Intravascular Transfusion Research Articles

Severe Rh(D) immunization: anti‐D quantitation and treatment possibilities during pregnancy and after birth

An extremely aggressive Rh(D), (C) and Kell alloimmunization during pregnancy is reported. Exceptionally high concentrations of anti-D were observed in the mother, in the fetus and in the amniotic fluid, indicating an active transport across the placenta and a passive excretion into the amniotic fluid. Treatment during pregnancy included maternal plasmapheresis and high-dose intravenous immunoglobulin. Intravascular transfusions were given to the fetus. Postpartum the newborn was given immunoglobulin, one exchange transfusion and four top-up transfusions. In the newborn the elimination rate of anti-D could be followed. Not until almost 4 months postpartum did the anti-D concentration drop below the level of detection. This coincided with an elevated reticulocyte production and appearance of the child's true blood group in parallel with ceasing need for blood transfusions. Elimination rate and absolute anti-D values can be used as a prognostic tool to predict the need of blood transfusions. Immunoglobulin treatment can also be considered as an optional form of treatment in newborns affected by alloimmunization.

Noninvasive assessment of fetal anaemia

In pregnancies complicated by severe red cell alloimmunization, fetal haemolytic anaemia can lead to intrauterine demise as early as 17 weeks' gestation. Intrauterine intraperitoneal blood transfusion, introduced by Liley in 1963, proved to be the first successful example of fetal therapy. The use of this complex procedure, involving X-ray guided puncture of the fetal peritoneal cavity, was limited to fetuses with a gestational age ranging from 24 to 33 weeks. When performed below 26 weeks, survival rates were as low as 16%. The need for intrauterine transfusion was mainly based on determination of bilirubin levels in amniotic fluid, and plotting the results in a three-zone chart devised by Liley. This chart was based on correlations of amniotic fluid bilirubin concentrations with the degree of neonatal anaemia, and ranged from 27 to 41 weeks' gestation. In the 1980s, with the introduction of ultrasound-guided intravascular transfusion, treatment became possible from 17–18 weeks' gestation onwards. Consequently, there was a need for diagnostic tests to assess the degree of anaemia in the second trimester fetus. The use of the Liley chart was shown to be unreliable in the prediction of disease severity before 27 weeks' gestation. Ultrasonographic detection of fetal hydrops in these pregnancies reliably indicates severe anaemia, but for reasons that are still unclear, a significant number of severely anaemic fetuses do not show ultrasonographic signs of hydrops. In 1988, Nicolaides et al studied the use of several ultrasonographic parameters to predict anaemia in nonhydropic fetuses. Their results were disappointing, and they concluded that the only reliable diagnostic test to assess the degree of fetal disease was fetal blood sampling.

Monitoring umbilical cord puncture and intravascular transfusions with Doppler ultrasound

Complications of percutaneous umbilical blood samplings and intravascular transfusions can be detected rapidly, easily and efficiently by Doppler ultrasound and therefore the operator can react as early as possible. In addition to real-time sonography Doppler ultrasound allows for assessment of haemodynamical changes due to intravascular transfusions both on the venous and arterial side of umbilical perfusion. Because of immediate recognition of bradycardia and other fetal cardiac frequency alterations as well as increase of resistance to blood flow on the arterial side the operator can react promptly. On the venous side correct application of transfused volume is monitored continuously by changes of flow velocity waveforms during injection and allows to assess dislocation of the needle.

