Non-RhD alloimmunization in pregnancy: an updated review.

RhD alloimmunization in pregnancy is still the main cause of hemolytic disease of the fetus and neonate (HDFN). Nevertheless, there are other antigens that may be associated with the occurrence of this phenomenon and that have been growing in proportion, given that current prevention strategies focus only on anti-RhD antibodies. Although not widespread, the screening and diagnostic management of the disease caused by these antibodies has recommendations in the literature. For this reason, the following review was carried out with the objective of listing the main red blood cell antigen groups described - such as Rh, ABO, Kell, MNS, Duffy, Kidd, among others - addressing the clinical importance of each one, prevalence in different countries, and recommended management when detecting such antibodies during pregnancy.

Receipt of RhD-positive whole blood for life-threatening bleeding in female children: A survey in alloimmunized mothers regarding minimum acceptable survival benefit relative to risk of maternal alloimmunization to anti-D.

BACKGROUND: Low-titer group O whole blood (LTOWB) for treatment of hemorrhagic shock sometimes necessitates transfusion of RhD-positive units due to short supply of RhD-negative LTOWB. Practitioners must choose between using RhD-positive LTOWB when RhD-negative is unavailable against the risk to a female of childbearing potential of becoming RhD-alloimmunized, risking hemolytic disease of the fetus and newborn (HDFN) in future children, or using component therapy with RhD-negative red cells. This survey asked females with a history of red blood cell (RBC) alloimmunization about their risk tolerance of RhD alloimmunization compared to the potential for improved survival following transfusion of RhD-positive blood for an injured RhD negative female child. STUDY DESIGN AND METHODS: A survey was administered to RBC alloimmunized mothers. Respondents were eligible if they were living in the United States with at least one red cell antibody known to cause HDFN and if they had at least one RBC alloimmunized pregnancy. RESULTS: Responses from 107 RBC alloimmmunized females were analyzed. There were 32/107 (30%) with a history of severe HDFN; 12/107 (11%) had a history of fetal or neonatal loss due to HDFN. The median (interquartile range) absolute improvement in survival at which the respondents would accept RhD-positive transfusions for a female child was 4% (1%-14%). This was not different between females with and without a history of severe or fatal HDFN (p = .08 and 0.38, respectively). CONCLUSION: Alloimmunized mothers would accept the risk of D-alloimmunization in a RhD-negative female child for improved survival in cases of life-threatening bleeding.

Rh immune globulin immunoprophylaxis after RhD-positive red cell exposure in RhD-negative patients via transfusion: A survey of practices.

BACKGROUND: Current Association for the Advancement of Blood & Biotherapies (AABB) standards require transfusion services to have a policy on Rh immune globulin (RhIG) immunoprophylaxis for when RhD-negative patients are exposed to RhD-positive red cells. This is a survey of AABB-accredited transfusion services in the United States (US) regarding institutional policies and practices on RhIG immunoprophylaxis after RhD-negative patients receive RhD-positive (i.e., RhD-incompatible) packed red blood cell (pRBC) and platelet transfusions. RESULTS: Approximately half of the respondents (50.4%, 116/230) have policies on RhIG administration after RhD-incompatible pRBC and platelet transfusions, while others had policies for only pRBC (13.5%, 31/230) or only platelet (17.8%, 41/230) transfusions, but not both. In contrast, 18.3% (42/230) report that their institution has no written policies on RhIG immunoprophylaxis after RhD-incompatible transfusions. Most institutions (70.2%, 99/141) do not have policies addressing safety parameters to mitigate the risk of hemolysis associated with the high dose of RhIG required to prevent RhD alloimmunization after RhD-incompatible pRBC transfusions. DISCUSSION: With approximately half of US AABB-accredited institutions report having policies on RhIG immunoprophylaxis after both RhD-incompatible pRBC and platelet transfusions, some institutions may not be in compliance with AABB standards. Further, most with policies on RhIG immunoprophylaxis after RhD-incompatible pRBC transfusion do not have written safeguards to mitigate the risk of hemolysis associated with the high dose of RhIG required. CONCLUSION: This survey underscores the diverse and inadequate institutional policies on RhIG immunoprophylaxis after RhD exposure in Rh-negative patients via transfusion. This observation identifies an opportunity to improve transfusion safety.

