Fetal hemolytic anemia and intrauterine death caused by anti-M immunization

BACKGROUND: Antibodies with anti-M specificity are detected in 10 percent of pregnant women with a positive antibody screen, but anti-M is only rarely associated with hemolytic anemia in the fetus. STUDY DESIGN AND METHODS: This study reports on three pregnancies in one family that all resulted in severe fetal anemia. The first fetus died in utero with hydrops fetalis during the 20th gestational week and the second child was delivered after 28 weeks of gestation with hydrops fetalis and a hemoglobin level of 16 g per L whereas the third affected child was treated with intrauterine red cell (RBC) transfusions before delivery at 28 weeks of gestation. RESULTS: The direct antiglobulin test was negative but anti-M in a low titer was detected through the three pregnancies, and its clinical relevance, which initially was uncertain, was confirmed by pronounced in vivo hemolysis in maternal blood of chromate ((51)Cr)-labeled M+ RBCs and normal survival of (51)Cr labeled M- RBCs. CONCLUSION: It is concluded that anti-M immunization in a few cases may cause severe fetal hemolytic anemia and intrauterine death. It remains to be elucidated why a normally clinically insignificant antibody is this aggressive in a small proportion of cases. Because the condition is treatable, anti-M must be considered as a possible cause of fetal anemia and intrauterine death.     

Anemic Disease of the Newborn With Little Increase in Hemolysis and Erythropoiesis Due to Maternal Anti-Jra: A Case Study and Review of the Literature

The severity of the hemolytic disease of the fetus and newborn (HDFN) due to Jr^a mismatch ranges from no symptoms to severe anemia that requires intrauterine and exchange transfusions. We encountered a newborn, born to a healthy mother having anti-Jr^a at 38 weeks of pregnancy, who had moderate anemia, a positive direct antiglobulin test (DAT) result, no increased erythropoiesis, and no jaundice at birth. Flow cytometry revealed that the Jr^a antigen of red cells in the infant was nearly negative at birth, biphasic at 5 weeks, and lowly expressed at 7 months of life. We searched online for previous case reports on HDFN due to Jr^a incompatibility. Among 63 reported cases, excluding 25 cases, 38 were included with the present case for analysis. Of 39 newborns, 10 developed clear anemia (hemoglobin <10.0 g/dL), and 1 died, 5 developed hydrops fetalis, 4 needed intrauterine transfusion and/or exchange transfusion, and 3 received red cell transfusion after birth; overlaps were included. Among 29 neonates with no anemia, 8 needed interventions including phototherapy and γ-globulin infusion, and the remaining 21 received conservative supports only. The maternal anti-Jr^a titer, ranging between 4 and 2048, did not correlate with the severity of anemia, levels of bilirubin, or any interventions required. The DAT of red cells was positive in 29 of 36 fetuses/newborns tested, whereas it was often negative among anemic neonates (4 of 9) (P < .05). Hematopoiesis did not increase effectively, as indicated by reticulocyte ratios between 1.7% and 22.3%, even with the increase in reticulocytes in anemic neonates compared with nonanemic neonates (P < .05). Total bilirubin levels ranged broadly between 0.2 and 14.3 mg/dL but were generally low. The maternal anti-Jr^a titer and IgG3 subclass did not correlate with the morbidity of the newborns. Being identical/compatible between mothers and their infants may possibly enhance infants' morbidity, as a weak tendency was observed (P = .053). Maternal anti-Jr^a may suppress erythropoiesis in fetuses via a mechanism different from the established HDFN, such as anti-D, as evidenced by the lower reticulocyte count and small increase in bilirubin in neonates. As the anti-Jr^a titer, IgG subclass, and DAT were not correlated with the severity, the mechanism of anti-Jr^a–induced HDFN remains to be elucidated.     