Placental transfer of sulindac and its active sulfide metabolite in humans

OJECTIVE: Our aim was to investigate whether the human placenta is permeableto sulindc or its active sulfide metabolite. STUDY DESIGN: Nine pregnant patients (median gestational age [range]: 31.8 [24.3 to 36.4] weeks) were given a 200 mg oral dose of sulindac 5.5 (4.4. to 6.7) hours before 18 intravascular transfusions for rhesus or Kell alloimmunization. At each procedure maternal and fetal serum levels of sulindac and the active sulfide metabolite were measured by high-performance liquid chromatography. RESULTS: The maternal sulfide level was significantly higher than the fetal sulfide levels, but no significant difference was noted between maternal and fetal sulindac levels. The sulfide fetal/maternal ratio was significantly lower than the sulindac fetal/maternal ratio. The sulfide/sulindac ratio was significantly higher in maternal serum versus fetal serum. The sulfide/sulindac ratio correlated with time from drug ingestion to sampling on the maternal side only. In patients studied on more than one occasion no consistent relationship between fetal sulindac, fetal sulfide, or fetal sulfide/sulindac ratio, and gestational age could be demonstrated. CONCLUSION: The placenta is permeable to sulindac but less so to its active surface metabolite. The reduction of sulindac to its active sulfide metabolite is decreased in the human fetus.

Fetal blood sampling and fetal thrombocytopenia.

The purpose of this investigation is to determine whether fetal thrombocytopenia is a risk factor for puncture site bleeding. Three groups of fetuses either with or at known risk for thrombocytopenia were identified from a prospectively maintained data base of 1,100 procedures: alloimmune thrombocytopenia (ATP, 29 cordocenteses); unexpected thrombocytopenia (53 cordoncenteses), and intravascular transfusion for fetal hemolytic anemia (194 transfusions). A fourth group (58 cordocenteses) included as a normal control consisted of all appropriately grown fetuses tested within the same gestational age range as those with ATP. In total, 276 fetal blood sampling procedures were included, of which 134 (49%) yielded a platelet count of < 120 x 10(3)/microliters and 38 (14%) a platelet count of < 50 x 10(3)/microliters. The first platelet count obtained from fetuses with ATP ranged from 1 x 10(3) to 159 x 10(3)/microliters. There was no correlation between the platelet count and bleeding time whether the analysis was limited to only pretreatment procedures or included all. Each fetus with unexpected thrombocytopenia was systemically ill. There was no correlation between platelet count and the duration of bleeding from the cord puncture site. Intravascular transfusion produced a significant decline in the platelet count (238 +/- 66 x 10(3) vs. 153 +/- 56 x 10(3)/microliters, p < 0.001). Twenty-nine percent of the post-transfusion platelet counts were below 120 x 10(3)/microliters. There was a significant negative correlation between the final platelet count and the duration of puncture site bleeding (r = -0.178, p = 0.03) independent of either the presence of hydrops, the initial or the increase in the umbilical venous pressure during transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal Hepatitis and Excessive Hepatic Iron Deposition Following Intrauterine Blood Transfusion

The management of hemolytic disease has undergone a number of significant changes over the past few decades. Intrauterine transfusion therapy, particularly intravascular transfusions, have significantly reduced the morbidity and mortality associated with isoimmunization. This therapy results not only in the transfusion of blood, but also in the transfusion of iron. The long-term consequences of iron loading in the fetus are unknown. We report a case of a newborn with Rh hemolytic disease who was treated with in utero transfusions and subsequently developed liver disease consistent with iron overload.

Needle modifications for invasive fetal procedures

To investigate the effect of needle size and siliconization on fetal blood sampling, transfusion, and electrocardiography. Standard needles were modified by increasing the internal (but not the external) diameter and either siliconization of the bore or external Teflon coating. The siliconized needles were subjected to a series of flow experiments with either blood or saline at various driving pressures, and assessed in clinical use during fetal transfusion and fetal blood sampling. The Teflon-coated needles were used for fetal transfusion to try and facilitate the fetal electrocardiogram (ECG). Under conditions simulating fetal transfusion, the siliconized needle allowed a 93% increase in flow rate compared to the standard needle (P < .05). Samples obtained after fetal transfusion with the siliconized needles were free of clots, whereas 50% of the post-transfusion samples with the standard needle had clots present. Similarly, samples taken for fetal platelet count were free of platelet clumping and clots with siliconized needles, but not with standard needles. Fetal ECG recordings were recorded successfully when Teflon-coated needles were used to access the fetal circulation via the intrahepatic vein. Modifications to standard needles improved blood flow and reduced the activation of coagulation during both fetal intravascular transfusion and platelet count measurement. Direct fetal ECG recording was facilitated by Teflon coating the external surface of the needle, insulating the fetal signal from maternal electrical signals.

