High-dose intravenous gamma globulin: does it have a role in the treatment of severe erythroblastosis fetalis?

The role of high-dose intravenous (IV) gamma globulin in the treatment of erythroblastosis fetalis was assessed in five pregnancies with severe Rh (four) or Kell (one) isoimmunization. These women were treated with IV gamma globulin (1.0 g/kg body weight) once a week. In addition, fetal blood transfusions were performed when indicated. In four patients with Rh sensitization, high-dose IV gamma globulin treatment had no apparent effect on the total number of intrauterine transfusions required, the interval between transfusions, or the volume of blood required at each transfusion. The treatment did not prevent fetal hydrops and had no effect on maternal antibody titers. In one patient with Kell sensitization, however, the course of the disease was less severe than anticipated, suggesting that IV gamma globulin treatment may have modified the severity of the disease. We conclude that high-dose IV gamma globulin does not appear to be useful in the treatment of severe Rh disease. Its role in Kell and other types of red-cell isoimmunization deserves further evaluation.     

Intravascular monitoring and management of erythroblastosis fetalis

Over a 27-month period 17 pregnancies in 16 patients with severe red blood cell isoimmunization were managed with intravascular transfusions performed in utero. Fourteen of these women were Rh negative and sensitized to D or to both D and C, and the remaining two patients were sensitized to the Kell antigen (K). In 12 of the 17 cases (71%) the first intravascular transfusion was performed at 26.5 weeks' gestation or earlier. Thirty-nine of 45 attempted transfusions (87%) were successfully performed. All were done percutaneously under ultrasonic guidance. Two procedures were partial exchanges, while the remainder were straight transfusions. Thirteen of the 17 fetuses (76%) were alive at birth and survived the neonatal period. Four fetuses died in utero at 25 to 26 weeks' gestation, all within 12 hours of an intravascular transfusion. When the 27 procedures attempted during the most recent 9 months of this series were compared with the 18 procedures attempted during the preceding 18 months, no appreciable differences in technical success or fetal outcome were evident. An analysis of this experience is presented, along with modifications in technique that have been implemented. Unresolved issues are discussed.     

Management of isoimmunized pregnancy by use of intravascular techniques

Twenty-two patients who had 23 pregnancies complicated by isoimmunization were managed by the use of intravascular methods on an outpatient basis. Nine patients underwent 30 percutaneous fetal blood sampling procedures to determine fetal blood type or hematocrit, without complication. Thirteen patients underwent 45 intrauterine fetal transfusions via the umbilical vessels and 16 intraperitoneal fetal transfusions. The overall survival rate in this series was 85.7%. Survival among fetuses that were hydropic at initial evaluation was 83.3%. The procedure-related perinatal mortality rate for intravascular intrauterine transfusions was 2.2%. Knowledge of fetal blood type and hematocrit allowed treatment individualized to the specific needs of each patient. In particular, the ability to transfuse blood directly into the vascular system of the hydropic fetus proved to be lifesaving in those patients.     

Ultrasound-guided fetal blood transfusion for severe rhesus isoimmunization

Four fetuses with severe rhesus isoimmunization were transfused with packed red blood cells directly into the umbilical vein. The outcome was successful in three. In one infant, this ultrasound-guided technique resulted in resolution of severe fetal hydrops at 27 weeks, allowing delivery of a healthy nonhydropic infant at 33 weeks, and in the other three infants in prolongation of the pregnancy. The last four transfusions were performed after fetal neuromuscular blockade with curare. The procedure would appear to be associated with a low risk of complication and to provide an excellent chance of a successful outcome of a fetus with severe rhesus isoimmunization even when fetal hydrops is present.     