Anti-Co(a) implicated in severe haemolytic disease of the foetus and newborn

summary .  The Colton (Co^a) antigen is of high frequency; its incidence in Caucasians is about 99.8%. Reports on haemolytic transfusion reactions and haemolytic disease of the foetus/newborn (HDFN) due to anti-Co^a are rare. We report a severe HDFN due to anti-Co^a. The first child of the mother was healthy. The second died a few hours after delivery because of hydrops fetalis, likely due to HDFN; anti-Co^a in the maternal serum, the father typed as Co(a+). The third pregnancy was followed up by the measurements of anti-Co^a titre (additional antibodies were excluded), its functional activity by the chemiluminescence test (CLT) and the Doppler flow in the middle cerebral artery of the foetus. Increased values of antibody titre up to 128, the CLT to 30% and multiplex of median of the peak systolic velocity to 1·71 indicated haemolytic disease and the necessity for an intrauterine transfusion. The foetus received the maternal red blood cells (RBCs). Delivery had to be by Caesarean section for obstetrical reasons at 34-week gestation. The newborn (anti-Co^a on red cells and in plasma, the rise of the bilirubin concentration up to 333 μmol L⁻¹) had four exchange transfusions: the first of maternal RBCs, the remaining of donor's Co(a+) cells and one top-up transfusion. The baby was discharged in good health. Anti-Co^a was responsible for severe HDFN. Proper monitoring during pregnancy and antenatal and post-natal therapy were successful. This is the second severe published HDFN due to anti-Co^a.     

Three non-classical mechanisms for anemic disease of the fetus and newborn,based on maternal anti-Kell,anti-Ge3, anti-M,and anti-Jra cases

Maternal alloantibody-mediated hemolytic disease of the fetus and newborn (HDFN) ranges from no or mild symptoms to severe hydrops and intrauterine fetal demise. Hemolytic anti-D-mediated HDFN proceeds via a long-known mechanism, to which three other pathways to fetal/neonatal anemia may be added: (0) Fetal erythrocyte destruction can proceed by extravascular phagocytosis. (1) An apoptotic pathway has been described for anti-Kell, and anti-Ge3. (2) Erythropoietic suppression may arise from altered or deformed erythroblast architecture in anti-M-mediated disease. (3) Clonal escape from erythropoietic suppression is hypothesized to arise from maternal anti-Jr^a immune pressure, albeit this requires further elucidation. Alloantibody-mediated anemic disease of the fetus and newborn (ADFN) is a designation we favor for cases when hemolysis or hyperbilirubinemia are not the dominant features, such as those provoked by anti-Kell, anti-Ge3, anti-M, and anti-Jr^a.     

Red Blood Cell Alloimmunization in the Pregnant Patient

Alloimmunization to red blood cell (RBC) antigens represents a challenge for physicians caring for women of child bearing potential. Exposure to non-self RBC antigens may occur during transfusion or pregnancy leading to the development of antibodies. If a subsequent fetus bears that antigen, maternal antibodies may attack the fetal red blood cells causing red cell destruction and clinically significant hemolytic disease of the fetus and newborn (HDFN). In the most severe cases, HDFN may result in intrauterine fetal demise due to high output cardiac failure, effusions and ascites, known as “hydrops fetalis”. This article reviews strategies for management and prevention of RBC alloimmunization in women of child bearing potential.     

Hydrops fetalis caused by homozygous alpha-thalassemia and Rh antigen alloimmunization: report of a survivor and literature review

Hematologic causes of hydrops fetalis include homozygous alpha-thalassemia and immune hemolytic anemias. We report the case of a boy with hydrops fetalis who had homozygous alpha-thalassemia and alloimmune hemolytic anemia due to anti-E and anti-C blood group antibodies. He received intrauterine red blood cell transfusions and postnatal chronic transfusion with iron chelation therapy. A non-myeloablative sibling stem cell transplant failed. He is now 5 years and 6 months of age, hypothyroid with short stature, but in overall good health. He is one of the oldest reported homozygous alpha-thalassemia survivors and, to our knowledge, the only survivor with immune- and nonimmune-induced hydrops fetalis.     

