I wanted to ask the authors if they have had any experience or interest in investigating this particular technique. DR. ALLAN G. CHARLES, Chicago, Illinois. I was going to ask the same question with regard to ultrasonic scanning. If you wait until hydrops has occurred, you are at an end point which diminishes your reSOle efforts. I was wondering if you measure or at least evaluate liver size and the dilatation of the hepatic vems. The other comment I wanted to make was that one slide indicated that perhaps the cause of continued sensitization was related to prenatal sensitization. It may be more likely due to inadequate RhoGAM given at the time of delivery in the cesarean section, Pitocinstimulated labors, and so on. DR. SCOTI (Closing). We believe that both early intervention and neonatal care were factors in improving our statistics. Since reviewing our data, we have become even more aggressive-beginning intrauterine transfusions as early as 22 weeks' gestation and repeating them as often as every 5 days if necessary. Direct transfusions into placental or umbilical vessels by fetoscopy may have potential for some severely sensitized secondtrimester fetuses. However, in most cases, ultrasounddirected intraperitoneal fetal transfusions are more practical, are technically easier, and involve less risk to the infant. We have not been impressed that pericardial effusion is an early constant sign of developing fetal hydrops. However, we are in the process of analyzing all ultrasound parameters in an attempt to develop a better prospective and predictive grading system. All of these infants are having long-term follow-up, but I have no specific information available at this time that I can comment on. I do know that at least two of the severely hydropic babies are developing normally. The etiology of Rh sensitization in women who receive postpartum Rh-immune globulin has been addressed by several previous studies including our own. To summarize, approximately 85% are sensitized during the antepartum period and only about 15% are sensitized because of an inadequate postpartum dose.
gradually increasing evidence that a great deal (far more than we have estimated) of perinatal brain damage occurs prior to the labor and delivery process, I think many of our academic efforts will be directed toward defining when perinatal brain damage occurs in order to exonerate the obstetrician from his responsibility for this while promoting educational techniques and patient care tools which will be available to everyone out there.
June I, 1984 Am. J. Obstet. Gynecol.
I do not like dogma, and I would hope that this would not be taken as dogma against fetal monitoring. REFERENCES 1. Sykes, G., Johnson, P., Ashworth, F., et al.: Do Apgar scores indicate asphyxia? Lancet 1:494, 1982. 2. Nelson, K. B., Ellenberg, J. H.: Apgar scores as predictors of chronic neurologic disability, Pediatrics 68:36, 1981.
Changes in the management of severely Rh-immunized patients James R. Scott, M.D., Neil K. Kochenour, M.D., Ronald M. Larkin, M.D., and Mary J. Scott Salt Lake City, Utah Since July 1, 1978, we have instituted the following changes in the management of severely Rh-immunized patients: (1) serial amniotic fluid optical density (1100450) values and real-time ultrasound scanning beginning at 21 weeks' gestation, (2) fetal transfusions as early as the twenty-third week, (3) ultrasound surveillance during and after intrauterine transfusions, and (4) planned premature delivery with neonatal exchange transfusions for selected cases between 29 to 32 weeks and for all patients after 32 weeks' gestation. The perinatal survival rate (83.8%) in 37 isoimmunized pregnancies managed with this regimen was significantly higher (p < 0.05) than in 34 such pregnancies (55.9%) managed according to the protocol utilized during the previous four years. (AM. J. OesTET. GVNECOL. 149:336, 1984.)
Standard guidelines for the use of intrauterine transfusion and preterm delivery in Rh-immunized patients have been based on serial amniotic fluid optical density (~OD450) values which were used to predict the severity of fetal erythroblastosis. Although some have questioned the value of intrauterine transfusion,l. 2 technical advances have improved the results obtainable with this procedure. At the same time, increased survival rates for low-birth weight infants in modern newborn intensive care units suggest that earlier delivery and neonatal exchange transfusion should also be considered for some cases traditionally treated with fetal transfusion. The purpose of this study was to assess the value of incorporating these technical advances into the obstetric management of severely Rh-immunized patients.