Fetal intravascular transfusion for hydropic disease due to rhesus isoimmunization

OBJECTIVE: To evaluate the management of hydropic fetuses, due to rhesus isoimmunization, with fetal intrauterine intravascular transfusions. MATERIAL AND METHODS: This is a retrospective analysis of 18 rhesus-negative pregnant women presenting at our hospital with fetal hydrops during a 7-year period. All cases were managed with serial intrauterine intravascular transfusions with the goal of delivery by cesarean section beyond 33 weeks of gestation. All patients received prophylactic ampicillin and ritodrine for 4 days after the procedure. RESULTS: There were 11 mildly and 7 severely hydropic fetuses. All fetuses with mild hydrops and 5 of the 7 with severe hydrops were delivered alive after 32 weeks of gestation in a good condition. Two fetuses both with severe hydrops died in utero, at 28 weeks of gestation. Intrauterine reversal of hydrops occurred in 90.9% of fetuses with mild hydrops and in 57.1% of severely hydropic fetuses. CONCLUSIONS: The survival rate for the hydropic fetuses in our study was 88.9% and it was associated with the severity of fetal hydrops.     

Management of isoimmunization in the presence of multiple maternal antibodies

OBJECTIVE: Evaluation and management of patients with multiple maternal antibody isoimmunization is unclear. The presence of > or = 1 maternal antibody may suggest a worse scenario. The objective of this study was 2-fold: first, to determine whether the presence of multiple antibodies predicts a more severe course than single antibodies and second, to determine the utility of the Queenan curves/protocol in evaluating multiple-antibody isoimmunization. STUDY DESIGN: Amniotic fluid DeltaOD(450) measurements were obtained from the antenatal testing logbook and confirmed by chart review. Cases were categorized by antibody type and clinical outcomes obtained by chart review. RESULTS: Twenty-four pregnancies with isoimmunization and multiple maternal antibodies were identified; of these, 17 had 2 antibodies (anti-D and -C in 13; anti-D and -E in 1; anti-D and -Jka in 1; anti-c and -E in 1; and anti-c and -Jka in 1), and 7 had > 2 antibodies (anti-D, -C, and -E in 4; anti-D, -C, and -N in 1; anti-c, -E, and -FYA in 1; and anti-E, -K, -Fya, -S, and -C in 1). Eleven patients (46%) required at least 1 intrauterine fetal transfusion (mean initial fetal hematocrit, 15%; range, 4.9%-24%). In those not transfused, no DeltaOD(450) measurements occurred in the Queenan "fetal death risk" zone. Poorest outcomes (multiple transfusions/hydrops/fetal demise) were in patients with anti-D and anti-C, with or without anti-E. The absence of anti-D was associated with no need for fetal transfusions. The overall transfusion rate was significantly higher compared with a group of 57 isoimmunization patients with only anti-D (46% vs. 25%, P < or =.05). CONCLUSIONS: The presence of anti-D appears to be the most significant factor guiding the course of isoimmunization with multiple antibodies. The presence of another antibody with anti-D appears to significantly increase the need for intrauterine fetal transfusions. The Queenan protocol can successfully treat patients with multiple maternal red blood cell antibodies.     

Two hundred intrauterine exchange transfusions in severe blood incompatibilities

Two hundred intrauterine exchange transfusions were performed under local anesthesia in 107 cases of blood incompatibilities (60 fetuses with severe anemia and 47 with hydrops). Under sonographic guidance, depending on fetal and placental position, an optimal puncturing site was selected along the umbilical vein: placental insertion, fetal insertion, or fetal intraabdominal segment. Tests were immediately performed to confirm fetal origin of blood obtained and estimate hemoglobin level. Blood used for exchange transfusion was compatible with maternal blood and had a hematocrit value of 75%. Exchange transfusion was continued until a hemoglobin level of 16 gm/dl was reached. This procedure was first associated with intraperitoneal transfusions and was subsequently used independently once a month to maintain an adequate hemoglobin level. In 4 fetuses with hydrops, antenatal regression of this sign was observed in 33 cases (70.2%). Overall outcome of 107 fetuses after exchanges was 84 living neonates (78.5%), 15 deaths in utero, and eight neonatal deaths. The survival rate was 91.6% for fetuses without hydrops and 61.7% for those with hydrops. The advantage of exchange transfusion appears to be rapid and efficient correction of anemia with elimination of incompatible fetal red blood cells.     

