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The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions.

Twenty-five severely rhesus-isoimmunized fetuses, including 15 with hydrops fetalis, underwent a total of 77 intrauterine transfusions between 19 and 32 weeks' gestation. Fifty-eight of the procedures were fetoscopically directed intravascular transfusions, nine were ultrasound-guided intraperitoneal transfusions, and 10 were a combination of intravascular transfusion, fetal paracentesis, and intraperitoneal transfusion. The average number of antenatal procedures per patient was three (range, one to five). The survival rate for the 19 fetuses that received their initial intrauterine transfusion at or before 25 weeks' gestation was 84%; 11 of the 13 hydropic fetuses and five of the six fetuses without antenatal evidence of hydrops survived. In six cases hydrops fetalis was reversed in utero. The outcome in patients referred after 25 weeks' gestation was poor; neither of the two hydropic fetuses and only two of the four nonhydropic ones survived, which suggests the importance of early referral to a team experienced in the management of this problem. However, most of these fetal losses occurred early in the series. Seven of the 20 neonates were hydropic, and nine had severe thrombocytopenia (platelet count, less than 50,000 X 10(6)/L). The mean cord blood hematocrit and bilirubin of the neonates were 25.1% and 82 mumol/L, respectively. The babies required a total of 69 exchange transfusions (range, 0 to 9) and 68 simple transfusions (range, 0 to 25). One newborn infant who had had ultrasound evidence of hydrops fetalis at 22 weeks' gestation did not require any exchange transfusions. Nine patients required intermittent positive pressure ventilation (eight had respiratory distress syndrome and one had apnea) for a range of 1 to 86 days. The neonatal survival rate was 90% (18/20).

Blood Transfusion, Intrauterine↗

Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy.

OBJECTIVE: Intravenous immune globulin (IVIG) reduces jaundice in many but not all cases of neonatal isoimmunization. We sought to elucidate the type of infant most likely to benefit from IVIG administration by attempting to define pretreatment parameters associated with both clinical symptomatology and therapeutic responsiveness to IVIG. METHODS: Term, healthy Coombs-positive infants were studied prospectively. IVIG was administered if, despite phototherapy, serum bilirubin reached > or = 222 mumol/l (13 mg/dl) at < or = 24 h of age and/or > or = 274 mumol/l (16 mg/dl) at > 24 h of age. Clinical data including serial serum total bilirubin levels, rate of bilirubin rise on day 1 of life, serial corrected carboxyhemoglobin levels (a sensitive indicator of hemolysis) and total hemoglobin (tHb) levels were collected. RESULTS: Infants were classified as IVIG responders (n = 18), those in whom total serum bilirubin levels either remained stable or decreased following IVIG administration; IVIG nonresponders (n = 5), those who developed a total serum bilirubin of > or = 2 mg/dl greater than pre-IVIG bilirubin levels within the first 24 h after IVIG administration, or nontreated, those not meeting IVIG treatment criteria (n = 13). Four of the five nonresponders proceeded to require exchange transfusion vs. none of the others (p < 0.001). Four of the five nonresponders had a pretreatment rate of bilirubin rise of > or = 1 mg/dl/h as compared with only 1 of 18 responders and none of the nontreated (p < 0.001). Pretreatment tHb levels were also different (13.2 +/- 1.3 vs. 15.5 +/- 2.3 vs. 17.7 +/- 2.4 g/dl for nonresponders vs. responders vs. nontreated infants, respectively; p < 0.005). The highest pretreatment COHbc levels were seen in the nonresponders (1.8 +/- 0.7 vs. 1.4 +/- 0.3 vs. 0.9 +/- 0.3% tHb, respectively). CONCLUSIONS: Our 3 groups represent a spectrum of hemolysis, ranging from severe to moderate to mild. This spectrum appears to relate not only to the severity of hemolysis, but also to the therapeutic responsiveness to IVIG. We speculate that some or all of the factors identified can be used prospectively to predict the subsequent clinical course of ABO-incompatible infants and to facilitate optimal management.

ABO Blood-Group System↗

Successful prevention of post-transfusion Rh alloimmunization by intravenous Rho (D) immune globulin (WinRho SD).

