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Treatment of Fetal Erythroblastosis by Intravascular Transfusions: Outcome at 6 Years

From the Department of Gynecology and Obstetrics, University of Ulm, Ulm, Germany.

Address reprint requests to: Dieter Grab, MD Department of Gynecology and Obstetrics University of Ulm Prittwitzstr. 43 D-89075 Germany E-mail: dieter.grab{at}medizin.uni-ulm.de

	Abstract

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Objective: To assess 6 years’ neurologic outcome of a complete cohort of survivors of intrauterine intravascular transfusions.

Methods: From January 1986 to December 1991, 136 intra-vascular transfusions were performed in 43 fetuses presenting with signs of severe erythroblastosis. Before the initial transfusion, 11 of 43 fetuses had some degree of hydrops fetalis, and hemoglobin values ranged between 1.5 and 10.7 g/dL. Neurologic outcome of a complete cohort of 35 long-time survivors was assessed for up to 6 years by reviewing the hospital charts and questionnaires sent to the family physicians or pediatricians.

Results: Long-time follow-up was available in all survivors with hydrops at initial transfusion (seven of seven) and in 23 of 28 survivors without hydrops. Only one of 35 survivors had mild psychomotoric disabilities up to 1 year of age, but was free of sensorineural problems on further examination. In a second case, delayed speech development was observed. Fetuses presenting with hydrops fetalis before initial transfusion tended to have a higher perinatal mortality and had a significantly higher rate of preterm delivery (P = .03). However, moderate or severe neurologic impairment was never observed, even when severe cases with hydrops fetalis or extremely low hemoglobin levels were included.

Conclusion: Treatment of severe fetal erythroblastosis by intrauterine intravascular transfusions is associated with a favorable neurologic long-time outcome.

Ultrasound-guided fetal intravascular transfusion of packed erythrocytes significantly improves the survival of fetuses suffering from severe erythroblastosis. Recently, survival rates of fetuses treated in utero were reported to exceed 90%.¹ However, there have been no actual reports to date of any long-time follow-up of survivors. The aim of this study was to evaluate physical and neurologic development in a cohort of survivors 6 years after intrauterine treatment for severe fetal erythroblastosis.

	Materials and Methods

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From January 1986 to December 1991, 136 intravascular transfusions of packed erythrocytes were performed on 43 fetuses (42 single pregnancies and one set of twins) suffering from severe anemia caused by anti-D-, anti-c-, anti-C-, anti-E-, anti-Kell-, anti-Kidd-erythroblastosis, or combinations thereof (Table 1). In a twin pregnancy, if only one fetus was suffering from erythroblastosis, only the treated child was included in the study. Patients were referred from an area of about two million inhabitants. Three women had two, and one had three consecutive pregnancies requiring intrauterine transfusion. All fetuses underwent routine ultrasound examinations for fetal anatomy and biometry including estimation of fetal weight. At first transfusion, 11 of 43 fetuses had some degree of hydrops fetalis. Gestational ages at first transfusion ranged between 18 and 35 weeks and hemoglobin values before the first transfusion ranged between 1.5 and 10.7 g/dL. Funipuncture was performed after local anesthesia of maternal skin, abdominal wall, and peritoneum with 50 mg mepivacain (Meaverin, Rhône-Poulenc Rorer, Köln, Germany). One mL of fetal blood was aspirated for evaluation of hemoglobin concentration. To avoid fetal body movements during transfusion, vecuronium bromide (Norcuron, Organon Teknika Ltd., Eppelheim, Germany) was injected into the umbilical vein (0.1 mg/kg estimated fetal weight). Transfusion therapy was initiated, when fetal hematocrit was below 30%. Depending on the gestational age and estimated weight, 20–120 mL packed, washed 0 rhesus negative erythrocytes (hematocrit 60–80%) were transfused, using a perfusing system with a flow between 300 and 600 mL/h. Transfusions were repeated at intervals between 2 and 4 weeks.