The peritoneal route as a safe pathway for early in utero therapies: illustration by a 12-year follow-up after conservative management of severe Rhesus allo-immunization

OBJECTIVE: We report a case of an extremely severe Rhesus allo-immunization treated very early in pregnancy 12 years ago. METHODS AND RESULTS: After chorionic villus sampling at 12 weeks for fetal blood phenotyping, two intraperitoneal transfusions at 14 and 15 weeks were given followed by two intravascular and seven exchange transfusions. A girl weighing 2,940 g was delivered vaginally at term after external cephalic version for breech presentation. To date her neurological and social development is normal. CONCLUSIONS: Since the success of haematopoietic stem cell transplantations for the treatment of congenital haematologic diseases could imply early and repetitive procedures, this observation enlightens the technical feasibility of such an invasive approach and its relative safety for subsequent development.     

Prevention of Rh isoimmunization and treatment of the compromised fetus

Intrauterine intravascular transfusion for the treatment of severe erythroblastosis fetalis has resulted in a number of benefits: (a) Direct access to the fetal vasculature allows an accurate assessment and prompt correction of anemia, albeit temporary. In contrast, intraperitoneally transfused blood may be absorbed erratically, especially in the face of ascites. (b) Intravascular treatments can be performed, in general, as early as 17 weeks of gestation, earlier than intraperitoneal approaches permit. (c) Reversal of hydrops along with the correction of anemia and hypoproteinemia has significantly reduced neonatal morbidity and mortality. None of the surviving neonates in our series required either thoracentesis or paracentesis following delivery, and 40% did not require neonatal exchange transfusion. (d) Treatments may be safely performed until pulmonic maturity has been established and/or an EFW of greater than 2,000 g has been reached, reducing problems of prematurity. (e) Central vein and umbilical vein hypertension may be arrested or prevented, thereby allowing fetal liver function to return to normal. While isoimmunization stands as a disease that has been quite successfully reduced in frequency and severity by the careful attention and treatment by obstetricians, cases still occur. Due to the reduced frequency of severe disease, fewer physicians are trained and experienced in performing this difficult procedure. As fewer transfusions are required, the value of regionalized treatment centers will have to be considered carefully, in order to maximize the experience and efficiency of the intravascular intrauterine transfusion treatment teams.     

Umbilical cord haematoma as a complication of intrauterine intravascular blood transfusion

Between October 1985 and February 1989, 49 ultrasound-guided intravascular fetal blood transfusions were performed in 16 patients (14 with rhesus (Rh) isoimmunization, 2 with non-immunologic hydrops fetalis (NIHF)). As an intra-operative complication, perivascular haematoma of the cord occurred in three patients (7 per cent). In two cases, fetal bradycardia necessitated delivery by Caesarean section at 30 and 32 weeks' gestation, respectively. In the third case, fetal bradycardia developed during transfusion, at 31 weeks' gestation, but normalized within 3 min. The baby was delivered as planned at 36 weeks of gestation, after another transfusion at 34 weeks. Dislodgement of the needle tip into perivascular tissue, caused by sudden fetal or maternal movements, is the reason for this complication. The haematoma develops as a result of delayed recognition and continuous transfusion into Wharton's jelly. Cord haematoma may be diagnosed in time by continuous ultrasound imaging, as illustrated in case 3. To minimize the risk of needle dislodgement during transfusion, sedation of the mother and complete immobilization of the fetus by injecting a short-acting muscle relaxant into the umbilical vessel are recommended.     

Hydrops fetalis associated with immunologic and nonimmunologic factors

Described is a pregnancy complicated by severe Rh sensitization and hydrops fetalis which was managed aggressively with frequent intrauterine transfusions initiated at 21 1/2 weeks of gestation. No improvement or only temporary improvement of the fetal hydrops was observed after each intrauterine transfusion. Postmortem examination of the infant revealed the additional presence of nonimmunologic factors involved such as pulmonic atresia and lung hypoplasia. In cases of severe Rh sensitization associated with persistent fetal hydrops despite frequent intrauterine transfusions, the presence of coexistent factors for nonimmunologic fetal hydrops should be considered.     

Treatment of fetal anemia in Rh isoimmunized pregnancies with intrauterine fetal blood transfusion

Introduction

Despite the availability of prophylactic rhesus immune globulin, hemolytic disease of the newborn and fetal death (hydrops fetalis) due to rhesus alloimmunization, is still a major contributor to perinatal morbidity and mortality in India. Pregnancy outcome after fetal therapy with ultrasound guided intrauterine transfusion (IUT) for fetal anemia was studied.

