Antenatal suppression of Rh alloimmunization.

For more than the past decade, attempts have been made to suppress HDN by the administration of drugs or biologic materials to the Rh-immunized pregnant woman. With the possible exceptions of IGIV therapy and plasma exchange substitution of IGIV for maternal IgG, all such attempts have been ineffective. On the other hand, antenatal administration of RhIg (300 micrograms at 28-30 weeks' gestation) to the pregnant, unimmunized Rh-negative woman is very effective in preventing Rh immunization and is now the accepted standard of obstetric care. Physicians who neglect to carry out antenatal prophylaxis neglect to do so at their patient's and their own peril.     

Fetal liver dysfunction in Rh alloimmunization

Summary. The liver enzymes, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first, second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group, GGT increased with advancing gestation (  r = 0.7  ;  P = 0.002  ), whereas ALP, AST and ALT did not correlate with gestational age. Rh hydropic fetuses (  n = 8  ) had higher blood ALT levels than the comparison fetuses (  P = 0.008  ) and significantly increased transaminases when compared with non hydropic fetuses (  n = 17  ). In hydropic fetuses, AST correlated with the nucleated red cell count before transfusion (  r = 0.94  ;  P = <0.0001  ). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses, GGT increased by the second transfusion (median percentage change +85%, range −83% to +596%;  P = 0.003  ). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (  r = 0.58  ;  P = 0.006  ). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.     

Fetal liver dysfunction in Rh alloimmunization.

The liver enzymes, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first, second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group, GGT increased with advancing gestation (r = 0.7; P = 0.002), whereas ALP, AST and ALT did not correlate with gestational age. Rh hydropic fetuses (n = 8) had higher blood ALT levels than the comparison fetuses (P = 0.008) had significantly increased transaminases when compared with non hydropic fetuses (n = 17). In hydropic fetuses, AST correlated with the nucleated red cell count before transfusion (r = 0.94; P = less than 0.0001). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses, GGT increased by the second transfusion (median percentage change +85%, range -83% to +596%; P = 0.003). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (r = 0.58; P = 0.006). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.     

Vasa previa and postpartum hysterectomy in maternal Rh alloimmunization

Velamentous insertion of the cord, or vasa previa, is a malady where fetal vessels tranverse membranes ahead of the fetal part. The incidence of vasa previa is 1: 2000-3000 deliveries. Fetal mortality is over 50-75%. Early diagnosis is needed because these deliveries require emergency cesarean section; it is especially more common with placenta percreta, uterine atony and hemorrhage. Intravascular infusion of red blood cells (RBCs) into the fetus is one of the most successful means of in utero therapy for severe fetal anemia caused by RBC alloimmunization. We performed four fetal intrauterine intravascular transfusions (IVT) as therapy for severe fetal anemia. The patient underwent elective cesarean section. After delivery, profound uterine atony and vaginal hemorrhage were noted and the patient underwent hysterectomy. Pathological examination of the placenta and umbilical cord documented velamentous insertion of the cord. Before intrauterine IVT a detailed US examination is necessary to exclude vasa previa or placenta previa. Uterine atony may be result after a diagnosis of placenta previa or vasa previa. Intrauterine IVT is an irreplaceable diagnostic procedure in the treatment of severe fetal anemia.     

Management and outcome of fetomaternal Rh alloimmunization in twin pregnancies

Between 1987 and 1996, nine twin pregnancies with fetomaternal Rh alloimmunization were delivered at our institution. Eight pregnancies were dizygotic, and the fetal blood groups were different in 3 cases. The remaining pregnancy was monozygotic and monochorionic-diamniotic. Intravenous fetal exchange transfusion was performed in five pregnancies, up to five times in each twin in one pregnancy. No fetal death occurred. The average gestational age at birth was 35 (range 33-37) weeks. The hemoglobin level was 13.2 (range 9.2-16.5) g/dl. Fetomaternal Rh alloimmunization in twin pregnancy is according to zygosity; each fetus has to be treated separately, except in case of transplacental communication.     