Alloimmunization to the D blood group antigen following the transfusion of D-positive red blood cells to a D-negative recipient may be prevented in most persons by a prompt and adequate dose of Rho (D) immune globulin (RhIG). Until recently, the only RhIG approved by the US Food and Drug Administration (FDA) for this indication required intramuscular injection, an inconvenient and painful route for the relatively large volume that may be required. We describe the successful prevention of Rh alloimmunization following the unintentional transfusion of D-positive red blood cells to a D-negative infant by the intravenous infusion of WinRho SD, a new RhIG that is FDA-approved for prevention of post-transfusion Rh alloimmunization by intravenous administration. We believe that this more convenient and less painful approach should be the treatment of choice for preventing Rh alloimmunization following the transfusion of D-positive red cells to a D-negative recipient.

Anemia, Sickle Cell↗

Increase of fetal hematocrit decreases the middle cerebral artery peak systolic velocity in pregnancies complicated by rhesus alloimmunization.

Our hypothesis for this study was that an increase in fetal hematocrit would decrease the middle cerebral artery peak systolic velocity. Seventeen pregnancies complicated by Rh alloimmunization were included in this study. Middle cerebral artery peak systolic velocity was studied by Doppler ultrasound before and after intrauterine transfusion with adult packed red blood cells (hematocrit = 80-85%). Mean gestational age at time of study was 27 weeks. Paired t-test was used for statistical comparison. A P value of < 0.05 was considered statistically significant. The fetal hematocrit ranged from 5.9% to 30% prior to the procedure, and it was 24.8-53.4%, following the procedure. Mean middle cerebral artery peak systolic velocity was 46.2 +/- 10.7 cm/s prior to the procedure, and it decreased to 31.7 +/- 9.5 cm/s following the procedure (P < 0.01). The increase of fetal hematocrit significantly decreases the middle cerebral artery peak systolic velocity supporting data that this Doppler measurement may be useful for the diagnosis of fetal anemia.

Anemia↗

Use of recombinant human erythropoietin (EPO-alfa) in a mother alloimmunized to the Js(b) antigen.

Erythropoietin (EPO) is a glycoprotein hormone and the principal regulator of erythropoiesis in the fetus, newborn, and adult. EPO-alfa is erythropoietin manufactured by recombinant human DNA technology (rhEPO). After counseling, a pregnant woman with anti-Js(b) in her serum was started on rhEPO (600 U/Kg, biweekly) to prevent anemia secondary to serial donations of her blood for fetal transfusions. After a total of 25 rhEPO infusions and autologous donation of 8 units of whole blood, maternal hemoglobin prior to the elective cesarean section at 37 weeks was 11.3 gm/dL. Serum EPO concentration was determined in paired maternal and fetal blood samples, before ultrasound guided intravascular transfusions, in this alloimmunized Js(b)-negative and another Rh(D) alloimmunized pregnancy to determine possible correlations between maternal and fetal serum EPO. rhEPO prevented anemia in a patient who donated 8 units of blood from 18-37 weeks of pregnancy without inducing adverse biological effects such as hypertension or thrombotic complications in the placenta. Data presented in this study suggest that EPO does not cross the human placenta.

Adult↗

Survival analysis of transfused fetuses affected by Rh-alloimmunization.

The aim of the present study was to evaluate the survival rate of a group of 86 fetuses affected by Rh-alloimmunization submitted to intrauterine red blood cell transfusion. All the women had antibody titres> or = 1:32 at the time of their enrollment in the study. Crude fetal survival rate was 89.5% (77/86 cases). Data were stratified according to specific cut-off points of (1) pre-transfusion fetal haemoglobin expressed as the rate between the observed and the estimated value for each gestational age at the time of the first transfusion; (2) the difference between the haemoglobin at the beginning of the second-transfusion less that at the end of the first transfusion (delta haemoglobin); and (3) presence of ultrasound detected anomalies. Statistically significant stratification of the survival rate was observed for the level of pre-transfusion fetal haemoglobin (95% and 76.9%, respectively, p= 0.009) using a cut-off value of < 70% and > or = 70% of the expected value. Again, delta haemoglobin showed a different survival rate when a cut-off value of 6 g/dl was used to generate subgroups of fetuses: 94.6% and 80%, respectively (p= 0.0145). Among the ultrasound anomalies, the presence of hydrops showed a correlation with the survival rates. The quoted values were 97.83% (absence) and 80.0% (presence) respectively (p= 0.0058). Cox regression showed a significant association of the studied variables with the outcome (survival). The presence of hydrops was the best predictor (Odds ratio= 8.7, p= 0.0073) followed by Delta haemoglobin (Odds ratio= 2.0, p= 0.0422). The rate of pre-treatment fetal haemoglobin < 70% of the expected value did not add any significant valu and was thus removed from the final model. Weight at delivery expressed in grams showed a direct correlation with the survival rate (Odds ratio= 0.9, p= 0.1529) and was added into the model as an adjustment quantitative variable.