Methods

A prospective cohort study of 99 Rh isoimmunized pregnancies, Indirect Coomb’s test Positive (ICT > 1:16) was conducted from July 2002 to June 2007. Intensive fetal monitoring by sériai ultrasound and middle cerebral artery peak systolic velocity using Color Doppler was performed to detect fetal anemia. When necessary, invasive testing with cordocentesis for Hb, PCV was per-formed if pregnancy was less than 32–34 weeks gestation. If PCV was <30, or there was fetal hydrops, Ultrasound guided intrauterine transfusion was carried out by the intravascular (IVT) or the intraperitoneal (IPT) routes. Primary outcome variables were fetal survival in relation to gestational age and procedure related factors.

Result

Of 99 pregnancies, 43 cases (25 — hydropic, 18-nonhydropic fetuses) required 135 intrauterine blood transfusions. The rest 56 pregnancies were managed conservatively and did not need IUT. IUTs were performed when indicated starting from 16 weeks (IPT) and 21 weeks (IVT) of gestation by the intraperitoneal / intravascular routes respectively. Pre-transfusion Hb ranged from 3g% to 8g%. The amount of blood transfused varied from 10 ml to > 110 ml depending on the period of gestation and degree of fetal anemia. The number of transfusions per pregnancy was 1–7, at intervals of 1–4 weeks, till delivery at 28 to 36 weeks of gestation. Survival of hydropic babies (88%) was almost similar to those without hydrops (83.3%) Prognosis was slightly better in Rh isoimmunized pregnancies not requiring IUT (94%) compared to fetuses receiving transfusions (85.6%)

Conclusion

Intrauterine fetal blood transfusion was found to be the only life saving therapy, and very effective in the management of preterm Rh isoimmunized pregnancies. Results are comparable with the best centers in the world, hence early referral to specialized centers with expertise of specialized intensive fetal monitoring for early diagnosis of fetal anemia, and of intrauterine fetal blood transfusion are important for optimal perinatal outcome.     

Serial fetal blood sampling for the management of pregnancies complicated by severe rhesus (D) isoimmunization

Fifty-one pregnancies complicated by rhesus (D) isoimmunization have been managed by serial fetal blood sampling between 17 and 36 weeks gestation as an alternative to amniocentesis for delta OD453 measurements. In 36 pregnancies where the fetus was shown to be rhesus (D) positive and both measurements were made before any intrauterine fetal transfusions, the delta OD453 value gave misleading predictions on 13 of 63 occasions (21%). Fetal haematocrit estimations provided a direct assessment of the haemopoietic compensation occurring, but fetal bilirubin and albumin concentrations did not correlate directly with disease severity. It is proposed that pregnancies complicated by severe isoimmunization can be more precisely managed by serial fetal blood sampling for haematocrit estimation than amniocentesis for delta OD453 measurement thus avoiding unnecessary intervention or delayed treatment.     

Aloinmunización eritrocitaria severa en paciente con síndrome de Ballantyne. Reporte de un caso

Rh(D) isoimmunization is rarely encountered today due to the introduction of Rh(D) immunoglobulin several decades ago. However, when a fetus is affected by this disease, there is a high risk of serious morbidity and mortality. This risk is even higher when the fetus develops erythroblastosis fetalis, which, in extreme instances, can also affect the mother. Ballantyne syndrome is a preeclampsia-like condition associated with hydrops fetalis and placentomegaly. This report describes the management of this entity with intraperitoneal fetal transfusion, plasma exchange and immunoglobulin therapy in a patient with Rh(D) isoimmunization and Ballantyne syndrome.     

