Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

Approach to red blood cell antibody testing during pregnancy: Answers to commonly asked questions.

OBJECTIVE: To provide family physicians with an understanding of blood bank tests performed during pregnancy. The value of routine blood type and antibody tests, as well as the follow-up required when a patient develops a red blood cell antibody or experiences a fetal-maternal hemorrhage (FMH) will be reviewed. SOURCES OF INFORMATION: The approach described is based on the authors' clinical expertise and peer-reviewed literature from 1967 to 2020. MAIN MESSAGE: An ABO and RhD group and antibody screen test is performed on every pregnant patient during the first trimester. Although antibodies to red blood cell antigens occur infrequently, some can lead to substantial adverse fetal or neonatal consequences including hemolytic disease of the fetus and newborn. Early identification and quantification of important antibodies ensures that at-risk mothers are referred to and followed by obstetricians experienced with high-risk care. Another valuable and related test is the FMH test. For RhD-negative women, these tests are performed at every delivery and following antepartum events that could contribute to FMH. This test determines the number of fetal red blood cells in the maternal circulation and is used to determine the dose of Rh immune globulin an RhD-negative mother requires to prevent alloimmunization to fetal RhD. CONCLUSION: An understanding of blood bank tests performed during pregnancy and their role and limitations is vital to optimal practice and aids clinicians in their decision making. When there is doubt or confusion regarding antenatal testing or immunoprophylaxis, consult the regional laboratory or transfusion medicine specialists for additional guidance.

Two cases of asymptomatic massive fetomaternal hemorrhage.

Evaluation of fetomaternal hemorrhage (FMH) in the immediate postpartum period is critical for the timely administration of Rh immunoglobulin (RhIG) prophylaxis to minimize the risk of alloimmunization in D-negative mothers of D-positive newborns. We report a series of two clinically-unsuspected cases of massive FMHs identified at our university medical center. Retrospective records of two cases of massive FMH were investigated using the electronic medical record. After positive fetal bleed screens, flow cytometric analysis for hemoglobin F was performed to quantify the volume of the hemorrhages in both cases. Flow cytometric enumeration with anti-D was also performed in one case. The two patients had 209.5 and 75 mL of fetal blood in circulation, resulting in 8 and 4 doses of RhIG administered, respectively. For the former patient, flow cytometric analysis with anti-D ruled out hereditary persistence of fetal hemoglobin and supported the fetal origin of the red cells. Due to the clinically-silent nature of both hemorrhages, further evaluation of the newborns' blood was not performed. These cases highlight the importance of rapidly obtaining accurate measurements of fetal blood loss via flow cytometric analysis in cases of FMH, particularly in clinically-unsuspected cases, to ensure timely administration of adequate immunoprophylaxis to D-negative mothers.

Anti-D alloimmunisation in pregnant women with DEL phenotype in China.

OBJECTIVES: To analyse anti-D alloimmunisation in pregnant women with D-elute (DEL) phenotype in China, for developing a predictive model to evaluate whether a person with the DEL phenotype can receive RhD-positive blood. BACKGROUND: Alloanti-D acquired by pregnancy or transfusion is one of the major causes of both haemolytic disease among newborns and haemolytic transfusion reactions. To date, there is little data available about the antigenic properties and immunogenicity of extremely weak D variants known as DEL. METHODS: RHD genotyping and D epitope mapping were performed using gene sequencing and comprehensive immunohaematological methods, respectively. DEL pregnant women carrying an RhD-positive fetus were tested for the presence of alloanti-D. RESULTS: A total of 130 of 142 (91·5%) pregnant women with a DEL phenotype were confirmed to carry the RHD (K409K) allele. Among 12 DEL women who appeared to have RHD-CE-D hybrid alleles, there were 1 RHD-CE (4-7)-D, 7 RHD-CE(4-9)-D, and 4 RHD-CE (2-5)-D alleles. Alloanti-D antibodies were detected in 6 of 142 DEL women, and all the six women had the partial DEL phenotype. CONCLUSION: The data indicate that partial DEL women appear at risk of alloimmunization to the D antigen. RhD immune globulin prophylaxis is necessary for partial DEL women. Partial DEL patients should receive only RhD-negative RBCs, whereas DEL patients with complete expression of antigen can safely receive RhD-positive RBCs.