	Results

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Fetuses presenting with hydrops fetalis at first transfusion and fetuses without hydrops were evaluated separately. Demographic data imply a low socioeconomic status in both groups. Only two mothers of 32 fetuses without hydrops and one of 11 with hydrops had private insurance. The number of immigrants was five of 32 in the group without hydrops and four of 11 in the hydrops group. Table 2 lists antepartum and postpartum variables in the presence or absence of hydrops fetalis. Fetuses with hydrops fetalis were more likely to be delivered by cesarean (P = .03). However, statistical power was low and conclusions should be drawn with caution. Perinatal mortality was four of 11 if fetal hydrops fetalis was present before first transfusion, and four of 32 without hydrops fetalis (P = .09). Intrauterine death occurred in two of 11 fetuses with hydrops and 3 of 33 fetuses without hydrops within 2 weeks after transfusion. All but one of these intrauterine deaths occurred before 28 weeks’ gestation. In one case, intrauterine death occurred at 28 weeks and 14 days after uneventful intrauterine transfusion. Postmortem examination revealed thrombosis of the punctured umbilical vein. In a following pregnancy also complicated by severe maternal red blood cell alloimmunization, the fetus received seven transfusions starting at 19 weeks’ gestation. The infant was spontaneously delivered at 37 weeks and had normal neurologic development.

Only two survivors showed mild sensorneurologic disabilities, both in the group without hydrops fetalis. One of those fetuses was given a first transfusion at 27 weeks’ gestation. Initial hemoglobin level was 7.1 g/dL. Additional intravascular transfusions were performed at 29, 31, 34 and 36 weeks’ gestation. At 38 weeks, a normal male of 2800 g with Apgar 9 and 10 at 1 and 5 minutes, respectively and an arterial pH of 7.32 was delivered from the vertex position after induction of labor. At 24 months of age, speech development was delayed. Further examinations were not available.

In a second case three uneventful transfusions were performed between 20 and 27 weeks’ gestation. Initial hemoglobin level before first transfusion was 2.3 g/dL. At 29 weeks an emergency cesarean delivery was performed because of persistent bradycardia at the time of the fourth transfusion. A premature female of 1060 g, Apgar 6 and 8 at 1 and 5 minutes, respectively, and pH 7.18 resulted. Initial hematocrit was 21% and an exchange transfusion was performed. The infant was ventilated for 12 days and discharged from the hospital at 79 days. At 12 months, mild psychomotor disability was noted. Further neurologic evaluations were without abnormalities and at 6 years of age, a normal school performance test was reported.

Moderate or severe neurologic disabilities were never observed in any of the survivors, even when hydrops fetalis or extremely low hemoglobin were present.

	Discussion

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Percutaneous umbilical blood sampling and intravascular transfusions have altered dramatically the diagnosis and treatment of fetal red blood cell isoimmunization.³ Until about 2 decades ago, mortality of intrauterine-treated, severe isoimmunized fetuses was about 50%.⁴ Those pregnancies were identified by serologic studies and monitored by amniotic fluid bilirubin examinations. Intraperitoneal transfusions were performed if amniotic bilirubin increased into Liley’s zone III. Intrauterine death and several neonatal complications such as respiratory distress, asphyxia, bilirubin encephalopathy, infection, and necrotizing enterocolitis were frequently observed in this group. Psychoneurologic impairment was reported in nearly 25% of survivors.⁴ Recent ACOG recommendations include the use of percutaneous umbilical cord blood sampling and intravascular transfusions in severe cases of fetal erythroblastosis.⁵

