Hyporegenerative anemia in anti-M-associated hemolytic disease of the fetus.

BACKGROUND: The anti-M antibody can lead to hemolytic disease of the fetus and newborn (HDFN) and adverse fetal outcomes, especially in the Asian population. However, fetal erythropoiesis resulting from M alloimmunization needs further investigation. STUDY DESIGN AND METHODS: We analyzed erythropoiesis in eight fetuses with M alloimmunization and compared them with the fetuses affected by anti-D. They were matched as pairs according to the gestational age of diagnosis and the hematocrit before treatment. Paired t-tests or paired Wilcoxon rank-sum tests were conducted to compare the difference in the cord blood indexes. Pearson correlation analysis was used to evaluate the correlativity between hematocrit and the reticulocyte percentage in the two groups. RESULTS: The fetuses in the MN group had lower reticulocyte count and percentage than those in the RhD group (p < .05). All of the fetal reticulocyte production indexes (RPIs) in the MN group were less than 2, indicating an inadequate hemopoietic response to anemia, while the majority of the RPIs in the RhD group (85.7%) were significantly higher (p = .003), with 6 cases greater than 2.5. Hematocrit was negatively correlated with reticulocyte percentage (y = 54.7-171.7x, r2  = 0.825, p = .005) in the RhD group, while no significant correlation was found in the MN group. No difference in the number of IUT, interval, or the fetal outcome was found between the two groups. CONCLUSION: Fetal reticulocytopenia provided direct evidence of an inadequate hemopoietic response in HDFN due to anti-M, leading to hyporegenerative anemia. Once the IgG component of anti-M is detected, close monitoring should be considered.

Effect of intravenous immunoglobulins to postpone the gestational age of first intrauterine transfusion in very severe red blood cell alloimmunization: A case-control study.

BACKGROUND: Early intrauterine transfusion (IUT) is associated with a higher risk of fetal loss. Our objective was to evaluate the efficiciency of intravenous immunoglobulins (IVIG) to postpone the gestational age at first IUT beyond 20 weeks of gestation (WG) compared to the previous pregnancy in case of very severe red blood cell (RBC) alloimmunization. STUDY DESIGN AND METHODS: Very severe RBC alloimmunization was defined by a high titer of antibodies and a previous pregnancy complicated by a first IUT before 24 WG and/or perinatal death directly related to alloimmunization. We performed a single-center case-control study. Cases and controls were patients respectively treated with weekly IVIG infusions started before 13 WG, and without. RESULTS: Twenty cases and 21 controls were included. Gestational age (GA) at first IUT was postponed after 20 WG in 18/20 (90 %) of patients treated with IVIG and in 15/21 (71 %) in the control group (p = 0.24). Compared to the previous pregnancy, the GA at first IUT was postponed by a median of 22 [+11; +49] days in the IVIG group and occurred in average 2 days earlier [-17 ; +12] in the non-treated group (p = 0.02). There was no difference between number of IUT and need for exchange-transfusion. IVIG treatment was associated with a significant decrease of antibodies' quantitation. CONCLUSION: In our series, IVIG tends to differ first IUT beyond 20 WG and have a significant effect in postponing the gestational age of the first IUT in patients with very severe RBC alloimmunization.

Conservative Management of Alloimmune Hemolysis and Cholestasis With Extreme Laboratory Abnormalities.

Alloimmune hemolytic disease of the fetus or newborn (HDFN) is a rare cause of neonatal cholestasis. HDFN-associated cholestasis has most often been reported secondary to anti-D alloimmunization. In utero transfusions are also an identified risk factor. A variety of diagnostic and therapeutic strategies have been described, mostly in case reports. Here, we report 2 cases of HDFN-associated cholestasis that were notable for extreme laboratory abnormalities including a peak ferritin of 24 700 ng/mL and a peak alanine aminotransferase of 1406 U/L (33.5-fold upper limit of normal). One case was due to alloimmunization other than anti-D. These cases help define the range of laboratory derangements that are consistent with HDFN-associated cholestasis, including extreme hyperferritinemia. Although in a number of cases, researchers have reported the use of iron chelation in these infants, herein, we describe successful management without iron chelation.

Conservative Management of Hyperferritinemia in Hemolytic Disease of the Fetus and Newborn: A Case Report and Review of the Literature.