From the Department of Obstetrics and Gynecology, University of Utah Medical Center. Presented at the Fifty-first Annual Meeting of The Central Association rif Obstetricians and Gynecologists, Colorado Springs, Colorado, October 14-16, 1983. Reprint requests: James R. Scott, M.D., Professor and Chairman, Department of Obstetrics and Gynecology, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132.
336
Methods For the purpose of evaluation, all Rh-immunized patients whose ~OD450 values exceeded 2.0 mU or entered zone 3 on the Liley graph at any time were considered to be potentially severely affected. Seventy-one such cases were treated at the University of Utah Medical Center from July 1, 1974, to June 30, 1982, and form the basis for this report. The presumed causes of Rh immunization in these women are summarized in Fig. 1. In the first study period from July 1, 1974, to June 30, 1978, the first amniocentesis was performed during the twenty-third to the twenty-fourth week of gestation or as soon as the case was referred if that period of gestation had passed. Intrauterine transfusions aided by a fluoroscope with an image intensifier were utilized between 24 and 34 weeks' gestation if the ~OD450 value reached zone 3 on the Liley graph. High-hematocrit group 0 Rh-negative blood with plasma and buffy coat removed was cross matched against the mother's blood and transfused in volumes that were calculated by the formula (number of weeks' gestation - 20) x 10 m!. The fetal heart rate was continuously monitored throughout the procedure; the transfusion was termi-
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0.5 01974 -1978 (n= 34)
0.4
•
0.3
1978-1982 (n=37)
0.2 I-
z
w a: w
30
0
L()
u
a...
0
0.1
20
Zone 2
.08 .06
10
.04
o
.. --.. 1974-1978 (n=87) /978-/982 (n= 127)
C>---<>
Zone I BLOOD TYPED WRONG
TRANSFUSION
SENSITIZED DURING FIRST PREGNANCY
POSTPARTUM RH IMMUNE GLOBULIN NOT GIVEN
RH IMMUNE GLOBULIN FAILURE
Fig. 1. Presumed causes of Rh immunization. The first two bars indicate patients who were incorrectly typed as Rh positive and the second two bars indicate patients who had received Rh-positive blood transfusions. Sensitization during the first pregnancy is usually the result of antepartum fetomaternal hemorrhage, and Rh-immune globulin failures may be due to antepartum fetomaternal bleeding or to a fetomaternal hemorrhage at delivery too large to be protected by 300 ILg of postpartum Rh-immune globulin.
.03 23 24 25 26 27 28 29 30 31 32 33 34 35 WEEKS GESTATION
Fig. 2. Comparison of amniotic fluid dOD.5o mIL values in severely Rh-immunized patients in study groups 1 and 2. N signifies the total number of dOD.5o values obtained in each group.
Table I. Clinical characteristics of the two groups of severely Rh-immunized patients studied Patients
nated if there was any evidence of fetal cardiac irregularity or bradycardia. Patients not treated with intrauterine transfusions included those with fetal deaths before the transfusion could be performed and those with falling amniotic fluid dOD 45o values. Any patient treated with betamethasone for fetal lung immaturity was given 12 mg intramuscularly 48 and 24 hours before delivery. Except for one case of premature labor and one of cervical effacement and dilatation at the predetermined time for delivery, all patients with live fetuses were delivered by cesarean section between 32 and 36 weeks' gestation. During study period 2 (July I, 1978, to June 30, 1982), the first amniocentesis was performed as early as 21 weeks' gestation. A rising dOD 45o value that reached high zone 2 or above on the Liley graph or sonographic evidence for the development of fetal hydrops have been the indications to begin fetal transfusions. Intrauterine transfusions were performed as early as 23 weeks' gestation, but no fetuses were transfused after the thirty-first week. During this period of time, ultrasound examinations were used to search for fetal hydrops and to aid in the performance of intrauterine transfusions as previously described. 3 The standard betamethasone regimen was usually utilized prior to delivery if the amniotic fluid lecithin/sphingomyelin ratio was <2.0. Seven patients were delivered before 32 weeks' gestation for the following reasons; premature labor (1), refusal of intrauterine transfusion (1), technical inability to perform an intrauterine transfusion (1), and severe hydrops or fetal distress (4). The route of
Total No. Mean age (yr) Mean gravidity Mean parity Previous pregnancies Intrauterine transfusion required Exchange transfusion required Perinatal deaths
1974-1978
1978-1982
34 28.6 4.3 2.4
37 29.3 4.7 3.2*
3
5
18
22
16
18
*p < 0.05.