Screening for HLA antibodies in plateletpheresis donors with a history of transfusion or pregnancy.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is known as a life-threatening complication of transfusion. HLA and HNA antibodies have been associated with the immune pathway of TRALI. Since donors with a history of transfusion and/or pregnancy are presumed to have an increased risk of carrying such antibodies, we investigated the association of a history of transfusion or pregnancy with the occurrence of HLA alloimmunization in our donor population. STUDY DESIGN AND METHODS: A total of 1018 female plateletpheresis donors and male plateletpheresis donors with a history of transfusion were enrolled in the study. Included donors were systematically screened, using Luminex technology, for anti-HLA Class I and II. The association of donor history with HLA alloimmunization status was analyzed. RESULTS: The overall alloimmunization rate was 20.2%. In 0.0% of the nulliparous transfused female donors and in 1.3% of the transfused male donors, anti-HLA were detected. Thirty-one percent of the parous women versus 4.2% of the nulliparous women screened positive for anti-HLA. The rate of HLA alloimmunization increased with parity. CONCLUSION: Our data indicate that a history of transfusion is a minor risk factor for immunization against HLA antigens. In contrast, former pregnancies constitute a major risk factor for the development of HLA antibodies. Since HLA alloimmunization rate increases with parity, TRALI risk reduction measures should focus on this particular donor population. Repeated testing of female plateletpheresis donors after each pregnancy is implemented in our blood service.

Assessment of feto-maternal hemorrhage among rhesus D negative pregnant mothers using the kleihauer-betke test (KBT) and flow cytometry (FCM) in Addis Ababa, Ethiopia.

BACKGROUND: This study aimed to assess fetomaternal hemorrhage (FMH) among RhD negative pregnant mothers using two techniques, Kleihauer-Betke (KBT) and Flow cytometry (FCM). To determine if patient-specific doses of prophylactic anti-D warrant further investigation in Ethiopia and wider Africa. METHODS: Hospital- based cross-sectional study was conducted among 75 RhD negative pregnant mothers using convenient sampling technique. RESULT: FMH has been detected in 52% and 60% by KBT and FCM techniques, respectively. The volume of FMH quantified in the majority of the cases (92.5% and 87%) was <10 mL fetal blood while >30 mL in 1.3% (1/75) and 2.7% (2/75) as calculated by KBT and FCM, respectively. The FMH calculated by the two methods have good correlation; r = 0.828 (p = 0.000) for categorized and r = 0.897 (p = 0.000) for continuous values and the agreement between the FCM and KBT was moderate with kappa (κ) value of 0.53 (p = 0.000). CONCLUSION: Most of FMH calculated (<10 mL) could have been neutralized by lower doses which might have lower costs than administering 300 µg dose which is currently in practice in our country for affording mothers. Besides, it also showed that the volume of FMH was >30 mL in 1.3% and 2.7% of the cases as calculated by KBT and FCM, respectively, which need more than 300 µg dose RhIG for neutralization. Further investigation into the cost- effectiveness and scalability of patient- specific dosing of prophylactic anti-D appears warranted.

Usefulness of maternal anti-HPA-1a antibody quantitation in predicting severity of foetomaternal alloimmune thrombocytopenia.