We report a newborn with hemolytic disease of the fetus and newborn (HDFN) with rapid resolution of extreme hyperferritinemia without chelation. An infant born at 35+3 weeks with HDFN and a history of 3 intrauterine transfusions developed severe hyperferritinemia (maximum, 8258 mcg/L) without evidence of toxic iron deposition on liver biopsy. Her hyperferritinemia was managed with observation alone, and ferritin levels normalized rapidly. This case supports observation as being the preferred alternative to chelation therapy for significant hyperferritinemia in newborns with HDFN in the absence of demonstrated toxic end-organ iron deposition. We also include a review of the related available literature.

Prevention of hemolytic disease of the fetus and newborn: what have we learned from animal models?

PURPOSE OF REVIEW: This review aims to highlight recent advances in our understanding of how anti-red blood cell (RBC) antibodies prevent erythrocyte immunization with an emphasis on new murine models. RECENT FINDINGS: New murine models with clinically relevant human erythrocyte antigens have been used to understand the alloimmunization process and its inhibition. The search to elucidate the mechanism of action of IgG-mediated inhibition of erythrocyte alloimmunization has provided new evidence in support of a potential role for epitope masking, immune deviation and/or antigen modulation in this process. In addition, recent evidence suggests that blends of monoclonal antibodies targeting nonoverlapping epitopes on the RBC surface can improve the efficacy of monoclonal antibodies approaching that of polyclonal IgG. SUMMARY: Animal models with defined alloantigens have helped to identify important mechanistic components that lead to alloimmunization and its inhibition by IgG. A better understanding of the underlying mechanisms leading to hemolytic disease of the fetus and newborn is required to develop the most effective prevention strategies for future patients.

Changes in middle cerebral artery velocimetry of fetuses diagnosed postnatally with mild or moderate hemolytic disease.

OBJECTIVES: To determine the longitudinal trends of middle cerebral artery peak systolic velocity (MCA PSV) in fetuses with mild or moderate hemolytic disease according to the need for postnatal therapy. DESIGN: Prospective cohort study. SETTING: University referral center. SAMPLE: Twenty-three fetuses from singleton alloimmunized pregnancies. METHODS: Serial measurements of MCA PSV were performed. After delivery, newborns were grouped by the need for postnatal management into mild hemolytic disease, which required no or only phototherapy (n = 14, group 1), and moderate hemolytic disease, where postnatal top-up or exchange transfusions were required (n = 9, group 2). MAIN OUTCOME MEASURES: Serial Doppler MCA PSV data transformed to multiples of the median, analyzed with linear regression and exponential models. RESULTS: We performed 83 measurements in group 1: 3-8 per fetus; mean GA at inclusion, 23 weeks and 65 measurements in group 2: 4-15 per fetus; mean GA at inclusion, 22 weeks. The estimated mean slopes of the MCA PSVs increased with the degree of postnatal therapy required (group 1: MCA PSV = 0.003 GA + 1.298; group 2: MCA PSV = 0.035 GA + 0.436). The relative average increments (RAI) were 4.7% and 7.1%, respectively. The two groups exhibited significant differences in mean slope and RAI (p<0.05). CONCLUSIONS: Fetuses that required postnatal transfusions due to hemolytic disease showed an enhanced progressive increase in MCA PSVs compared to those without transfusion requirement. This information might enable their identification during pregnancy.

Possible suppression of fetal erythropoiesis by the Kell blood group antibody anti-Kp(a).

Antibodies to antigens in the Kell blood group system are usually immunoglobulin G, and, notoriously, anti-K, anti-k, and anti-Kp(a) can cause severe hemolytic transfusion reactions, as well as severe hemolytic disease of the fetus and newborn (HDFN). It has been shown that the titer of anti-K does not correlate with the severity of HDFN because, in addition to immune destruction of red blood cells (RBCs), anti-K causes suppression of erythropoiesis in the fetus, which can result in severe anemia. We report a case involving anti-Kp(a) in which one twin was anemic and the other was not. Standard hemagglutination and polymerase chain reaction (PCR)-based tests were used. At delivery, anti-Kp(a) was identified in serum from the mother and twin A, and in the eluate prepared from the baby's RBCs. PCR-based assays showed twin A (boy) was KEL*841T/C (KEL*03/KEL*04), which is predicted to encode Kp(a+b+). Twin B (girl) was KEL*841C/C (KEL*04/KEL*04), which is predicted to encode Kp(a­b+). We describe the first reported case of probable suppression of erythropoiesis attributable to anti-Kp(a). One twin born to a woman whose serum contained anti-Kp(a) experienced HDFN while the other did not. Based on DNA analysis, the predicted blood type of the affected twin was Kp(a+b+) and that of the unaffected twin was Kp(a­b+). The laboratory findings and clinical course of the affected twin were consistent with suppression of erythropoiesis in addition to immune RBC destruction.