Clinical value of an antibody-dependent cell-mediated cytotoxicity assay in the management of Rh D alloimmunization

OBJECTIVE: The aim of this study was to evaluate the clinical value of an antibody-dependent cell-mediated cytotoxicity assay relative to the indirect antiglobulin test titer in the management of Rh D-alloimmunized pregnancies. STUDY DESIGN: Data from 172 Rh D-alloimmunized pregnancies were analyzed retrospectively. The accuracies of the highest antibody titer and of the highest antibody-dependent cell-mediated cytotoxicity assay result during pregnancy to predict fetal and neonatal Rh disease, defined as the need for intrauterine (n = 30) or neonatal (n = 37) blood transfusion, respectively, were assessed. RESULTS: At different cutoff levels with equal sensitivities the antibody-dependent cell-mediated cytotoxicity assay consistently showed a higher specificity than the antibody titer for the prediction of fetal disease. No difference was found between the receiver operating characteristic curves of the 2 tests for the prediction of neonatal disease. CONCLUSIONS: Selection of patients for referral and invasive testing for Rh D alloimmunization may be improved with the use of an antibody-dependent cell-mediated cytotoxicity assay.     

Doppler ultrasonographic evaluation of twins discordant for Rh alloimmunization

Minimally invasive methods have been used successfully to diagnose and treat maternal red blood cell alloimmunization. We present a case of a dizygotic twin pregnancy discordant for the Rh allele. Serial Doppler ultrasonography helped to diagnose the fetus that was at-risk for anemia caused by Rh alloimmunization and to direct treatment.     

Fetoplacental blood volume estimation in pregnancies with Rh alloimmunization

Direct intravascular fetal transfusion under ultrasound guidance has become an important method of treating fetal anemia secondary to maternal red cell alloimmunization. An estimate of normal circulating volume would be useful in selecting the volume of donor blood to be transfused to achieve a desired final hematocrit. Thirty-five fetuses between 21 and 35 weeks of gestation underwent 67 direct intravascular transfusions. The fetoplacental volume relative to fetal weight estimated by ultrasound was found to be relatively constant throughout gestation at approximately 100 cm3/kg. The severity of fetal hemolytic disease and its treatment with intrauterine transfusions did not appear to alter the fetoplacental volume. A nomogram for fetoplacental blood volume versus gestational age is described.     

Relationship between obstetric history and Rh(D) alloimmunization severity

Background To evaluate the relationship between obstetric history and Rh(D) alloimmunization severity, employing the gestational age at the first intrauterine fetal transfusion (IUT) as an indicator of this severity. Methods From 1996 to 2006, Rh(D) alloimmunized pregnancies submitted to IUT had their data assessed. Gestational age at the first IUT was modeled as a linear outcome. The associations between obstetric history variables, anti-Rh(D) antibodies titer and gestational age at the first IUT were analyzed. Statistics are presented with 95% confidence intervals (P < 0.05). Results A total of 82 non-hydropic anemic fetuses, ensuing in 92.7% (n = 76) of perinatal survival, were submitted to IUT. Nineteen (23,2%) pregnant women did not present with any previous stillbirth, neonatal death, IUT, hydrops or neonatal exchange transfusion (group 1); and 63 (76.8%) reported at least one of these events (group 2). Gestational age at the first IUT differed significantly between the groups (P = 0.0001). For group 1, it ranged from 24 to 35 weeks (median 32.5 weeks), whereas for group 2 it ranged from 19 to 34 weeks (median 27 weeks). In the multivariated analysis, previous neonatal death (P = 0.040), previous IUT (P = 0.000) and previous neonatal exchange transfusion (P = 0.036) were independently associated with the gestational age at the first IUT. Conclusions The evaluation of the obstetrical history is an important diagnostic tool for predicting Rh(D) alloimmunization severity. Alloimmunized pregnant women who reported previous neonatal death(s), neonatal exchange transfusion(s) or IUT(s) should receive a closer fetal surveillance due to the risk of a higher rate of fetal hemolysis and the need of an earlier IUT.     