delivery at 32 to 36 weeks was vaginal in five instances and by cesarean section in the remaining 25 cases. The infant outcome for the 34 severely Rh-immunized patients managed from July I, 1974, to June 30, 1978, was compared with that from the 37 patients treated between July I, 1978, to June 30, 1982. The statistical significance of the data was evaluated by the Students' t test and by tests.
x:
Results
The clinical characteristics of the patients in both groups were comparable, as shown in Table I, and the mean amniotic fluid dOD 45o values for the two groups were similar, as shown in Fig. 2. During the first 4 years, two infants died in utero before an intrauterine transfusion could be accomplished, and eight fetal deaths occurred despite the use of intrauterine transfusions. Of the 24 live-born infants, one was delivered for fetal distress, one was de-
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J.
June 1, 1984 Obstet. Gynecol.
Table II. Patients purposely delivered prior to 32 weeks' gestation
Patient
2 3
4
5
6
Reason for delivery
Sudden fetal bradycardia 4 hr after intrauterine transfusion Refused intrauterine transfusion, fetal hydrops Late referral, severe fetal hydrops Fetal distress I week after intrauterine transfusion, fetal hydrops Unsuccessful intrauterine transfusion with persistent transverse lie with back up Persistent severe fetal bradycardia after intrauterine transfusion
Delivery (weeks' gestation)
No. of exchange transfusions
29
Infant complications
Infant outcome
Lacerated intra-abdominal vessel and fetal exsanguination
Stillborn
29
8
Respiratory distress syndrome
Survived
30
II
Respiratory distress syndrome, congestive heart failure
Survived
30
5
31
9
Mild respiratory distress syndrome
Survived
29
3
Respiratory distress syndrome, pneumothorax
Survived
livered because of premature spontaneous labor, and an amniotic fluid lecithin/sphingomyelin ratio was not obtained in one other case. Sixteen of the remaining 21 had lecithin/sphingomyelin ratios >2.0 prior to delivery; four whose mothers were not treated with betamethasone had a lecithin/sphingomyelin ratios <2.0, and one had a lecithin/sphingomyelin ratio <2.0, but the mother had received betamethasone. Five infants died after delivery, primarily from respiratory distress syndrome. Three of these were from the group with lecithin/sphingomyelin ratios <2.0 whose mothers had not received betamethasone, and two had lecithin/ sphingomyelin ratios >2.0. During the second 4-year period, one fetus died before an intrauterine transfusion could be carried out, and four fetal deaths occurred in the group treated with intrauterine transfusions. Six of 32 patients who were delivered of living children had unknown lecithin/ sphingomyelin ratios and/or were delivered prematurely for fetal distress or spontaneous labor. Of the remaining 26, 10 had lecithin/sphingomyelin ratios >2.0, one had a lecithin/sphingomyelin ratio <2.0 (not treated with betamethasone), and 15 had lecithin/ sphingomyelin ratios <2.0 (treated with betamethasone). The only neonatal death was a result of severe respiratory distress and intracranial hemorrhage following spontaneous premature labor and delivery at 27 weeks' gestation. The six patients in this group who were deliberately delivered before 32 weeks' gestation are listed in Table II. All five surviving infants are developing normally at the present time. As summarized in Table III, infant outcome improved in all categories in the groups both treated and not treated with intrauterine transfusions during the
Survived
last four years, with an overall perinatal survival rate of 55.9% during study period 1 and 83.8% during study period 2 (p < 0.05). In addition to reducing the amount of radiation exposure, the use of ultrasound after July 1, 1978, decreased the incidence of traumatic deaths and improved the prognosis for hydropic fetuses. Comment