Diagnosis and treatment of fetal anemia due to isoimmunization.

45 pregnant women affected by rhesus incompatibility were treated at the Department of Prenatal Diagnosis and Therapy, Vienna, between January 1992 and March 1993. 32 patients had a cordocentesis and on 21 fetuses, anemia requiring treatment was diagnosed. A total of 71 intravascular transfusions via the umbilical vein was given. The mean number of transfusions per fetus was 3.4 (range 1-11). Of the 7 fetuses who had already developed hydrops when therapy was started (hematocrit < 13%), 5 (71%) survived. The survival rate of non-hydropic anemic fetuses was 93% (13/14). By using intravascular transfusion for treatment of severe fetal anemia, a success rate of 86% (18/21) was achieved.

The Effect of Neuromuscular Blockade on Human Fetal Heart Rate and Its Variation

Objective To determine the effect of neuromuscular blockade on fetal heart rate and its variation. Design Case control study. Setting Tertiary referral fetal medicine unit in a London teaching hospital. Subject Forty women with rhesus iso-immunisation requiring an intravascular fetal blood transfusion between 28 and 34 weeks gestation. Intervention Intravascular injection of pancuronium to the fetus prior to fetal blood transfusion in 20 cases. Main outcome measures Comparison between the group receiving pancuronium and the control group with regard to differences in perceived fetal activity and computer derived numerical indices of fetal heart rate and fetal heart rate variation after fetal blood transfusion. Results After transfusion in the control group, there were fewer perceived fetal movements, a small reduction in fetal heart rate but no differences in number of fetal heart rate accelerations or measures of fetal heart rate variation. In the study group, pancuronium produced no change in fetal heart rate despite a virtual abolition of perceived fetal movements and fetal heart rate accelerations. Measures of fetal heart rate variation were reduced by 60%. Comparison of the pre- to post-transfusion changes between the two groups showed significant differences for all fetal heart rate indices. Conclusion Fetal activity accounts for more than half the measured variation of the human fetal heart rate.

Fetal liver hemangioma and chorioangioma: two unusual cases of severe fetal anemia detected by ultrasonography and its perinatal management.

Severe anemia was diagnosed by cordocentesis in two fetuses, one with a large chorioangioma, the other with a liver hemangioma. Despite the presence of a chronic fetotumoral shunt, both cases were partly treated by a fetal intravascular transfusion, followed by an elective Cesarean section. This 'predelivery' management of anemia should improve neonatal morbidity associated with severe hematological and acid-base balance disorders.

Ultrasound-guided fetal intravascular transfusions for severe erythroblastosis, 1984-1993.

The results of the first 10 years' experience in ultrasound-guided fetal intravascular transfusions at the Royal Women's Hospital were reviewed. Since the first transfusion, a variety of techniques have been employed in 78 fetuses, all with severe erythroblastosis. A total of 288 intrauterine transfusions have been attempted with an overall survival rate of 75.6% (59 of 78). The overall survival rate for delivered fetuses improved from 64.3% (18 of 28) in 1984-1987, to 82.0% (41 of 50) in 1988-1993. There was a total of 33 hydropic fetuses, of whom 20 (60.6%) survived, significantly fewer compared with 86.7% (39 of 45) of the nonhydropic fetuses (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.09 to 0.70, p < .01). Fetuses who were sicker at the time of transfusion, as reflected by larger haemoglobin deficits, had lower survival rates, as did those requiring transfusions at earlier gestational ages. When these variables were allowed for, the survival rate significantly improved over time (OR 6.3, 95% CI 1.3 to 30.4, p < 0.05), probably reflecting the increased skill of the ultrasonologists, but the presence of hydrops per se was no longer important. Variations of the technique employed, such as exchange or intraperitoneal transfusion, or different sites for transfusion, were not significantly related to survival.