Neurosonographic Findings in Infants with Rhesus Hemolytic Disease of Newborn: A Prospective Observational Study.

We estimated the incidence of intraventricular hemorrhage (IVH) and/or periventricular leukomalacia/echogenicity (PVL/E) in Rhesus isoimmunized infants. Seventy-one infants underwent cranial ultrasound within the first 3 days of life or discharge, whichever was earlier. Of these, 27 (38%) infants had IVH/ PVL/E. On multivariate analysis, lower gestational age (P = 0.035), small for gestational age [aOR (95% CI) 10.6 (1.9, 58.9)], and sepsis [aOR (95% CI) 4.5 (1.1, 18.4)] were independently associated with IVH/PVL.

Guideline No. 448: Prevention of Rh D Alloimmunization.

OBJECTIVE: This guideline provides recommendations for the prevention of Rh D alloimmunization (isoimmunization) in pregnancy, including parental testing, routine postpartum and antepartum prophylaxis, and other clinical indications for prophylaxis. Prevention of red cell alloimmunization in pregnancy with atypical antigens (other than the D antigen), for which immunoprophylaxis is not currently available, is not addressed in this guideline. TARGET POPULATION: All Rh D-negative pregnant individuals at risk for Rh D alloimmunization due to potential exposure to a paternally derived fetal Rh D antigen. OUTCOMES: Routine postpartum and antepartum Rh D immunoprophylaxis reduces the risk of Rh D alloimmunization at 6 months postpartum and in a subsequent pregnancy. BENEFITS, HARMS, AND COSTS: This guideline details the population of pregnant individuals who may benefit from Rho(D) immune globulin (RhIG) immunoprophylaxis. Thus, those for whom the intervention is not required may avoid adverse effects, while those who are at risk of alloimmunization may mitigate this risk for themselves and/or their fetus. EVIDENCE: For recommendations regarding use of RhIG, Medline and Medline in Process via Ovid and Embase Classic + Embase via Ovid were searched using both the trials and observational studies search strategies with study design filters. For trials, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects via Ovid were also searched. All databases were searched from January 2000 to November 26, 2019. Studies published before 2000 were captured from the grey literature of national obstetrics and gynaecology specialty societies, luminary specialty journals, and bibliographic searching. A formal process for the systematic review was undertaken for this update, as described in the systematic review manuscript published separately. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the SOGC's modified GRADE approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: The intended users of this guideline include prenatal care providers such as obstetricians, midwives, family physicians, emergency room physicians, and residents, as well as registered nurses and nurse practitioners. TWEETABLE ABSTRACT: An updated Canadian guideline for prevention of Rh D alloimmunization addresses D variants, cffDNA for fetal Rh type, and updates recommendations on timing of RhIG administration. SUMMARY STATEMENTS: RECOMMENDATIONS.

Guide to Rho(D) Immune Globulin in Women With Molecularly Defined Asian-type DEL (c.1227G>A).

Rh hemolytic disease of the fetus and newborn is a potential risk for D-negative mothers who produce anti-D during pregnancy, which can lead to morbidity and mortality in subsequent pregnancies. To prevent this hemolytic disease, Rho(D) immune globulin (RhIG) is generally administered to D-negative mothers without anti-D at 28 weeks of gestation and shortly after delivery. However, current guidelines suggest that pregnant mothers with molecularly defined weak D types 1, 2, 3, 4.0, and 4.1 do not need RhIG as they are unlikely to produce alloanti-D when exposed to fetuses with D-positive red cells. This issue and the necessity of RHD genotyping have been extensively discussed in Western countries, where these variants are relatively common. Recent evidence indicates that women with Asian-type DEL (c.1227G>A) also do not form alloanti-D when exposed to D-positive red cells. We report that mothers with molecularly defined Asian-type DEL, similar to those with weak D types 1, 2, 3, 4.0, and 4.1, do not require RhIG before and after delivery. Collectively, this review could pave the way for the revision of international guidelines to include the selective use of RhIG based on specific genotypes, particularly in women with the Asian-type DEL.

Low titer group O whole blood and risk of RhD alloimmunization: Rationale for use in Finland.