Experience with intrauterine transfusions for severe Rh alloimmunization in a developing country

This study reports our experience with 67 intrauterine transfusions (IUTs) carried out for 27 cases of severe Rh alloimmunization, which could be useful to other developing countries with similar situations. Most of the mothers were from sections of India other than Mumbai, their socioeconomic status was low, and they were referred during the second or third trimester. The mean gestation age at first IUT was 27 × 2.9 weeks and maternal anti-D titer ranged from 1:32 to 1:512. Ultrasonography (USG) was normal in eight cases, but showed minimal or gross ascites in 8 and 11 cases, respectively. The mean × SD hematocrit (HCT) in three groups defined by USG was 23.5 × 1.7, 15.9 × 4, and 12 × 5.9, respectively. Amniotic fluid analysis, which proved to be an important investigation, indicated IUT in eight cases having normal USG. Six cases were severely anemic (Hb deficit > 7 g/dl). By fetal cell staining, the percentage of the donor's red cells in the fetal circulation was determined. Besides Hb, blood group, direct antiglobulin test, and mean cell volume, this parameter was also useful in asessing efficacy of IUT and the need for an exchange transfusion after birth. Of 11 fetuses having gross ascites, eight and one each from the remaining two groups, were stillborn. One death may be procedure related. Two neonates died due to hemorrhagic disorder and prematurity. The overall survival rate was 55.6%. Late referral, severe Rh alloimmunization, volume overload, delay in IUT because of nonavailability of blood and use of nonirradiated blood could be the reasons for the poor outcome. Strategies for improving results are discussed.     

Current clinical management of anti-Kell alloimmunization in pregnancy

OBJECTIVES: Few reports have been published of the current clinical management of anti-Kell alloimmunization in pregnancy; its low frequency of occurrence means that the few long series published have covered very ample time periods in which different kinds of clinical management have overlapped. The objective of the present paper is to present our experience in the current clinical management of pregnant women who are positive for the anti-Kell antibody. STUDY DESIGN: A retrospective analysis was carried out of the case histories of pregnant women who were alloimmunized for the Kell antigen and who were studied and/or treated at the Department of Fetal Medicine in the Virgen de las Nieves University Hospital in Granada (Spain), between 2000 and 2004. The clinical management included the basal measurement of the titre of antibodies, the identification of the paternal phenotype (and that of the fetus, if necessary), the ultrasonographic monitoring of the fetus to detect signs of anaemia, sampling of fetal blood by cordocentesis when fetal anaemia was suspected, and fetal intravascular transfusion when necessary. RESULTS: Of the 10 pregnancies with anti-Kell antibodies, The Kell antigen was confirmed in the fetus in three cases, in all of which moderate to severe fetal anaemia developed, requiring fetal intravascular transfusions. Although one of the fetus developed antenatal hydrops, a good perinatal result was advised. CONCLUSIONS: The current approach to anti-Kell alloimmunization enables pregnant women who have Kell-positive fetuses to be treated successfully.     

Anti-E alloimmunization in pregnancy: management dilemmas

Compared to anti-D alloimmunization, anti-E alloimmunization is a less common cause of hemolytic diseases of the newborn. Being a less potent immunogen, clinical manifestations of anti-E alloimmunization are more variable and usually of less severity. However, the clinical obstetric management of these cases of anti-E alloimmunization is just as challenging. We report here the management of a patient with anti-E alloimmunization to illustrate the controversies of invasive and non-invasive monitoring in the management of such cases.     

Combined intravascular-intraperitoneal transfusions in hydropic twins due to Rh (D) alloimmunization

Fetal hydrops due to Rh (D) alloimmunization can be reversed by ultrasound-guided intravascular transfusions with improvement in perinatal morbidity and mortality. We report a case of in utero intravascular transfusion in hydropic twins which reversed all the hydropic findings within 3 days. A simple intraperitoneal transfusion was performed in each twin 2 weeks later, and only one neonatal exchange transfusion was required for the ultimate survival of both twins.     

Chorionic biopsy in management of severe Kell alloimmunization

Determination of fetal red blood cell Kell antigen is possible on fetal red blood cells obtained at 10 weeks of gestation by chorionic biopsy and may contribute to the management of severe Kell-hemolytic disease.     