Unbound bilirubin predicts abnormal automated auditory brainstem response in a diverse newborn population.

OBJECTIVE: The objective of this study was to determine if plasma unbound or 'free' bilirubin concentration (B(f)) measured during the first 30 days of life is associated with subsequent abnormal hearing screening testing by automated auditory brainstem response (AABR) in a diverse population of newborns. STUDY DESIGN: An observational study of newborns receiving AABR, plasma total bilirubin concentration (TBC) and B(f) measurements and without underlying conditions known to affect hearing was conducted. Logistic regression was used to determine associations between abnormal AABR and B(f) or TBC. The impacts of a variety of clinical factors on the regression model were also assessed. RESULT: A total of 191 patients with birth weights and gestations ranging from 406 to 4727 g and 24 to 42 weeks, respectively, were studied. Among them, 175 (92%) had normal (bilateral PASS) AABR and 16 had abnormal AABR (6 had unilateral REFER AABR, and 10 had bilateral REFER AABR). Mean TBC was not significantly different in babies with normal or abnormal AABR, but mean B(f) was greater in the latter group (1.76 versus 0.93 microg per 100 ml, respectively, P=0.012). B(f), but not TBC, was associated with an abnormal AABR (B(f) adjusted odds ratio 3.3, 95% CI 1.8 to 6.1). Comparing receiver-operating characteristics curves, the B(f)/TBC ratio was a better predictor of an abnormal AABR than B(f) alone. Intraventricular hemorrhage was the only confounding clinical variable. CONCLUSION: An abnormal AABR is associated with an elevated B(f) or B(f)/TBC ratio, but not the TBC alone. The prevalence of bilirubin neurotoxicity as a cause of audiological dysfunction may be underestimated if the TBC alone is used to assess the severity of newborn jaundice.

Lutheran.

The Lutheran blood group system consists of 19 antigens: four pairs of antithetical antigens--Lu(a)/Lu(b), Lu6/Lu9, Lu8/Lu14, and Au(a)/Au(b)--and 11 antigens of very high frequency. These antigens are located on four of the five immunoglobulin-like domains of both isoforms of the Lutheran glycoprotein. The LU gene is on chromosome 19 and comprises 15 exons. The two glycoprotein isoforms differ in the length of their cytoplasmic tails as a result of alternative splicing of intron 13. Lu(null) phenotype arises from homozygosity for inactivating mutations in the LU gene.The dominantly inherited Lu(mod) phenotype, In(Lu), results from heterozygosity for inactivating mutations in KLF1, the gene for the erythroid transcription binding factor EKLF. Clinically, antibodies of the Lutheran system are relatively benign. When hemolytic, they generally cause only mild, delayed hemolytic transfusion reactions or hemolytic disease of the fetus and newborn that can be treated by phototherapy. The Lutheran glycoproteins, which are members of the immunoglobulin superfamily of adhesion molecules and receptors, bind isoforms of laminin with alpha5 chains,components of the extracellular matrix abundant in vascular endothelia. The primary function of the Lutheran glycoproteins on RBCs could involve the transfer of maturing RBCs from the bone marrow to the peripheral circulation. They could also be involved in vascular occlusion and thrombotic events as complications of sickle cell disease and polycythemia vera, respectively.

Reversion of the Ballantyne syndrome despite fetal hydrops persistence.