Evaluation of standard parameters to predict exchange transfusions in the erythroblastotic newborn.

During the time period 1983-90, 91,300 consecutive pregnancies were monitored for red cell alloimmunization. Once revealed, the immunizations were followed by means of repeated maternal antibody titers, maternal anti-D quantitation in D-immunized women, amniotic fluid bilirubin levels and fetal hemoglobin concentrations. High dose intravenous immunoglobulin and/or intrauterine intravascular transfusion was given to prevent or treat fetal anemia. Delivery was induced for all before term when antibody titers were > or = 16. Nevertheless, exchange transfusions were performed in 41 newborns with mothers alloimmunized to Rh(D), Rh(c), Rh(E) and Kell antigens. Eight of the mothers were Rh(D) positive. Phototherapy alone was given to 35 newborns. Both maternal antibody titers and amniotic fluid bilirubin levels were found to be unreliable to predict the need of exchange transfusions in the newborns. Quantitation of maternal anti-D concentration was found to be significantly better predicting 62% at a cut-off level of 0.7 microgram/mL. Analysis of fetal hemoglobin concentration by cordocentesis is the only direct method to evaluate the degree of fetal affection, and should probably be performed when maternal antibody titers are > or = 64, anti-D concentration is > or = 0.7 microgram/mL and data indicate an aggravation of the immunization.

Changes in hemorheology with fetal intravascular transfusion

OBJECTIVE: Our aim was to determine the changes in fetal hemorheologic parameters caused by fetal intravascular transfusion for alloimmune anemia. STUDY DESIGN: Fetal blood samples were collected before and after 95 fetal transfusions in 31 women. Fetal hematocrit, whole-blood viscosity at a variety of shear rates, plasma viscosity, fetal fibrinogen, and fetal plasma proteins were measured. RESULTS: Fetal whole-blood viscosity increased, sometimes massively, with transfusion. The rise in viscosity was principally dependent on the rise in hematocrit, with a linear rise in hematocrit producing a linear rise in the logarithm of whole-blood viscosity, but was also affected by the amount of adult plasma proteins present in the donor blood. CONCLUSIONS: Rises in fetal whole-blood viscosity during transfusion can be minimized by using donor blood that has been serum depleted to a high hematocrit (>90%) and by restricting the end hematocrit to 50% to 55%. (AM J OBSTET GYNECOL 1994;170:726-32.)

Acute intravascular haemolysis following exchange transfusion with G-6-PD deficient blood

Acute intravascular haemolysis following exchange transfusion with G-6-PD deficient blood

No Beneficial Effect of Low-Dose Fetal Intravenous Gammaglobulin Administration in Combination with Intravascular Transfusions in Severe Rh D Haemolytic Disease

Recent observations have shown that treatment with high-dose intravenous gammaglobulin (IVIgG) given to the mother may improve fetal outcome in cases of severe Rh D alloimmunization. Unfortunately, the costs of this new method of treatment are too high for routine use. Therefore, we decided to apply this treatment to the fetus and to investigate whether the effect of IVIgG might be attributable to blockade of the fetal mononuclear phagocyte system. We have performed a randomized study in which 20 fetuses with severe Rh D-haemolytic disease (HDN) were treated with intrauterine intravascular red cell transfusions (IUT). In 10 of these 20 cases transfusions were followed by administration to the fetus of low-dose IVIgG (85.7 ± 11.6 mg/kg by ultra- sound-estimated fetal weight because of fetal vascular volume considerations). We compared the number of IUTs, postnatal exchange transfusions, haematocrit (Ht) and haemoglobulin (Hb) values before and after transfusion (s) needed by the newborns of the two groups. No significant differences in the transfusion requirements of the fetuses and in the clinical outcome could be demonstrated. However, the 95% confidence interval for the difference in the improvement of cord blood Ht was too wide for any conclusions. The 95% confidence interval for the difference in the improvement of Hb levels suggests that any clinically relevant advantage of IVIgG on Hb is unlikely.