BACKGROUND: Prehospital low-titer group O whole blood (LTOWB) used for patients with life-threatening hemorrhage is often RhD positive. The most important complication following RhD alloimmunization is hemolytic disease of the fetus and newborn (HDFN). Preceding clinical use of RhD positive LTOWB, we estimated the risk of HDFN due to LTOWB prehospital transfusion in the Finnish population. STUDY DESIGN AND METHODS: We collected data on prehospital transfusions in Tampere and Helsinki University Hospital areas. Using the mean of reported alloimmunization rates in trauma studies (24%) and a higher reported rate representing trauma patients of 13-50 years old (42.7%), we estimated the risk of HDFN and extrapolated it to the whole of Finland. RESULTS: We estimated that in Finland, with the current prehospital transfusion rate we would see 1-3 cases of severe HDFN due to prehospital LTOWB transfusions every 10 years, and fetal death due to HDFN caused by LTOWB transfusion less than once in 100 years. DISCUSSION: The estimated risk of serious HDFN due to prehospital LTOWB transfusion in the Finnish population is similar to previous estimates. As Finland routinely screens expectant mothers for red blood cell antibodies and as the contemporary treatment of HDFN is very effective, we support the prehospital use of RhD positive LTOWB in all patient groups.

Prevention of Rhesus-D Alloimmunization in the First Trimester of Pregnancy: Economic Analysis of Three Management Strategies.

Anti-D alloimmunization in the first trimester of pregnancy has long been the subject of prevention with anti-D immunoglobulins during events at risk of fetomaternal hemorrhage. Although the efficacy of preventing anti-D alloimmunization by an injection of immunoglobulin at 28 weeks of gestation (WG) is obvious, the literature provides little evidence of the effectiveness before 12+6 WG and several countries have modified their recommendations. In the presumed absence of a difference in alloimmunization risk between early and late prevention, our objective was to evaluate and compare the cost of treatment for 3 alloimmunization prevention strategies in France, the United Kingdom, and the Netherlands. This was a single-center retrospective study. Our target population included all women who received anti-D immunoglobulins (Rhophylac) in the first trimester of pregnancy before 12+6 WG at Nantes University Hospital in 2018 (N = 356). Within the target population, 2 other populations were constituted based on British (N = 145) and Dutch (N = 142) clinical practice guidelines (CPG). These 3 populations were analyzed for the comparative cost of treatment for prevention from a health system perspective. The average cost of Rhophylac alloimmunization prevention for 1 episode was €117.8 from a health system perspective. The total cost attributed to prevention in 2018 at Nantes University Hospital (N = 356) was €41,931.4 according to this perspective. If the UK CPG or Dutch CPG had been applied to the Nantes target population, a saving of around 60% would have been achieved. At the national level, the cost according to the health system perspective specifically attributable to induced abortion (N estimated = 26,916) could represent a total cost of €3,170,704. This study highlighted the high cost of the French prevention strategy in the first trimester of pregnancy compared with British or Dutch strategies. The modification of our practices would allow substantial financial savings to the French health system but would also avoid the nonrecommended exposure to a blood product at this term, would allow a faster medical management and a relief of the care system.

Fetal Anemia: Determinants and Perinatal Outcomes according to the Method of Intrauterine Blood Transfusion.

INTRODUCTION: Fetal anemia from hemolytic disease treated by intrauterine transfusion (IUT) can be performed by intraperitoneal, intracardiac, and intravascular transfusion (IVT). Objective of our study was to compare different transfusion techniques. METHODS: Retrospective review of IUT secondary to red cell alloimmunization was conducted at eight international centers from 2012 to 2020. Severe anemia suspected if middle cerebral artery peaks systolic velocity ≥1.5 multiples of the median. Demographic, delivery, and postnatal variables were analyzed. RESULTS: Total of 344 procedures, 325 IVT and 19 other techniques (non-IVT) included. No difference in demographics, history of stillbirth (20.5 vs. 15.8%, p = 0.7), prior pregnancy IUT (25.6 vs. 31.6%, p = 0.5) or neonatal transfusion (36.1 vs. 43.8%, p = 0.5). At first IUT, non-IVT had higher hydrops (42.1% vs. 20.4%, p = 0.03), lower starting hematocrit (13.3% [±6] vs. 17.7% [±8.2], p = 0.04), and trend toward lower gestational age (24.6 [20.1-27] vs. 26.4 [23.2-29.6] weeks, p = 0.08). No difference in birthweight, neonatal phototherapy, exchange, or simple transfusion was observed. CONCLUSION: This is one of the largest studies comparing techniques to treat fetal anemia. IVT was most performed, other techniques were more likely performed in hydrops, and lower starting hematocrit was seen. Neither technique affected outcomes. This study may suggest that physician's experience may be the strongest contributor of outcomes.