OBJECTIVE: To study the clinical usefulness of maternal anti-HPA-1a antibody levels in predicting severe foetomaternal alloimmune thrombocytopenia (FMAIT). BACKGROUND: Recent studies using an international anti-HPA-1a standard have shown a correlation between maternal antibody levels and neonatal thrombocytopenia. Cut-off values for identifying high-risk pregnancies have also been suggested. MATERIALS: In 1986-2010, HPA-1a alloimmunisation was confirmed in 84 women with 129 pregnancies. Maternal samples were obtained at delivery and during subsequent pregnancies. Anti-HPA-1a was quantified using a MAIPA assay with a detection limit of 0·8 IU mL(-1) (WHO reference serum 03/152). Antibody levels were compared with the severity of neonatal disease in the index and in the subsequent pregnancies. RESULTS: In the index cases, the correlation between an anti-HPA-1a level and neonatal platelet count did not reach statistical significance (n = 77, P = 0·074). However, the platelet counts and antibody levels in cases with cutaneous (n = 45) or intracranial haemorrhage (n = 7) were significantly different from cases with no evidence of bleeding (n = 20). In the subsequent pregnancies, there was a stronger association between the second trimester anti-HPA-1a level and the foetal platelet count (n = 16, P = 0·046). The positive predictive value of the maternal antibody level for a foetal platelet count <20 × 10(9) L(-1) was 90%, but the negative predictive value only 31%. CONCLUSION: Although a higher anti-HPA-1a level correlated with a more severe neonatal disease, barely detectable antibody levels were also observed in severely affected pregnancies. Cut-off values with sufficient sensitivity and specificity to identify these foetuses could not be found. A previous obstetric history still remains the most useful predictive parameter for severe FMAIT in clinical practice.

[Guideline for prevention of RhD alloimmunizationin RhD negative women]. / Doporucení k provádení prevence RhD aloimunizace u RhD negativních zen.

Events following which immunoglobulin (Ig) G anti-D should be given to all RhD negative women with no anti-D alloantibodies: First trimester indications (IgG anti-D sufficient dose of 50 µg*) - termination of pregnancy, spontaneous abortion followed by instrumentation, ectopic pregnancy, chorionic villus sampling, partial molar pregnancy; Second and third trimester indications (IgG anti-D sufficient dose of 100 µg*) - amniocentesis, cordocentesis, other invasive prenatal diagnostic or therapeutic procedures, spontaneous or induced abortion, intrauterine fetal death, attempt at external cephalic version of a breech presentation, abdominal trauma, obstetric hemorrhage; Antenatal prophylaxis at 28th weeks of gestation (IgG anti-D sufficient dose of 250 µg*); Delivery of an RhD positive infant** (IgG anti-D sufficient dose of 100 µg*); Minimal dose*: before 20 weeks gestation - 50 µg (250 IU), after 20 weeks gestation*** - 100 µg (500 IU); Timing: as soon as possible, but no later than 72 hours after the event. In cases where prevention of RhD alloimmunization is not performed within 72 hours of a potentially sensitising event, it is still reasonable to administer IgG anti-D within 13 days, and in special cases, administration is still recommended up to a maximum interval of 28 days postpartum; Legend: *administration of a higher dose of IgG anti-D is not a mistake, ** also if the D type is not known, *** simultaneous assessment of the volume of fetomaternal hemorrhage (FMH) to specify the dose is suitable; The FMH volume assessment - If the volume of fetal erythrocytes (red bood cells, RBCs) which entered maternal circulation is assessed, intramuscular administration of IgG anti-D in a dose of 10 µg per 0.5 mL of fetal RBCs or 1 mL of whole fetal blood is indicated. IgG anti-D in a dose of 10 µg administered intramuscularly should cover 0.5 mL of fetal RhD positive RBCs or 1mL of whole fetal blood. FMH is the fetal RBC volume; fetal blood volume is double (expected fetal hematocrit is 50%).

Maternal red blood cell alloimmunisation in south western Uganda.