INTRODUCTION: The Ballantyne syndrome (or mirror syndrome) is a gestational proteinuric hypertension associated with fetal hydrops. This report describes a case in which Ballantyne syndrome reversion occurred despite fetal hydrops persistence. CASE REPORT: A 24-year-old woman showed fetoplacental hydrops at 28 2/7 gestational weeks. Severe Rh(D) alloimmunization and fetal hemolytic anemia (fetal hematocrit 15.4%) were confirmed by cordocentesis, and an intrauterine transfusion was performed. She also revealed hypertension (160/100 mm Hg), edema and proteinuria (845 mg/day). After four intrauterine transfusions, blood pressure was normalized; urinary proteinuria was not significant, and the edema vanished completely. Fetal hydrops persisted until delivery at 32 gestational weeks, but a partial reduction of placental hydrops was noted. DISCUSSION: Total or partial reduction of the placental edema may be responsible for the reversal of the Ballantyne syndrome despite the fetal hydrops persistence.

Severe hemolytic disease of the newborn from anti-e.

Maternal antibody-mediated fetal red blood cell destruction secondary to non-D Rhesus (Rh) antibodies is a significant cause of hemolytic disease of the newborn (HDN). Here, we report a rare case of severe HDN associated with maternal antibody to Rh e. In addition to severe anemia, the infant developed thrombocytopenia, conjugated hyperbilirubinemia and cholelithiasis. Resolution of the infant's cholelithiasis occurred following treatment with ursodeoxycholic acid.

[Indexes of a functional condition of a liver with hemolytic disease of the newborn stipulated incompatibility between the mother and fetus].

The hemolytic disease of the newborn, originating as a result of sensitization of the mother to the Rh-antigen of erythrocytes of the fetus (Rh-HDN) is one of the most important causes of the loss of a fetus and newborn. One of the pathogenetic mechanisms of Rh-HDN is the hyperbilirubinemia at the expense of the toxiferous fraction of a bilirubin negatively influencing many organs of the child, including the liver. The purpose of the work was the complex study of indexes of a functional condition of a liver newborn with a various degree of gravity Rh-HDN and definition of effectiveness of the conducted therapy. The direct association between severity of illness and indexes of pigmental, excretion and detoxication of the function of the liver in newborns with Rh-HDN has been found. There were found significant relations of ALT/AP, AST/AP, GT/AP, albumin and globulin factors with the degree of cholestasis and toxic damage of the liver. The lack of normalization of indexes of the peptide uptake and the excretion function of the liver on the background of treatment indicate to the necessity of further monitoring of functional condition of the liver and realization of the correction of therapy after discharge of children from the hospital, especially with the serious form of Rh- HDN.

Alteracões ultra-sonográficas na gravidez Rh negativo sensibilizada avaliada pela espectrofotometria do líquido amniótico e pela dopplervelocimetria da artéria cerebral média / Ultrasound findings in Rh-alloimmunized pregnancies assessed by spectrophotometric analysis of amniotic fluid and Doppler velocimetry of fetal middle cerebral artery

OBJETIVO: Avaliar e confrontar a presenca de alteracões ultra-sonográficas nas gestacões Rh negativo sensibilizadas, quando a anemia fetal foi determinada ou pela espectrofotometria do líquido amniótico, ou pela dopplervelocimetria da artéria cerebral média. MATERIAIS E MÉTODOS: Observacional descritivo com grupo de comparacão. Nosso grupo de estudo foi constituído por 99 pacientes, avaliadas no período de janeiro de 1995 a janeiro de 2004. Foram analisados e comparados dois grupos: 74 gestantes sensibilizadas pelo fator Rh cuja anemia fetal foi acompanhada pela espectrofotometria (grupo SE) e 25 gestantes sensibilizadas pelo fator Rh cuja anemia fetal foi acompanhada pela dopplervelocimetria (grupo SD). Avaliamos a presenca ou não de alteracões ultra-sonográficas no acompanhamento pré-natal e confrontamos os dois grupos de estudo. RESULTADOS: No grupo cuja anemia fetal foi acompanhada através da espectrofotometria (grupo SE), apuramos modificacões placentárias, principalmente o aumento da espessura e sua alteracão textural, mais assiduamente que as encontradicas no grupo de gestantes sensibilizadas, em que a anemia foi determinada através da dopplervelocimetria (grupo SD) (64 por cento X 32 por cento, p = 6,294). CONCLUSAO: As alteracões ultra-sonográficas foram detectadas em dobro quando a anemia foi avaliada pela espectrofotometria em comparacão com o grupo seguido pela dopplervelocimetria.