MRI在胎儿非免疫性水肿中的应用

目的探讨MRI在诊断胎儿非免疫性水肿的临床应用价值。材料与方法对8例非免疫性胎儿水肿的产前MRI影像进行回顾性分析。结果 8例胎儿经尸检和出生后诊断为典型非免疫性胎儿水肿。病因中,先天性肺囊腺瘤样畸形25%(2/8)、乳糜胸25%(2/8)、胎粪性腹膜炎25%(2/8)、心血管异常12.5%(1/8)、宫内缺氧12.5%(1/8)。4例出生后经治疗或手术预后良好,4例生后(包括引产)死亡。结论非免疫性胎儿水肿病因复杂,MRI检查能够较好评价胎儿水肿程度以及为分析病因提供可靠的影像学依据,是产前评价非免疫性胎儿水肿的重要检查手段。     

Haemolytic disease of the newborn due to maternal irregular antibodies in the Chinese population in Taiwan

From 1991 to 2000, amongst 23,886 full-term healthy Chinese babies delivered at our hospital, 2615 babies developed neonatal hyperbilirubinaemia. After excluding other causes of hyperbilirubinaemia and identifying the irregular antibodies, 15 cases of haemolytic disease of the newborn (HDN) due to maternal irregular antibodies were diagnosed; three cases were born in our hospital and 12 cases were referred. Amongst these 15 babies, six cases had HDN due to anti-E, three cases due to anti-E + c, three cases due to anti-D, one case due to anti-c and two cases due to 'Mi' antibodies reacting with MiIII phenotype cells (anti-Hil and anti-Mur). Although there were four cases of hydrops fetalis, only one of the patients expired. The prevalence of HDN caused by maternal irregular antibodies has been estimated to be 0.01%. Therefore, routine prenatal screening for irregular antibodies was not rational in the Chinese population in Taiwan. Anti-E and anti-E + c were the important irregular antibodies resulting in HDN. Although few cases of HDN due to anti-'Mi' have been reported, Anti-'Mi' is significant in regions with a high prevalence of the MiIII phenotype.     

Pathophysiology and treatment of fetal anemia due to placental chorioangioma.

Placental chorioangiomas occur in 1% of pregnancies. Large chorioangiomas may cause serious complications such as fetal anemia, hydrops and fetal death. In this case report, a pregnancy complicated by a large placental chorioangioma is described. Severe fetal anemia without the occurrence of hydrops fetalis was suspected using ultrasound and Doppler examinations. Successful intrauterine blood transfusion was performed, with an unusually large amount of blood needed to obtain an adequate rise in fetal hematocrit. Two weeks later, at 32 weeks, the infant was born in good condition. In pregnancies with large chorioangiomas, we advise regular ultrasound and Doppler examinations, with the aim of detecting fetal anemia before hydrops develops. When anemia is suspected, fetal blood sampling is indicated and intrauterine transfusion therapy may be beneficial to preserve fetal health until maturity is reached.     

Exacerbation of autoimmune hemolytic anemia associated with pure red cell aplasia after COVID-19: A case report

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are rare complications of coronavirus disease 2019 (COVID-19). Herein, we report the case of a 28-year-old Japanese man who showed severe AIHA exacerbation associated with PRCA after COVID-19. AIHA was diagnosed and maintained for 5 years. Approximately 4 weeks after COVID-19, the patient developed severe anemia (hemoglobin level, 3.4 g/dL). Laboratory test results confirmed hemolytic exacerbation of IgG-mediated warm-type AIHA. Despite the hemolysis phase, the bone marrow revealed extreme hypoplasia of erythroblasts with a decreased reticulocyte count, similar to that observed in patients with PRCA. During oral prednisolone treatment, the patient recovered from anemia and showed increased reticulocyte count and reduced hypoplasia of marrow erythroblasts. Exacerbation of AIHA and PRCA was triggered by COVID-19 because other causes were ruled out. Although this case report highlights that COVID-19 could lead to hematological complications such as AIHA and PRCA, the exact mechanisms remain unclear.     

Transient hydrops fetalis of the donor fetus in twin-twin transfusion syndrome after therapeutic amnioreduction.

We present a case of twin-twin transfusion syndrome associated with transient hydrops fetalis observed in the donor after therapeutic amnioreduction at 22 weeks of gestation. After the amnioreduction, the bladder of the donor could be visualized and the donor subsequently began to make amniotic fluid, with spontaneous regression of hydrops fetalis. It is suspected that after therapeutic amnioreduction, intrauterine hemodynamic changes occurred and the donor developed transient hydrops fetalis due to volume overload.     