AIMS/OBJECTIVES: To identify the frequency and nature of maternal red blood cell (RBC) alloimmunisation in Uganda and to determine the prevalence of RhD negativity and the rate of RBC alloimmunisation in Ugandan pregnant women. BACKGROUND: Haemolytic disease of the foetus and newborn (HDFN) results from maternal alloimmunisation following exposure to allogeneic RBCs during pregnancy or blood transfusion. The prevalence of maternal RBC alloimmunisation in Ugandans is not known. MATERIALS AND METHODS: Pregnant women at Mbarara Hospital, South Western Uganda, were investigated in a cross-sectional study. Demographics, transfusion and obstetric histories were recorded. Maternal RBC alloimmunisation was demonstrated using immunohaematological techniques. RESULTS: A total of 2001 pregnant women were recruited; 3.6% of them being RhD negative. Forty-five women (2.2%; 95% CI: 1.6-2.9) were found to be alloimmunised to RBC antigens. There were 38 RBC alloantibodies of known specificity including anti-S, 12; anti-M, 11; anti-Le(a) , 6; anti-D, 4 and 1 each of anti-K, anti-Fy(b) , anti-Jk(a) , anti-Lu(a) and anti-Kp(a) . In two women (4.4%), there were antibody combinations (anti-M+S and anti-K+Kp(a) ). Obstetric history, gestational age and previous immunising events were not significantly associated with the rate of alloimmunisation. CONCLUSIONS: This study revealed a maternal RBC alloimmunisation rate of 2.2% which was comparable with findings from a Zimbabwean study where the prevalence was 1.7%. Given the 6·0% prevalence of anti-D among RhD-negative women in our study and the high immunogenicity of the D antigen, programmes for preventing anti-D alloimmunisation and HDFN in Uganda should be considered seriously.

Peanut allergy: is maternal transmission of antigens during pregnancy and breastfeeding a risk factor?

BACKGROUND: Peanut allergy is an important public health problem in western countries. However, the risk factors associated with this allergy remain uncertain. OBJECTIVE: To determine whether the consumption of peanuts during pregnancy and breastfeeding is a risk factor for peanut allergy in infants. METHODS: We enrolled 403 infants in a case-control study. The cases were infants aged 18 months or less with a diagnosis of peanut allergy based on a history of clinical reaction after exposure to peanuts and the presence of peanut-specific immunoglobulin E. Controls were age-matched infants with no known clinical history or signs of atopic disease. The mothers of the children filled out a detailed questionnaire about maternal diet during pregnancy and breastfeeding, the infant's diet, the presence of peanut products in the infant's environment, and family history of atopy. RESULTS: The mean (SD) age of cases was 1.23 (0.03) years. The groups were comparable in terms of the rate and duration of breastfeeding. However, the reported consumption of peanuts during pregnancy and breastfeeding was higher in the case group and associated with an increased risk of peanut allergy in offspring (odds ratio [OR], 4.22 [95% confidence interval [CI], 1.57-11.30 and OR, 2.28 [95% CI, 1.31-3.97] for pregnancy and breastfeeding, respectively). Overall, the infants with peanut allergy did not seem to be more exposed to peanut products in their environment than the controls. CONCLUSION: Early exposure to peanut allergens, whether in utero or through human breast milk, seems to increase the risk of developing peanut allergy.

Scleroderma.

The prototypic autoimmune diseases involving skin (lupus, dermatomyositis) typically result in epithelial injury and autoantibodies to characteristic cellular antigens. Disease-specific autoantibodies are also found in scleroderma, but scleroderma is different from other cutaneous autoimmune diseases because epithelial injury does not occur. Multiple factors and combinations of factors (immune system, vascular and extracellular matrix abnormalities) are the most likely triggers in an individual with a genetic predisposition to scleroderma. These lead to increased synthesis of normal collagen in skin, lungs and gut in the systemic form of scleroderma, systemic sclerosis. The hypotheses for the pathophysiology of scleroderma are diverse and include abnormal immunologic processes such as cytokine and chemokine dysregulation, abnormal T cell signaling, B cell dysfunction, injury due to autoantibodies to endothelial cells, persistent wound healing condition due to dysregulation of matrix homeostasis, abnormalities in the fibrinolytic system, polymorphisms in critical molecules of the immune system and matrix homeostasis, and microchimerism due to fetal/maternal placental exchange of HLAcompatible cells. Systemic sclerosis/scleroderma is chronic and progressive. To date, no definitive therapy is effective for any of the scleroderma variants, although agents for the vascular dysfunction have some utility. Hematopoietic bone marrow or stem cell transplantation before significant tissue fibrosis has occurred may be the most effective treatment.