Intrauterine transfusions have been recommended for severely Rh-immunized patients when a rising amniotic fluid ~OD450 value reaches high zone 2 or zone 3 on the Liley graph between 22 and 24 and 32 and 34 weeks' gestation. 4. 5 Because we have observed fetal ascites as early as 21 weeks' gestation, we believe that ultrasound examinations and amniocenteses should be started by that time. Recent technical advances in performing intrauterine transfusions have resulted in perinatal survival rates of 69% to 92%.6-8 In addition to amniotic fluid ~OD450 values, serial ultrasound examinations are helpful in deciding when and for which patient an intrauterine transfusion is necessary. Since there is no consistent correlation between amniotic fluid ~OD450 values and ultrasound findings, the two should be used in conjunction when the severity of fetal involvement is assessed and proper management is decided. We and others 9 have observed patients with no sonographic evidence of fetal ascites, subcutaneous edema, or pericardial effusion whose initial ~OD450 values in low zone 3 of the Liley curve gradually decreased without intrauterine transfusion. Conversely, we have seen other patients with severe fetal hydrops by sonography who required intrauterine transfusion before the
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Table III. Data on clinical management, intrauterine transfusions, and infant outcome of severely Rh-immunized patients from July 1, 1974, to June 30, 1982 Data
Not treated with intrauterine transfusion No. of patients Live-born infants (No. and %) Week delivered (mean and range) Surviving neonatal period (No. and %) Treated with intrauterine transfusion No. of patients All fetal transfusions (No.) Week of first intrauterine transfusion (mean and range) Hydrops, transfused (No. and %) Hydrops, surviving neonatal period (No. and %) Traumatic deaths (No. and %) Traumatic death rate per transfusion (%) Total live-born infants (No. and %) Week delivered (mean and range) Surviving neonatal period (No. and %) Total patients in both groups Week delivered (mean and range) Live-born infants (No. and %) Surviving neonatal period (No. and %)
1974-1978
1978-1982
18 16 (88.9%) 34.3 (32-36) 11 (61.1 %)
17 16 (94.1%) 32.9 (27-36)* 15 (88.2%)
16 25 27.6 (24-32) 5 (31.3%) 1 (20.0%) 2 (11.1%) 8.0 8 (50.0%) 33.8 (30-36) 8 (50.0%)
20 43 26.6 (23-31) 6 (30.0%) 4 (66.7%) 1 (5.9%) 2.3 16 (80.0%) 32.8 (29-35) 16 (80.0%)
34.1 (30-36) 24 (70.6%) 19 (55.9%)
32.9 (27-36) 32 (86.5%) 31 (83.8%)*
*p < 0.05. dOD45o value reached zone 3. Once the infant has been transfused, frequent ultrasound examinations are extremely useful for timing the next intrauterine transfusion. Specifically, ultrasound evidence of increasing or decreasing fetal peritoneal fluid accumulation can be used to determine whether transfusion intervals should be decreased or increased. 9 However, even with the use of ultrasound examinations, the risk of traumatic fetal death exists with each intrauterine transfusion. During the last 4 years of our study, one fetus died at 29 weeks' gestation from intra-abdominal bleeding after the procedure. Moreover, severe anemia and hydrops can be more reliably and rapidly corrected by an exchange transfusion, the use of digitalis, and diuretic therapy after delivery. The successful management of markedly premature infants requires all the resources of a tertiary intensive care nursery; lengthy hospitalizations for these infants are not uncommon. Nevertheless, the survival rate of very low-birth weight infants has steadily improved and long-term morbidity has decreased with the introd