Adult↗

Anti-D administration in pregnancy for preventing rhesus alloimmunisation.

BACKGROUND: A woman may develop Rh-negative antibodies during her first pregnancy when her fetus is Rh-positive. Antibodies develop most frequently after the 28th week of gestation. OBJECTIVES: The objective of this review was to asses the effects of giving antenatal anti-D immunoglobulin at 28 weeks or more of pregnancy on the incidence of RhD alloimmunisation when given to Rhesus negative mothers without anti-D antibodies. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, Cochrane Controlled Trials Register, and bibliographies. Date of last search: December 1998. SELECTION CRITERIA: Randomised trials in Rhesus negative women without anti-D antibodies given anti-D after 28 weeks of pregnancy, compared with no treatment or placebo. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and double entered. MAIN RESULTS: Two eligible trials, which involved over 4500 women, compared anti-D prophylaxis with no treatment. Although the data suggested, when women receive anti-D at 28 and 34 weeks gestation, a reduced incidence of immunisation during pregnancy (0R O.44, 95% CI 0.18-1.12), after the birth of a Rhesus positive infant (OR 0.44, 95% CI 0.18-1.12), and within 12 months after birth of a Rhesus positive infant (OR 0.44, 95% CI 0.19-1.01), none of these differences were statistically significant. In the trial, which used the larger dose of anti-D (100ug; 500IU), there was a clear reduction in the incidence of immunisation at 2-12 months following birth in women who had received Anti-D at 28 and 34 weeks (OR 0.22 95% CI 0.05-0.88). No data were available for the risk of RhD alloimmunisation in a subsequent pregnancy. No differences were observed in the incidence of neonatal jaundice. REVIEWER'S CONCLUSIONS: The risk of RhD alloimmunisation during or immediately after a first pregnancy is about 1.5%. Administration of 100ug (500IU) anti-D at 28 weeks and 34 weeks gestation to women in their first pregnancy can reduce this risk to about 0.2% without, to date, any adverse effects. Although such a policy is unlikely to confer benefit or improve outcome in the present pregnancy, fewer women will have Rhesus D antibodies in their next pregnancy. Adoption of such a policy will need to consider the costs of prophylaxis against the costs of care for women who become sensitised and their affected infants, and local adequacy of supply of anti-D gammaglobulin.

Female↗

Anti-D administration after childbirth for preventing Rhesus alloimmunisation.

BACKGROUND: The development of Rh immunisation and its prophylactic use since the 1970s has meant that severe Rhesus D (RhD) alloimmunisation is now rarely seen. OBJECTIVES: The objective of this systematic review was to assess the effects of giving anti-D to Rhesus negative women, with no anti-D antibodies, who had given birth to a Rhesus positive infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register, MEDLINE (from 1966 to January 1999) and reference lists of relevant articles. Date of last search of Cochrane Controlled Trials Register: January 1999. SELECTION CRITERIA: Randomised trials in Rhesus negative women without antibodies who were given anti-D immunoglobulin postpartum compared with no treatment or placebo. DATA COLLECTION AND ANALYSIS: Assessments of inclusion criteria, trial quality and data extraction were done by each author independently. Initial analyses included all trials. Other analyses assessed the effect of trial quality, ABO compatibility and dose. MAIN RESULTS: Six eligible trials compared postpartum anti-D prophylaxis with no treatment or placebo. The trials involved over 10,000 women, but trial quality varied. Anti-D lowered the incidence of RhD alloimmunisation six months after birth (relative risk 0.04, 95% confidence interval 0.02 to 0.06), and in a subsequent pregnancy (relative risk 0.12, 95% confidence interval 0. 07 to 0.23). These benefits were seen regardless of the ABO status of the mother and baby and when anti-D was given within 72 hours of birth. Higher doses (up to 200 micro grams) were more effective than lower doses (up to 50 micro grams) in preventing RhD alloimmunisation in a subsequent pregnancy. REVIEWER'S CONCLUSIONS: Anti-D, given within 72 hours after childbirth, reduces the risk of RhD alloimmunisation in Rhesus negative women who have given birth to a Rhesus positive infant. However the evidence on the optimal dose is limited.

Female↗

Comparison of transabdominal and transcervical CVS and amniocentesis: sampling success and risk.