Basal ganglia and thalamic calcification following intrauterine intravascular transfusion.

In recent years intrauterine intravascular transfusion has become the method of choice for the treatment of severe fetal erythroblastosis. Despite the association of the procedure with fetal complications such as bradycardia and overtransfusion, later neonatal neurological consequences have been only rarely reported. A case is described of a neonate who underwent repeated intrauterine intravascular transfusion for treatment of erythroblastosis and who later developed calcification in the thalamus and the basal ganglia. The possible pathogenetic mechanisms are discussed.

49 Fetal Venous Flow Velocities Before and After Intravascular Transfusion for Red Cell Allovviniunization

49 Fetal Venous Flow Velocities Before and After Intravascular Transfusion for Red Cell Allovviniunization

Intrauterine intravascular transfusions in fetal erythroblastosis: the influence of net transfusion volume on fetal survival.

The intravascular volume load that an anemic fetus can tolerate was studied retrospectively in 124 consecutive intravascular transfusions in 35 erythroblastic fetuses. The tolerated volume load correlated well to the estimated fetal weight. Transfusion volume loads above 20 ml/kg of the estimated fetal weight resulted in a lower fetal survival. We recommend an upper transfusion limit at 20 ml/kg corresponding to approximately 20% of the feto-placental blood volume.

Intrauterine intravascular transfusion for fetal haemolytic anaemia: the Western Australian experience.

To report the first four years' clinical experience with fetal intravascular blood transfusion for the treatment of fetal haemolytic anaemia in Western Australia. King Edward Memorial Hospital, Perth, which is the sole tertiary level perinatal centre in Western Australia with a referral base of approximately 25,000 pregnancies each year. Transfusion was by injection of packed cells from Rh-negative donors into the fetal umbilical vein near the site of insertion into the placenta. Fetal haemoglobin levels were measured before and after each transfusion. In most cases, the fetus was paralysed by intramuscular tubocurarine. Sixty intravenous transfusions were performed in 20 pregnancies. At the time of the initial transfusion, the mean haemoglobin level was 5.8 g/dL (range, 2.5-8.5 g/dL) and six fetuses had signs of hydrops. The case survival rate was 80% and the procedure survival rate was 93%. Three of the deaths occurred in the first five cases. Caesarean section was performed during two of the procedures, one because of bleeding from the cord puncture site and one because of tamponade of the umbilical vessels. Fetal intravascular transfusion is a highly effective treatment for fetal alloimmunisation and allows pregnancies to continue to term and to be delivered vaginally. However, the procedure may be difficult and requires a team approach with ready access to fetal monitoring and emergency caesarean section. Our results suggest that increasing experience of the team is a major factor in improved outcome.

FETAL HAEMOPOIETIC RESPONSES TO INTRAVASCULAR TRANSFUSION

Intravascular transfusion therapy (IVT) is the accepted treatment for severe rhesus iso-immunisation. The timing and frequency of IVT is controversial, and is currently based on change in fetal haematocrit (Hct). The aims of this study were to measure fetal erythropoietin concentration (EPO), haematocrit and red cell volume following serial (IVT) and to study their inter-relationship as anaemia is corrected.Methods & Results: Twelve pregnancies were studied with serial data in 4 cases. Pre-transfusion fetal EPO correlated inversely with Hct (R2 31%; p = .004) and fell significantly between IVT 1 and IVT 2 (314 to 31 mU/ml:mean values). Hct fell between IVT1 and IVT 2 (35 to 25% : mean values n=4). Neither fetal, or donor red cell volumes fell during this time, though circulating fetoplacental blood volume increased (179 to 357 mis; mean values n=4).Conclusions: Fetal EPO is inversely related to Hct, and is suppressed by IVT through increases in total red cell volume. The fall in Hct between IVT 1 and IVT 2 is due to the physiological increase in fetoplacental blood volume rather than destruction of transfused red cells.