Fetal-maternal microchimerism in normal parous females and parous female cancer patients.

OBJECTIVE: The prevalence of male microchimerism (MC) in parous females, nonparous females, and parous female cancer patients was examined. MATERIALS AND METHODS: DNA extracted from peripheral blood leukocytes and male Y-chromosomal DNA was amplified using a sensitive two-stage polymerase chain reaction technique. Controls prepared by mixing human male and female cell lines demonstrated the sensitivity of the technique to be in the range of 1 male cell per 1 million female cells. RESULTS: Findings of this study showed that the percentage of MC-positive females was highly dependent on the amount of DNA analyzed; 57% of normal parous females who bore at least one son were found to have male cells in their blood when 25 mug DNA or more from the samples was analyzed. This frequency is much higher than previous reports indicating a prevalence of 33% for normal parous females. Analysis of samples obtained from 200 parous female cancer patients revealed an incidence of 34% MC(+); 7.4% of normal nonparous female controls had evidence of MC. CONCLUSION: The long-term persistence of male cells in the maternal circulation could indicate maternal immune tolerance of paternally inherited fetal antigens. This maternal tolerance might be exploited in female patients with malignant disease to deliver immune cellular therapy from their sons.

"Provoked" feto-maternal hemorrhage may represent insensible cell exchange in pregnancies from 6 to 22 weeks gestational age.

OBJECTIVE: To quantify spontaneous and provoked fetal to maternal cell exchange in the first half of pregnancy. Transfer of fetal red blood cells (FRBCs) into the maternal circulation during the first half of pregnancy is poorly characterized but of clinical relevance for miscarriage management and invasive procedures. STUDY DESIGN: Prospective, descriptive cohort study of women presenting for surgical termination of pregnancy with sonographically confirmed gestational age (GA). Pre-procedural and post-procedural blood samples were collected to characterize both spontaneous (pre) and provoked (post) cell exchange with analysis via flow cytometry to quantify FRBC count. RESULTS: A total of 100 patients at 6-22 weeks GA contributed 200 matched pre- and post-procedural samples. FRBCs were identified in 69 patients including 4 who exhibited FRBCs pre-procedure only and 9 post-procedure only, for a total of 65 patients having post-procedural FRBCs. Of patients with FRBCs following their procedure, the majority (n=56, 86%) also exhibited evidence of cells before the procedure with just 9 patients (14%) exhibiting FRBCs only after. No dose-response relationship was appreciable between GA and FRBC count. CONCLUSION: After experiencing disruption of the placenta with instrumentation, roughly two thirds of patients had detectable FRBCs in maternal circulation following their procedure but-among those that did-the majority also exhibited cell presence prior to the procedure. This leads to further questions regarding the relationship between risk events and alloimmunization potential in previable pregnancies as the rate of spontaneous transplacental cell exchange may be underappreciated and the magnitude of provoked transfer may be overestimated. IMPLICATIONS: The relationship between feto-maternal hemorrhage risk events and alloimmunization potential in previable pregnancies has previously been poorly characterized but these data reveal spontaneous transplacental cell exchange may be underappreciated and the magnitude of provoked transfer may be overestimated.

Evaluation of Automatic Blood Analyzer as Screening Method in Fetomaternal Hemorrhage.

Screening of fetomaternal hemorrhage (FMH) is essential in management of fetomaternal antigen incompatibilities of blood. The objective in this study was to evaluate the ability of automatic blood analyzer (ABA) to screen FMH, also comparing this method with flow cytometry (FCM). The contents of fetal red blood cells and fetal hemoglobin were evaluated by FCM and ABA, respectively, using both blood samples of male adults laced with umbilical cord blood diluted at 1/10, 1/100, 1/1,000, and 1/10,000, or blood from puerperal women collected within 48 hours following delivery. FCM had better performance (area under curve, AUC = 0.8723) than ABA (AUC = 0.6569) in detecting fetal blood laced with blood from male adults. At a critical level of 0.5%, ABA indicated that 27.5% of puerperal women would have FMH while FCM did not detect FMH. Our results showed that ABA overestimates FMH and disagrees with FCM on indicating puerperal women with FMH. ABA is inadequate for being used to screen for or to measure FMH.