A total of 2931 women randomized to either transabdominal CVS, transcervical CVS, or amniocentesis were studied. Unless intended or unintended abortion had occurred, they had completed up to 28 weeks of pregnancy. No significant difference was seen between total fetal loss in the transabdominal CVS group and the amniocentesis group (6.5 and 6.8 per cent, respectively, SE difference = 0.92 per cent, p = 0.01). The total fetal loss in the transcervical CVS group was 10.1 per cent. After pooling our data with data from the Canadian randomized study and the American non-randomized study, the difference in risk between transcervical CVS and amniocentesis was 1.8 per cent (SE difference = 0.64 per cent, p = 0.8). When the number of failed procedures and those cases evaluated as unfeasible for the assigned method--for anatomical reasons--are compared, the overall sampling efficacy is poorer transcervically than transabdominally.

Adolescent↗

Fetal, neonatal cord, and maternal plasma concentrations of angiotensin-converting enzyme (ACE).

OBJECTIVES: Angiotensin converting enzyme (ACE), a component of the renin-angiotensin system (RAS), catalyses the degradation of angiotensin I to angiotensin II. It was the aim of the present study to measure ACE activity in human fetal blood and to determine its changes with advancing gestational age. METHODS: Fetal blood was sampled by cordocentesis from six control fetuses and six fetuses with Rh isoimmunisation. Cord blood was sampled from six preterm neonates, 15 neonates after spontaneous delivery at term and six neonates at term after caesarean section. In addition, maternal ACE values were determined. ACE activity was measured using the miniaturised fluorimetric method. RESULTS: In normal fetuses (13.31+/-1.41 nmol HL/min/ml) and fetuses with Rh isoimmunisation (13.08+/-2.00 nmol HL/min/ml, p<0.05). Neonatal cord blood of preterm newborns (10.43+/-0.69 nmol HL/min/ml) and term newborns (8.99+/-0.49 nmol HL/min/ml) showed a significantly decreased ACE activity compared to the fetal controls. CONCLUSION: We conclude that the high fetal ACE activity and the stringent regulation with advancing gestational age indicate the physiological importance of the enzyme during prenatal development.

Female↗

Single umbilical artery stenosis associated with intrauterine fetal death post-transfusion.

Single umbilical artery is among the most common funicular vascular anomalies. In contrast, umbilical artery stenosis is rare, and has only been reported in three-vessel cords. We describe a case of single umbilical artery stenosis in a fetus with no associated malformations. Intrauterine fetal death occurred at 28 weeks' gestation following cordocentesis and intravascular transfusion for Rhesus alloimmunization. Single umbilical artery stenosis may place the fetus at increased risk, particularly in cases requiring interventions involving cord manipulation.

Adult↗

Fetal serum alpha-fetoprotein in alloimmunised pregnancies.

OBJECTIVES: Maternal serum alpha-fetoprotein (AFP) levels have been known to be increased in red blood cell alloimmunisation. Since AFP is now thought be a pro-erythropoietic factor, we wished to evaluate fetal serum levels of AFP in cases of alloimmunised pregnancies. METHODS: We studied AFP levels in 32 fetal serum samples from women with red blood cell alloimmunisation at the time of the first fetal blood sampling. We expressed the levels of AFP and haemoglobin as absolute numbers and as delta values (number of SDs by which the observed value differed from the normal mean for the same gestation). Main outcome measures were fetal serum AFP levels and fetal haemoglobin concentration. RESULTS: Overall, fetal AFP level was higher than normal in the cases (delta values 2.4 +/- 5.5 SD). However, mildly affected non-hydropic cases had higher levels than severely affected fetuses with hydrops. CONCLUSIONS: Fetuses affected by red blood cell alloimmunisation have increased levels of serum AFP but these levels fall back to low levels in severe anaemia especially with hydrops, which could represent the failing of a compensatory erythropoietic mechanism. Our results suggest that fetal haematopoiesis is activated early in red blood cell alloimmunisation but was subsequently impaired.

Adult↗

Derivated fetal haemoglobin as a marker for red cell age in the human fetus reflecting stimulated or impaired red blood cell production.