uction of sophisticated life-support systems. lO • 11 Since the perinatal survival rate for all infants born at the University of Utah Medical Center at 32 weeks' gestation is now 97%, we no longer employ intrauterine transfusions after that time. After 28 weeks' gestation, the infant survival rate is 90% and after 30 weeks it is 96%. For these reasons, we believe that consideration should be given to the delivery of severely Rhimmunized patients who are past these stages of gestation if: (1) the placental and/or fetal position remains unfavorable for intrauterine transfusion, (2) attempts at intrauterine transfusion are unsuccessful, or (3) se-
vere fetal hydrops is present. This view is supported by our data which include the death of one fetus in 1977 at 34 weeks' gestation after an intrauterine transfusion and the absence of any neonatal deaths of erythroblastotic infants delivered after 29 weeks' gestation from 1978 to 1982. In our series two fetuses exhibited severe hydrops by 22 weeks and both died in utero. Should these women attempt another pregnancy, or in any case in which the severity of fetal involvement can be predicted from the prior obstetric history, experimental regimens may be indicated. Two such regimens are plasmapheresis and/or immunosuppression beginning after 12 weeks' gestation and continuing until the first intrauterine transfusion can be accomplished. 12 In summary, both the antepartum management and neonatal care of the erythroblastotic infant are improving. Regular surveillance is necessary to determine the risk of infant morbidity and mortality as a consequence of allowing the pregnancy to continue versus that of premature delivery. Aggressive and early use of new diagnostic techniques and of advances in fetal therapy, the proper timing of delivery, and modern changes in neonatal care have all contributed to the improved perinatal outcome for severely Rh-immunized patients.
REFERENCES 1. Palmer, A., Gordon, R. R.: A critical review of intrauterine transfusion, Br. J. Obstet. Gynaecol. 83:688, 1976. 2. Robertson, E. G., Brown, A., Ellis, M. I., et al.: Intrauterine transfusion in the management of severe rhesus isoimmunization, Br. J. Obstet. Gynaecol. 83:694, 1976. 3. Larkin, R. M., Knochel, J. Q., and Lee, T. G.: In-
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4. 5. 6. 7. 8. 9.
10.
11. 12.
Scott et al.
trauterine transfusions: New techniques and results, Clin. Obstet. Gynecol. 25:303, 1982. Queenan,J. T.: Modern Management of the Rh Problem, ed. 2, Hagerstown, Maryland, 1977, Harper & Row, Publishers, p. 154. Bowman, J. M.: The management of Rh-isoimmunization, Obstet. Gynecol. 52: I, 1978. Berkowitz, R. L., and Hobbins, J. c.: Intrauterine transfusion utilizing ultrasound, Obstet. Gynecol. 57:33,1981. Clewell, W. H., Dunne, M. G., Johnson, M. L., et al.: Fetal transfusion with real-time ultrasound guidance, Obstet. Gynecol. 57:516, 1981. Bowman, J. M., and Manning, F. A.: Intrauterine transfusions: Winnipeg 1982, Obstet. Gynecol. 61:203, 1983. Frigoletto, F. D., Greene, M. F., Acker, D., et al.: Management of severe Rh isoimmune disease without intrauterine transfusion, presented at the Third Annual Meeting of the Society of Perinatal Obstetricians, San Antonio, Texas, January 27-29, 1983. Hack, M., Merkatz, I. R., Jones, P. K., et al.: Changing trends of neonatal and postneonatal deaths in very-lowbirth-weight infants, AM. J. OBSTET. GYNECOL. 137:797, 1980. Fairweather, D. V. I.: Obstetric management and followup of the very-low-birth-weight infant, J. Reprod. Med. 26:387, 1982. Caudle, M. R., and Scott, J. R.: The potential role of immunosuppression, plasmapheresis, and desensitization as treatment modalities for ·Rh immunization, Clin. Obstet. Gynecol. 25:313, 1982.