A combined flow cytometry-based method for fetomaternal hemorrhage and maternal D.

BACKGROUND: The fetomaternal bleed assay by flow cytometry is a semiquantitative test used to determine the volume of fetomaternal hemorrhage (FMH). We have enhanced this method by combining the fetomaternal bleed assay with a D antibody in the same tube to determine the maternal D as well as the need for Rh immune globulin (RhIG) administration. STUDY DESIGN AND METHODS: The performance of the FMB/D assay was compared against the Kleihauer-Betke (KB) acid elution method for the quantitation of fetal bleed and tube method for the maternal D determination. Peripheral blood cells from the pregnant women were fixed and permeabilized, incubated with monoclonal antibodies directed against fetal hemoglobin (Hb F) and D, and analyzed by flow cytometry. The relative concentration of Hb F-containing cells to adult cells was used to determine the volume of the FMH. In addition, the cells were identified as D+ or D-. RESULTS: D typing of nonpregnant adult donors matched in all cases with the tube method with a mean value of 0.01% Hb F-positive cells (n = 25). D typing of pregnant or postpartum samples matched in all cases (n = 100), and the RhIG dose calculated by the percentage of Hb F for each method matched 97 percent (n = 36; p = 0.324). The one discrepant sample was consistent with the acknowledged overestimation when using the KB method. CONCLUSION: The highly precise anti-Hb F flow cytometric method was combined with maternal D determination by anti-D. This method correlates well with standard assays eliminating the need for additional testing without sacrificing clinical information.

The assessment of feto-maternal hemorrhage in an artificial model using anti-D and anti-fetal hemoglobin antibody by flow cytometry.

BACKGROUND: When fetal red cells enter the maternal circulation from placenta, an event would be happened that is described as feto-maternal hemorrhage (FMH). This life-threatening condition could be detected by using RBC antigens (surface antigens and intracellular antigens). Therefore, the measurement of fetal RBC in an artificial model would be useful to calculate FMH and consequently the dosage of Rhogam for prophylaxis. The aim of the present study was to evaluate FMH in an artificial mixture model. METHODS: A series of 40 artificial specimens were prepared consisting of Rh(D) negative adult blood (non-immunized) spiked with varying amounts of Rh(D) positive cord blood from mothers between 20-30 years old in Shahid Beheshti Hospital, Tehran, Iran. Monoclonal anti-D and anti-HbF (fetal hemoglobin) were used for detection of fetal RBC in artificial mixture sample modeling. RESULTS: This study showed that the percentage of fetal cells in artificial sample for anti-D antigen is in ranges of 0.28%-0.32% for a 0.25% dilution mixture, and 1.3%-2.05% for the mixture with dilution 2%. In addition, the ranges of data for anti-HbF staining was obtained 0.2%-0.34% for the 0.25% dilution sample, and the ranges of 1.04-1.8% for the 2% dilution. The regression analysis indicated that the correlation of anti-D assessment with expected standard method was r2 = 0.9672 and anti-HbF assessment was r2 = 0.8842. CONCLUSION: Although both molecule targets could be used for detection of fetal RBC, in this model, anti-D staining was more accurate than anti-HbF staining. However, since anti-D can not be utilized for low-density or weak phenotype and other incompatibility, the anti-HbF labeling could be used for all FMH.

ACOG Practice Bulletin No. 192 Summary: Management of Alloimmunization During Pregnancy.

When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal-maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies, or "alloimmunization," may lead to various degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antigenicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of alloimmunization is addressed in another Practice Bulletin ().

ACOG Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy.

When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal-maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies, or "alloimmunization," may lead to various degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antigenicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of alloimmunization is addressed in another Practice Bulletin ().