We have determined whether derivated fetal haemoglobin (dHbF, consisting of glycated and acetylated HbF) can be used as a cell age marker for fetal red blood cells (RBCs). Cord blood was obtained between 19 and 39 weeks of gestation from 28 alloimmunised anaemic fetuses (23 RhD+ and 5 Kell) and from 20 non-anaemic fetuses and newborns (controls). Density gradient centrifugation was applied to 36 samples (20 RhD+, 15 controls and 1 Kell) to obtain fractions of increasing cell age. Blood samples were used for measurements of mean cellular volume (MCV), mean cell haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), pyruvate kinase activity (PK) and derivated fetal haemoglobin (dHbF) by cation-exchange HPLC. Reticulocytes were counted only in the whole blood samples. In all density gradient separated RBC fractions, the values for MCV, MCH and PK activity decreased and those of MCHC and dHbF increased with increasing density (equivalent to increasing cell age). The mean density was lower for RBCs of the anaemic RHD group (1.072+/-0.007 g/ml) than for the non-anaemic controls (1.077+/-0.005 g/ml) (p<0.05) The RBC density of the Kell sensitised fetus did not differ from those of the controls. In the control group, the values of the cell age markers in whole blood changed significantly with the gestational age, showing an increase of mean age of the erythrocyte population. The best linear relationship was found for dHbF (y=6.28+0.17*weeks; r=0.84; p<0.001). In the anaemic RhD+ fetuses, the RBC age markers did not change with gestational age; the dHbF percentages were lower, and the MCV, MCH, PK values and the reticulocyte counts were higher than in the controls (0.05<p<0.001). The dHbF values of the Kell sensitised fetuses were above (p<0.01) and the reticulocyte counts were below normal (p<0.05) for gestational age. For the anaemic fetuses, a significant number of the dHbF values (86%) and of the reticulocyte counts (78%) differed from the values of the controls (p<0.01). The dHbF percentages in RhD+ fetuses showed the best correlation with the Hb deficit, which is a measure for anaemia (r=-0.81, p<0.0001). We conclude that the percentage derivated HbF may indicate whether the RBC production is normal for gestational age. It may in that sense reflect stimulated or impaired erythropoiesis in alloimmunised haemolytic anaemia.

Anemia, Hemolytic↗

Comparison of different reference values of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia.

OBJECTIVES: To compare different normal reference ranges of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia. METHODS: Eight reference ranges of either middle cerebral artery peak or time-averaged mean velocities were compared using the area under the receiver-operating characteristics (ROC) curve for 113 fetal blood samples from 60 women at risk of fetal red blood cell alloimmunization. RESULTS: The areas under the ROC curves of the different ranges were not significantly different but there were marked differences in sensitivity (range, 7.14-91.78%) and specificity (range, 31.25-96.88%) with the currently used cut-offs. Except for Mari's range, the best theoretical cut-offs, defined as those having the best sensitivity with the best specificity, differed from those in current use, especially when using time-averaged mean velocity. CONCLUSIONS: Any of the previously reported reference ranges perform well in the non-invasive prediction of fetal anemia. However, with the exception of Mari's curve, the currently employed cut-offs for predicting fetal anemia should be changed, some of them markedly, in order to provide reliable support for clinical decisions.

Blood Flow Velocity↗

The effects of serial intravascular transfusions in ascitic/hydropic RhD-alloimmunized fetuses.

OBJECTIVE: To evaluate the effects of serial intravascular transfusions on RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion by measuring multiple hematological/biochemical blood variables. METHODS: Thirty-one singleton pregnancies were referred for management of RhD alloimmunization. Seven fetuses had hydrops on presentation and were transfused immediately. The remainder underwent weekly ultrasound examinations, and fetal blood sampling and transfusion were performed on development of ascites. In the 104 samples collected overall from the 31 fetuses, glucose, uric acid, urea, creatinine, total protein, total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, lactic dehydrogenase, amylase, pseudocholinesterase (PCHE), creatine kinase, triglycerides and cholesterol were measured and compared with a reference range for non-anemic fetuses. RESULTS: The median gestational age at first transfusion was 26 (range, 18-34) weeks. There were three fetal losses after the first transfusion, two of which were due to procedure-related complications; one further loss occurred. At the first transfusion fetal hematocrit, pO2, total protein, PCHE, creatinine and urea concentrations were significantly decreased compared to reference data, while total and direct bilirubin, AST, ALT, amylase, triglyceride and uric acid concentrations were increased. In all surviving fetuses ascites/hydrops had disappeared by the second transfusion. Fetal pO2, total protein, AST, ALT and PCHE concentrations had normalized by the third transfusion. Correction of fetal anemia did not affect the other variables. CONCLUSIONS: RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion had a survival rate of 87%. Alterations of several biochemical fetal blood indices are present at the first sampling/transfusion, but most variables normalize with intravascular transfusions.

Ascites↗