Discussion DR. L. A. AARO, Rochester, Minnesota. In their current management of severely Rh-immunized patients, the authors have recognized and employed two very significant recent advances in the care of the obstetric patient and the premature infant. The first of these advances has been the use of diagnostic ultrasound for the intrauterine evaluation of the fetus. With serial intrauterine ultrasound examinations, the development, progression, and treatment of erythroblastosis fetalis may be closely followed before, during, and after intrauterine transfusions. This useful tool has greatly increased the effectiveness of the management of the Rh-sensitized pregnant patient. The other significant recent advance in caring for the erythroblastotic infant has been the development of excellent neonatal care as provided by our pediatric colleagues in modern neonatal intensive care units. As the authors have pointed out, the perinatal survival rate for all infants born at their medical center is 97% at 32 weeks, 96% at 30 weeks, and 90% at 28 weeks' gestation. These survival rates reveal spectacular improvement when compared with the survival rates of similar low-birth weight infants born only a decade ago.! Modern neonatal care has markedly improved the outlook for the infant with severe hemolytic disease. The authors have recommended early amniotic fluid studies, fetal transfusions as early as the twenty-third week, ultrasound surveillance, and planned delivery of all patients after 32 weeks' gestation. These recommendations are already accepted practices at most tertiary care centers. Bowman and Manning2 have reported a large series of patients and recommended
June I, 1984 Am. J. Obstet. Gynecol.
amniotic fluid studies beginning at 20Y2 weeks and intrauterine transfusions, carried out under ultrasound guidance, beginning as early as 22Y2 weeks gestation. These same Canadian authors 2 have also reported the survival of up to 92% of fetuses that received intrauterine transfusions. Although Dr. Scott and co-workers have advocated early intrauterine transfusions and early delivery of transfused fetuses, their actual data reveal only a mean difference of 1 weeks' gestation between the times of transfusion and delivery of their two study groups, yet the results, as measured by neonatal survival, are much better in their latest group that received intrauterine transfusions. I would like to ask the authors if they believe the improved results are due to early intervention or to improved transfusion techniques and neonatal care. In terms of future technologies that may become available to deal with intrauterine transfusions, the most promising techniques seem to be associated with fetoscopy. The British, in particular, have taken the lead in utilizing fetoscopy for direct intrauterine transfusions via the umbilical vein. With this technique, direct measurements of fetal hemoglobin and hematocrit may be made from the umbilical vein and direct intravenous fetal transfusions may be accomplished. Another advantage claimed for this new technique is that drugs may also be administered to the fetus by the intravenous route. This paper reminds many obstetricians of the days, only 15 years ago, when Rh immunization was common among pregnant patients. In 1968, the Food and Drug Administration granted approval for the postpartum administration of Rh-immune globulin and since then its widespread usage has almost eliminated severe Rh immunization. The authors have outlined an excellent plan to follow when obstetricians encounter the rare unfortunate pregnant patient who has developed a severe Rh immunity. REFERENCES
1. Stewart, A. L., and Reynolds, E. R.: Improved prognosis for infants of very low birth weight, Pediatrics 54:724, 1974. 2. Bowman, J. M., and Manning, F. A.: Intrauterine fetal transfusions: Winnipeg, 1982, Obstet. Gynecol. 61:203, 1983.