Appropriate use of funipuncture for diagnosis and therapy of severe fetal erythroblastosis permits term delivery in the majority of cases. In larger studies, survival of intrauterine-transfused fetuses ranges between 79 and 96%.^1,6–10 However, long-time neurologic outcome of survivors is unclear. There are only two recent reports, showing no difference in developmental outcome of treated children suffering from severe rhesus disease compared with the fetal population as a whole.^2,11 Doyle et al² examined 38 survivors of 52 consecutive fetuses with severe erythroblastosis, who obtained intravascular transfusions between March 1984 and May 1990. Psychologic assessment and neurodevelopmental examinations were performed. Thirty-five children (92%) had no sensorineural disabilities at 2 years of age. One of three children with sensorineural impairments had cerebral palsy and in two cases developmental delay was observed. Mental developmental index scores were not significantly related to the fetal hemoglobin deficit, gestational age at the first transfusion, or the presence of hydrops. In the smaller study of Stewart et al,¹¹ eight children with intravascular-intrauterine transfusions were assessed for developmental outcome at 18 months of age. There was no difference in developmental outcome between children treated in utero and those exchanged postnatally. Neither group was different from the population as a whole.

The present study supports existing data, that intrauterine-treated children suffering from severe erythroblastosis are at low risk for moderate or severe neurologic impairment. At 6 years of age, school performance test revealed that all survivors, excluding five cases which were lost to follow-up, were able to attend a regular primary school. Only one of 35 survivors had mild psychomotor disabilities up to 1 year of age, but was free of sensorineural problems at further examinations. Another child had delayed speech development. Cases presenting with hydrops fetalis before treatment tended to have a higher mortality and had a significantly higher rate of preterm delivery. However, no delayed neurologic development was observed in any of the surviving children in this group.

Thus, intrauterine-treated children with erythroblastosis are at low risk for neurologic impairment. Treatment of fetal anemia by intrauterine-intravascular transfusion is associated with a high survival rate and a favorable neurologic outcome, even when severe cases with extremely low hemoglobin levels or hydrops are included.

	Footnotes

 
PII S0029-7844(98)00421-9

Received May 4, 1998. Received in revised form August 11, 1998. Accepted August 20, 1998.

	References

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2. Doyle LW, Kelly EA, Rickards AL, Ford GW, Callanan C. Sensorineural outcome at 2 years for survivors of erythroblastosis treated with fetal intravascular transfusions. Obstet Gynecol 1993; 81:931–5.[Abstract/Free Full Text]

3. Bell JG, Weiner S. Has percutaneous umbilical blood sampling improved the outcome of high-risk pregnancies? Clin Perinatol 1993;20:61–75.[Medline]

4. Hardyment AF, Salvador HS, Towell ME, Carpenter CW, Jan JE, Tingle AJ. Follow-up of intrauterine transfused surviving children. Am J Obstet Gynecol 1979;133:235–41.[Medline]

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7. Poissonnier MH, Brossard Y, Demedeiros N, Vassileva J, Parnet F, Larsen M, et al. Two hundred intrauterine exchange transfusions in severe blood incompatibilities. Am J Obstet Gynecol 1989;161: 709–13.[Medline]

8. Harman CR, Bowman JM, Manning FA, Menticoglou SM. Intrauterine transfusion-intraperitoneal versus intravascular approach: A case-control comparison. Am J Obstet Gynecol 1990;162:1053–9.[Medline]

9. Sampson AJ, Permezel M, Doyle LW, de Crespigny L, Ngu A, Robinson H. Ultrasound-guided fetal intravascular transfusions for severe erythroblastosis, 1984–1993. Aust NZ J Obstet Gynaecol 1994;34:125–30.[Medline]

10. Plockinger B, Strumpflen I, Deutinger J, Bernaschek G. Diagnosis and treatment of fetal anemia due to isoimmunization. Arch Gynecol Obstet 1994;255:195–200.[Medline]

11. Stewart G, Day RE, Del Priore C, Whittle MJ, Turner TL, Holland BM. Developmental outcome after intravascular intrauterine transfusion for rhesus haemolytic disease. Arch Dis Child Fetal Neonatal Ed 1994;70:52–3.

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