Antecedents to and Outcomes of Rh(D) Isoimmunization: Mater Mothers Hospital, Brisbane, 1988–1995

Summary: We analyzed the antecedents and outcomes of Rh(D) isoimmunization in a local population. Forty-two Rh(D) isoimmunized women attending Mater Mothers Hospital for antenatal care were identified through the Mater Hospital Blood Bank database; their records were reviewed for variables including sensitizing events, obstetric interventions and pregnancy outcomes. In this group, 74% of women became sensitized despite receiving anti-D immune globulin, 17% did not receive anti-D appropriately and the others failed to attend for treatment of bleeding in pregnancy. Antenatal sensitization was implicated in 6 women (14%) and potentially responsible for isoimmunization in another 18. Over half of the 80 viable pregnancies in this study group required some form of obstetric intervention. Thirty pregnancies required amniocentesis and 1 in 3 babies underwent either intrauterine or exchange transfusion. Three fetal deaths occurred as a result of severe disease. This study offers information highlighting circumstances in which immunoprophylaxis guidelines have failed to impart protection against Rh(D) sensitization and the consequences of such failures.     

Serial fetal blood sampling for the management of pregnancies complicated by severe rhesus (D) isoimmunization

Summary. Fifty-one pregnancies complicated by rhesus (D) isoimmunization have been managed by serial fetal blood sampling between 17 and 36 weeks gestation as an alternative to amniocentesis for ΔOD⁴⁵³ measurements. In 36 pregnancies where the fetus was shown to be rhesus (D) positive and both measurements were made before any intrauterine fetal transfusions, the ΔOD⁴⁵³ value gave misleading predictions on 13 of 63 occasions (21%). Fetal haematocrit estimations provided a direct assessment of the haemopoietic compensation occurring, but fetal bilirubin and albumin concentrations did not correlate directly with disease severity. It is proposed that pregnancies complicated by severe isoimmunization can be more precisely managed by serial fetal blood sampling for haematocrit estimation than amniocentesis for ΔOD⁴⁵³ measurement thus avoiding unnecessary intervention or delayed treatment.     

Erythroblastosis and reticulocytosis in anemic fetuses

The fetal blood erythroblast and reticulocyte counts were determined in umbilical cord samples obtained at 17 to 36 weeks' gestation from 127 pregnancies complicated by red blood cell isoimmunization. The reticulocyte count increased linearly with fetal anemia, and the erythroblast count increased exponentially. Significant erythroblastosis was observed only when the hemoglobin concentration deficit was greater than 7 gm/dl. Of the 52 fetuses with a hemoglobin concentration deficit greater than 7 gm/dl, 35 had ultrasonographic evidence of hydrops. These data suggest that medullary hematopoiesis is stimulated by mild anemia and that recruitment of extramedullary sites occurs when anemia is severe. Extensive hepatic erythropoiesis may be the cause of fetal hydrops in red blood cell isoimmunization.     

Rh0(D) and Du cord blood typing during elective abortion operations

During dilatation and suction or evacuation abortion operations, the umbilical cord can be delivered and sufficient fetal blood can be sampled to type for the Rho(D) and Du factors in about 30% of cases at 14 menstrual weeks of pregnancy. By 16 weeks, more than 75% can be sampled successfully. When cord blood can be Rh typed, about 40% of the fetuses of Rh negative women were found also to be Rh negative. In these cases, anti-Rho(D) immunoglobulin prophylaxis is unnecessary.     

Hematological values in fetal blood by cordocentesis]

Reference ranges for four hematological parameters--hemoglobin, hematocrit, white blood cell and platelet count--in each gestation were established from values for fetal blood samples obtained by cordocentesis from 72 pregnancies at 16-39 weeks gestation. These 72 fetuses turned out as normal or single malformations which should not affect fetal hematological values. Significant correlations were observed between hemoglobin, hematocrit and platelet counts and the number of weeks of gestation. No correlation was found between the white blood cell count and gestational age. Fetal anemia (hematocrit was below the lower limit of the 95% confidence interval) was found in 18 (7%) of all the fetuses that underwent cordocentesis, including nonimmune hydrops fetalis (8 cases), Rh isoimmunization (4 cases), twin-to-twin transfusion syndrome (3 cases), trisomy 18 (2 cases) and autoimmune thrombocytopenia (1 case). Of 26 hydropic fetuses, 8 (31%) were anemic. The prognosis of those fetuses depended on either the gestational age or the severity of the fetal anemia. Our results are useful in diagnosing fetal hematological disorders and to make decisions for fetal therapy.