DR. REBECCA D. SHAW, Des Moines, Iowa. This paper is an excellent demonstration of how the improvement in techniques for intrauterine transfusions and the advances in the management of low-birth weight infants by the neonatologists have had an additive if not a synergistic effect on the increased survival rates of infants of severely Rh-sensitized women. Dr. Scott and associates mention that ultrasound is used to search for fetal hydrops which is characterized by universal edema and extreme ascites. The development of fetal hydrops is not totally understood. A
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number of authors, including Dr. Bowman! from Winnipeg, describe the process as stemming from severe hemolysis followed by extensive hepatic erythropoiesis, causing marked distortion and enlargement of hepatic parenchyma. The development of portal and umbilical venous hypertension results in ascites. Perhaps the authors could comment on whether they have had any success in detecting hepatomegaly with ultrasound, since this may have a direct role in the development of hydrops. White et al.,2 from the University of Iowa, published a study, in 1978, which evaluated 15 intrauterine transfusion survivors over the age of 3 years, comparing them with two control groups matched for birth weight, gestational age, and mode of delivery. The only significant differences among the intrauterine transfusion survivors were an increased incidence of inguinal and umbilical hernias and an increased number of dental caries. Intellectual, academic, and behavioral studies were normal in the study and the control groups. No significant differences were found between groups in height, weight, immune competence, and renal and hepatic function. Although sufficient time has not elapsed to study the group of intrauterine transfusion survivors from 1978 to 1982 from the University of Utah, I would be interested if the authors are seeing any notable differences compared with control patients in their group from 1974 to 1978. In a report from London in 1981, the authors3 described their experience with intravascular transfusions via fetoscopy for management of Rh isoimmunization. Although the risks of fetal intravascular transfusion are not known, the authors suggest that fetal intravascular and intraperitoneal transfusions may ultimately have a complementary role in managing severely Rh-sensitized patients. I would appreciate the authors' thoughts about the roles of fetoscopy and intravascular transfusions in the future management of these patients. REFERENCES 1. Bowman, J.: The management of Rh-isoimmunization, Obstet. Gynecol. 52: 1, 1978. 2. White, C. A., Goplerud, C. P., Kisker, C. T., et al.: Intrauterine fetal transfusion, 1965-1976, with an assessment of the surviving children, AM. J. OBSTET. GYNECOL. 130:933, 1978. 3. Rodeck, C. H., et al.: Direct intravascular fetal blood transfusion by fetoscopy in severe rhesus isoimmunization, Lancet 1:625, 1981. DR. RICHARD P. PERKINS, Albuquerque, New Mexico. I want to congratulate the authors on their results, particularly in regard to the results that they have achieved with hydropic babies.
Management of severely Rh-immunized patients
341
My question is: Have they had sufficient opportunity to anticipate the development of hydrops in order to be able to avoid some of the morbidity which seems irreducible in dealing with the hydropic fetus. DeVore and others have reported that the development of pericardial fluid on M-mode echocardiography has been a useful tool in anticipating the development of hydrops, and I wanted to ask the authors if they have had any experience or interest in investigating this particular technique. DR. ALLAN G. CHARLES, Chicago, Illinois. I was going to ask the same question with regard to ultrasonic scanning. If you wait until hydrops has occurred, you are at an end point which diminishes your reSOle efforts. I was wondering if you measure or at least evaluate liver size and the dilatation of the hepatic vems. The other comment I wanted to make was that one slide indicated that perhaps the cause of continued sensitization was related to prenatal sensitization. It may be more likely due to inadequate RhoGAM given at the time of delivery in the cesarean section, Pitocinstimulated labors, and so on. DR. SCOTI (Closing). We believe that both early intervention and neonatal care were factors in improving our statistics. Since reviewing our data, we have become even more aggressive-beginning intrauterine transfusions as early as 22 weeks' gestation and repeating them as often as every 5 days if necessary. Direct transfusions into placental or umbilical vessels by fetoscopy may have potential for some severely sensitized secondtrimester fetuses. However, in most cases, ultrasounddirected intraperitoneal fetal transfusions are more practical, are technically easier, and involve less risk to the infant. We have not been impressed that pericardial effusion is an early constant sign of developing fetal hydrops. However, we are in the process of analyzing all ultrasound parameters in an attempt to develop a better prospective and predictive grading system. All of these infants are having long-term follow-up, but I have no specific information available at this time that I can comment on. I do know that at least two of the severely hydropic babies are developing normally. The etiology of Rh sensitization in women who receive postpartum Rh-immune globulin has been addressed by several previous studies including our own. To summarize, approximately 85% are sensitized during the antepartum period and only about 15% are sensitized because of an inadequate postpartum dose.