Is hydrops fetalis a manifestation of fetal pulmonary edema caused by impaired lymphatic drainage?

Hydrops fetalis is the final common hemodynamic pathway for a variety of fetal cardiovascular pathologies, including high-output states associated with fetal anemia or arteriovenous fistulas, and abnormalities of both cardiac structure and rhythm. Hydrops fetalis secondary to cardiovascular decompensation is usually accompanied by increases in fetal systemic venous pressure as evidenced by alterations in venous Doppler blood flow velocities. We present two cases of severe fetal aortic stenosis with left ventricular fibroelastosis and mitral regurgitation, and in-utero closure or stenosis of the foramen ovale, with severe hydrops fetalis, despite normal systemic venous Doppler flow profiles. These cases have led us to reconsider the presumed etiology of cardiovascular-based hydrops fetalis in fetuses with severely impaired left ventricular pump function and secondary mitral regurgitation. We hypothesize that raised pulmonary venous pressure, with only mildly increased central venous pressure, may impact negatively on pulmonary lymphatic flow, decrease serum oncotic pressure, increase venous hydrostatic pressure, and lead to hydrops fetalis.     

Non-immune hydrops fetalis: Two case reports

BACKGROUNDFetal hydrops is a serious condition difficult to manage, often with a poor prognosis, and it is characterized by the collection of fluid in the extravascular compartments. Before 1968, the most frequent cause was the maternal-fetal Rh incompatibility. Today, 90% of the cases are non-immune hydrops fetalis. Multiple fetal anatomic and functional disorders can cause non-immune hydrops fetalis and the pathogenesis is incompletely understood. Etiology varies from viral infections to heart disease, chromosomal abnormalities, hematological and autoimmune causes.CASE SUMMARYA 38-year-old pregnant woman has neck lymphoadenomegaly, fever, cough, tonsillar plaques at 14 wk of amenorrhea and a rash with widespread itching. At 27.5 wk a fetal ultrasound shows signs of severe anemia and hydrops. Cordocentesis is performed with confirmation of severe fetal anemia and subsequent fetal transfusion. The karyotype is 46, XX, array-comparative genome hybridization (CGH) negative, and infectious tests are not conclusive. In the following days there is a progressive improvement of the indirect signs of fetal anemia. At 33.6 wk, for relapse of severe fetal anemia, further fetal transfusions are necessary and an urgent cesarean section is performed. On the day 12 of life, for the detection of anemia, the newborn is subjected to transfusion of concentrated red blood cells and begins treatment with erythropoietin. Later there is a normalization of blood chemistry values and the baby does not need new transfusions. A 29-year-old pregnant woman, with Sjogren''s syndrome and positive Anti-Ro/SSA antibodies, is subjected to serial fetal ecocardio for branch block. At 26.5 wk there is a finding of fetal ascites. Infectious disease tests on amniotic fluid are negative as well as quantitative fluorescent polymerase chain reaction, Array CGH. At cordocentesis Hb is 1.3 mmol/L, consequently fetal transfusion is performed. Also in this case, due to continuous episodes of relapse of fetal anemia with consequent transfusions, at 29.4 wk a cesarean section is performed. On day 9 of life, a treatment with erythropoietin is started in the newborn, but the baby needs three blood transfusions. The search for autoantibodies in the baby found SS-A Ro60 positive, SSA-Ro52 positive and SS-B negative. The hemoglobin values normalized after the disappearance of maternal autoantibodies.CONCLUSIONAn attempt to determine the etiology of hydrops should be made at the time of diagnosis because the goal is to treat underlying cause, whenever possible. Even if the infectious examinations are not conclusive, but the pregnancy history is strongly suggestive of infection as in the first case, the infectious etiology must not be excluded. In the second case, instead, transplacental passage of maternal autoantibodies caused hydrops fetalis and severe anemia. Finally, obstetric management must be aimed at fetal support up to an optimal timing for delivery by evaluating risks and benefits to increase the chances of survival without sequelae.     

First-trimester treatment of fetal anemia secondary to parvovirus B19 infection.