The effect of intrauterine intravascular blood transfusion on iron metabolism in fetuses with Rh alloimmunization

Fetal plasma ferritin concentrations were measured in 43 normal fetuses at 18-36 weeks and in 78 blood samples collected before transfusion from 23 fetuses with Rh alloimmunization. Among controls, there was a significant correlation between fetal serum ferritin and gestational age (r = 0.39, P = .009), consistent with an increase in fetal storage of iron during normal pregnancy. In Rh-alloimmunized fetuses, the ferritin concentration was above the reference range in 63% of the samples. Before the first transfusion, the fetal ferritin concentration was increased compared with controls (mean multiples of the mean = 2.6, range 1-26) and showed a negative correlation with fetal hematocrit (r = -0.43, P less than .05), suggesting that the worse the fetal anemia, the higher the iron store. Serial transfusions were associated with further increase in serum ferritin, which correlated primarily with the total volume of blood transfused. Three fetuses had plasma serum ferritin concentrations above 1 mg/L, a level compatible with a diagnosis of iron overload in children. These observations suggest that there is a potential risk of iron overload in Rh-alloimmunized fetuses undergoing intrauterine blood transfusion.     

Kell alloimmunization, hemolytic disease of the newborn, and perinatal management

The relative frequency of Kell (K:1) antibodies in pregnant women and a series of cases of Kell hemolytic disease of newborns were evaluated to review the strategy of managing potential disease. Among reproductive-aged women, Kell antibodies are about 60% as frequent as Rho (D) antibodies, but Kell disease is only 3% as common as Rho hemolytic disease. The reason is related to frequent transfusion-alloimmunization by Kell antigen and the low frequency of the K:1 gene among fathers. Kell hemolysis is severe in about half of cases. Amniocentesis is indicated in only a few circumstances: previous child with erythroblastosis fetalis, significant increase in maternal Coombs titer, presence of Kell antigen in the father, and after comparison of the relative risks of hemolytic disease and amniocentesis in each patient. Screening for Kell antigen before transfusing premenopausal women would be a means of avoiding erythroblastosis, but the rarity of severe disease does not justify this approach.     

Relationship between Cardiofemoral Index and the plasma concentration of brain natriuretic peptide in anemic fetuses associated with Rh alloimmunization

Background  Fetal anemia is a common result of alloimunization and is an important cause of fetal congestive heart failure resulting in heart dilation. Fetuses suspected of having heart failure present a higher Cardiofemoral Index and an increase in plasma BNP levels, because the cardiac hormonal system is activated by increased heart wall stretch due to increased left ventricular volume and pressure overload. Methods  Our group studied 33 pregnant women (22–31 weeks’ gestation at the first cordocentesis) referred for intrauterine fetal transfusion due to severe red blood cells isoimmunization. Up to 6 h prior to each cordocentesis, all fetuses were submitted to ultrasonography measurements where the Cardiofemoral Index was calculated. Samples of blood from the umbilical vein were collected for hemoglobin concentration and blood gas measurements. Plasma levels of BNP were determined with the use of plasma that had previously been frozen and thawed once. Plasma BNP was measured by radioimmunoassay. Pearson’s correlation test and regression analysis were used to determine the association between the plasma concentration of BNP and the Cardiofemoral Index of the anemic fetuses with RH alloimmunization. Results  Anemia was severe in 17 (50%) fetuses, mild in 9 (26.47%) and in 8 patients (23.53%) the fetuses were not anemic; hemoglobin ranged from 3.10 to 15.70 g/dl. The Cardiofemoral Index ranged from 0.43 to 0.87 and it was altered (≥0.59) in 23 fetuses. A significant positive correlation was observed between BNP plasma fetal concentration and Cardiofemoral Index (Pearson r = 0.61, P < 0.0001). Conclusions  These results suggest that fetal plasma concentration of BNP may increase in fetuses with heart dilation leading to a positive association between Cardiofemoral Index and plasma concentration of BNP. An erratum to this article can be found at