Serial blood donations for intrauterine transfusions of severe hemolytic disease of the newborn with the use of recombinant erythropoietin in a pregnant woman alloimmunized with anti-Ku.

BACKGROUND: The management of a pregnant woman with the rare Ko phenotype and anti-Ku is a special challenge, because matched blood is extremely rare and the possibility of severe hemolytic disease of the newborn is high. CASE REPORT: A 30-year-old woman with rare Ko (Knull) phenotype presented at 18 weeks of gestation with positive indirect agglutination test results. She had anti-Ku due to previous blood transfusion, one pregnancy, and two abortions. STUDY DESIGN AND METHODS: During this pregnancy, anti-Ku titers ranged from 1024 to 4096. At the 26th week of gestation ultrasound showed a hydropic fetus and urgent intrauterine exchange transfusion was performed with the maternal red blood cells (RBCs). Recombinant human erythropoietin (rHu-EPO) and intravenous (IV) iron were administered to the mother to ensure an adequate supply of matched RBCs for intrauterine transfusions and possible perinatal hemorrhage. RESULTS: Intrauterine transfusions were repeated every 1 to 3 weeks. By 35 weeks 2 days of gestation, the mother had donated 4 units of blood, and four intrauterine transfusions had been performed. Cesarean section was then decided and a healthy male newborn was born. He was treated with phototherapy but without exchange transfusions. By the 15th day of life rHu-EPO was administrated to the newborn because of anemia. The maternal RBCs completely disappeared from the child's blood by Day 100. CONCLUSIONS: As shown in this case, treatment with rHu-EPO and IV Fe has effectively increased the mother's capacity to donate RBCs for autologous use and intrauterine transfusions, with no adverse effects to the mother or the child.

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.

[Doppler measurements of blood flow in the middle cerebral artery for the diagnosis of fetal anemia]. / Ocena przydatnosci pomiarów przeplywów krwi metoda Dopplera w tetnicy srodkowej mózgu w diagnostyce anemii u plodu.

OBJECTIVES: This paper presents a possibility of non-invasive diagnosis of fetal anemia based on the Doppler assessing of peak systolic velocity (PSV) in the fetal middle cerebral artery. The results of Doppler measurements were compared with fetal peripheral blood count estimated after cordocentesis. MATERIALS AND METHODS: Doppler measurements of blood flow velocity in the fetal middle cerebral artery were performed in years 2000 and 2001 in 22 pregnancies complicated by maternal blood group alloimmunisation. Gestation age varied from 27 to 36 weeks, the mean gestation age was 32 weeks. Depending on hemoglobin concentration in the fetal blood sample the severity of anemia was divided into three groups: severe anemia (Hb = < 7 g%), middle (Hb = = 8-10 g%) and light (Hb = = 10-12 g%). The fourth group consisted of fetuses without anemia (Hb > 12 g%). The results were statistically analyzed to estimate correlation between the Doppler blood flow indexes (PI, RI, SD and PSV) in the middle cerebral artery and the peripheral blood count (Hb, Ht, erythrocyte count) of fetal blood received by cordocentesis. Using T-Student-test the differences of average maximal blood flow velocities and mean Doppler indexes in the group of fetuses with severe anemia (Hb < 7 g%) and fetuses without anemia (Hb > 12 g%) were compared. RESULTS: Highest (negative) correlation was found between the peak systolic velocity and the fetal hemoglobin concentration. The correlation index was -0, 85, which means the higher the peak systolic velocity the lower the hemoglobin concentration. The difference between the mean peak systolic velocity in the group of fetuses with severe anemia and the group without anemia was statistically significant (p < 0.001). However, there was no statistical significant difference in the mean peak systolic velocity between the group with middle anemia (Hb = 10-12 g%) and the group without anemia (Hb > 12 g%). CONCLUSIONS: Doppler ultrasonography with the measurement of peak systolic velocity in the middle cerebral artery is a good method in evaluating of fetal peripheral blood count. Non-invasive peak systolic velocity measurements in the middle cerebral artery allow to assess the fetal hemoglobin concentration and also to reduce the count of diagnostic cordocentesis.