Here we report two cases of first-trimester parvovirus B19 (PV-B19) infection that were successfully treated by intrauterine blood transfusion into the umbilical vein. At 13 weeks' gestation both fetuses presented with increased nuchal translucency (NT) and cardiomegaly. In both cases pulsed Doppler ultrasound examination of the fetal middle cerebral artery (MCA) revealed increased peak systolic velocity (PSV), which led to a suspicion of fetal anemia. Maternal PV infection was confirmed by a positive polymerase chain reaction result. Each fetus received a 3-mL intravenous transfusion of packed red blood cells into the umbilical vein, using a 25-G spinal needle. Follow-up ultrasound and Doppler examination demonstrated fetal well-being, decline of the MCA-PSV and resolution of the NT. Case 1 was readmitted at 25 weeks' gestation with severe hydrops fetalis, and both mother and fetus still tested positive for PV-B19 DNA. Three more intrauterine blood transfusions were performed and the fetal hydrops resolved. In Case 2 no additional transfusions were needed. Both babies had a good neonatal outcome and uneventful follow-up. Our findings demonstrate that the MCA-PSV is helpful in establishing the diagnosis of first-trimester fetal anemia. Intravasal transfusion can be attempted as early as the first trimester.     

Autoimmune hemolytic anemia with anti Jka specificity in a patient taking aldomet

Autoimmune hemolytic anemia (hemoglobin 5.2 g, reticulocyte count 31.0 per cent) developed in a 53-year-old hypertensive woman who was taking Aldomet. Both the patient's serum and the eluate prepared from her red blood cells contained an antibody with anti-Jka specificity. Rapid sustained improvement in the anemia occurred after cessation of Aldomet and a two week course of prednisone therapy. Eight months later, anti- Jka was no longer detectable in the patient's serum and the direct antiglobulin test was nonreactive.     

Intrauterine management of fetal parvovirus B19 infection.

OBJECTIVES: The aim of our study was to determine the outcome of pregnancies after intrauterine management of fetal parvovirus B19 infection. DESIGN: Retrospective study. SUBJECTS: A total of 37 cases of maternofetal parvovirus B19 infection, 35 of which were associated with hydrops fetalis, were referred to our tertiary level center between 1989 and 1996. With regard to fetal hydrops, no apparent cause other than parvovirus B19 infection was found in any patient. METHODS: In all patients, cordocentesis was performed to assess the degree of fetal anemia. When anemia was present, cordocentesis was followed by intrauterine transfusion with packed red cells into the umbilical vein. Further management depended on the degree of fetal anemia and gestational age and included follow-up fetal blood sampling/transfusion as well as ultrasound examinations as deemed appropriate. RESULTS: Packed red cell transfusion was performed in 30 patients with significant fetal anemia (Z-score 1.6-7.8 below the mean for gestational age). The fetal hemoglobin values ranged from 2.1 to 9.6 g/dl. Serum levels of platelets in the transfusion group were 9-228 x 10(9)/l with Z-scores in the range of < 1 to 3.8 below the mean. During treatment and follow-up, there were five intrauterine deaths (13.5%), one neonatal death (2.7%) and 31 live births (83.8%). CONCLUSIONS: Fetal parvovirus infection can lead to marked anemia and hydrops formation. Cordocentesis allows precise assessment of fetal anemia which can then be corrected by intravenous transfusion. Under this regimen, the outcome proved favorable in the majority of fetuses, even those that were severely anemic.     

A single-center,retrospective analysis of 17 cases of hemolytic disease of the fetus and newborn caused by anti-M antibodies

Objective

We aimed to summarize the laboratory findings and clinical features of hemolytic disease of the fetus and newborn (HDFN).

Methods

We retrospectively analyzed the data for 17 infants with anti-M-induced HDFN (anti-M-HDFN) diagnosed between June 2013 and May 2019. Their maternal history, neonatal diagnosis on admission, and laboratory test results were compared with those of 15 infants with HDFN involving the ABO blood group system, 15 infants with HDFN involving the Rh system, and 15 premature infants.

Results

In the anti-M-HDFN group, 94.12% (16/17), 35.29% (6/17), and 17.65% (3/17) had free antibodies in plasma, a positive direct antiglobulin test, and a positive elution test, respectively. In 12 infants, free antibody reactions were stronger at 4°C than at 37°C, and the antibody titer at 4°C ranged from 1 to 512. All 17 infants with anti-M-HDFN developed anemia: 14 were treated with blood transfusion and 1 with neonatal exchange transfusion. Sixteen infants improved, and one died. Anti-M-HDFN had a higher rate of maternal stillbirth, lower gestational age, lower birthweight, and higher incidence of respiratory distress than other HDFN types.

Conclusion

Anti-M may cause HDFN. It may present with varying degrees of anemia, low regenerative anemia, and low bilirubin levels. In addition, infants with anti-M-HDFN may have a negative elution test and direct antiglobulin test. These tests are helpful in examining antibody responses at a low temperature of 4°C.     

Microsatellite markers within --SEA breakpoints for prenatal diagnosis of HbBarts hydrops fetalis

BACKGROUND: We sought to develop a rapid prenatal diagnostic test for simultaneous detection of HbBarts hydrops fetalis and exclusion of maternal contamination. METHODS: We developed a multiplex quantitative fluorescent PCR (QF-PCR) test that detects the presence/ absence of 2 microsatellite markers (16PTEL05/16PTEL06) located within breakpoints of the Southeast Asia ((-SEA)) deletion. HbBarts hydrops fetalis ((-SEA/-SEA)) is diagnosed by absence of both markers, and maternal contamination of fetal DNA is excluded by absence of noninherited maternal alleles. Fetal and parental DNA samples from 50 families were analyzed in a blinded clinical validation study, and QF-PCR results were compared with their respective molecular genotypes. RESULTS: The multiplex QF-PCR results included correct diagnoses of HbBarts hydrops fetalis in 11 of the fetuses tested, correct verification as unaffected in 20 fetuses, and correct identification as either carriers (alphaalpha/(-SEA)) or unaffected homozygotes in 18. Misidentification as unaffected occurred for 1 carrier. Sensitivity for diagnosis of HbBarts hydrops fetalis was 100% [lower 95% confidence interval, 76.2%], and specificity was 100% (lower 95% confidence interval, 92.6%). None of the samples tested showed any traces of noninherited maternal alleles; thus false-positives because of maternal contamination were eliminated. CONCLUSIONS: In this QF-PCR method, detection of maternally and paternally inherited fetal alleles allowed diagnosis of the double-deletion syndrome, and the ability to differentiate between these alleles allowed simultaneous exclusion of maternal contamination of the fetal genetic material. This novel strategy using cell-free fetal DNA in maternal plasma could form the basis for noninvasive testing for HbBarts hydrops fetalis.     

Comparison of automated solid phase versus manual saline indirect antiglobulin test methodology for non-ABO antibody titration: Implications for perinatal antibody monitoring

Background

Accurate antibody titration is crucial in prenatal evaluations to identify patients who need clinical monitoring for hemolytic disease of the fetus and newborn (HDFN) causing fetal anemia. This study compares the established gold standard method of manual tube saline indirect antiglobulin testing (SIAT) with the newer automated solid phase (ASP) method of antibody titration and aims to establish the critical titer threshold for ASP that corresponds to the previously established SIAT critical threshold of ≥16 used in our laboratory.

Study Design and Methods

One hundred fifty-seven prenatal and donor plasma samples with known antibodies were tested using both SIAT and ASP methodologies and results were compared.

Results

The study found that ASP titers were, on average, 1.33 dilutions higher than SIAT titers. The critical titer cutoff for ASP was determined to be ≥32, which is one tube higher than the SIAT cutoff of ≥16.

Discussion

The ASP method for antibody titration offers greater reproducibility and efficiency compared with manual SIAT titration. This study suggests that a titer cutoff of ≥32 is appropriate for most clinically significant antibodies using ASP. However, further research is needed to determine the comparability of ASP with SIAT in samples with multiple antibodies, anti-M antibodies, and other less common antibodies. Validation of the ASP titer cutoff against HDFN clinical outcomes is required before implementing this test for routine use in perinatal antibody titration.