Induced Abortion and the Risk of Rh Sensitization.

Importance: While population-level data suggest Rh immunoglobulin is unnecessary before 12 weeks' gestation, clinical evidence is limited. Thus, guidelines vary, creating confusion surrounding risks and benefits of Rh testing and treatment. As abortion care in traditional clinical settings becomes harder to access, many people are choosing to self-manage and need to know if ancillary blood type testing is necessary. Objective: To determine how frequently maternal exposure to fetal red blood cells (fRBCs) exceeds the most conservative published threshold for Rh sensitization in induced first-trimester abortion. Design, Setting, and Participants: Multicenter, observational, prospective cohort study using high-throughput flow cytometry to detect circulating fRBCs in paired maternal blood samples before and after induced first-trimester abortion (medication or procedural). Individuals undergoing induced first-trimester abortion before 12 weeks 0 days' gestation were included. Paired blood samples were available from 506 participants who underwent either medical (n = 319 [63.0%]) or procedural (n = 187 [37.0%]) abortion. Exposure: Induced first-trimester abortion. Main Outcomes and Measures: The primary outcome was the proportion of participants with fRBC counts above the sensitization threshold (125 fRBCs/5 million total RBCs) after induced first-trimester abortion. Results: Among the 506 participants, the mean (SD) age was 27.4 (5.5) years, 313 (61.9%) were Black, and 123 (24.3%) were White. Three of the 506 participants had elevated fRBC counts at baseline; 1 of these patients had an elevated fRBC count following the abortion (0.2% [95% CI, 0%-0.93%]). No other participants had elevated fRBC counts above the sensitization threshold after induced first-trimester abortion. The median change from baseline was 0 fRBCs, with upper 95th and 99th percentiles of 24 and 35.6 fRBCs, respectively. Although there was a strong association between the preabortion and postabortion fRBC counts, no other baseline characteristic was significantly associated with postabortion fRBC count. Conclusions and Relevance: Induced first-trimester abortion is not a risk factor for Rh sensitization, indicating that Rh testing and treatment are unnecessary before 12 weeks' gestation. This evidence may be used to inform international guidelines for Rh immunoglobulin administration following first-trimester induced abortion.

Isoinmunización Rh en bajas respondedoras: Reporte de caso / Rh Isoimmunization in Low Responders: Case Report / Isoimunização Rh em pacientes com baixa resposta: relato de caso

Introducción. La isoinmunización Rh consiste en la producción de anticuerpos maternos en una gestante Rh negativa contra los antígenos de los eritrocitos Rh positivos fetales ocasionados por una hemorragia fetomaterna. En población gestante, el 15% son Rh negativo y la severidad de la afectación fetal está relacionada con una serie de procesos inmunológicos y la historia obstétrica. Si una gestante Rh negativa con riesgo de isoinmunización no recibe profilaxis con inmunoglobulina Anti-D se inmuniza el 16% en la primera gestación, el 30% en la segunda y el 50% después de la tercera. Con este reporte de caso queremos describir el subgrupo de pacientes gestantes con isoinmunización Rh bajas respondedoras. Presentación del caso. G9P5C1A2Gem1V7 de 43 años, remitida en semana 30 de gestación por isoinmunización Rh, no recibió inmunoglobulina Anti-D durante este embarazo, ni en los anteriores ni en el posparto, reporte de Coombs indirecto de 1/4 que se eleva a 1/16, seguimiento ecográfico normal. En semana 35.3 presenta anemia fetal leve y por tratarse de un embarazo alrededor del término se finaliza por cesárea. Recién nacido con adecuado peso para la edad gestacional, quien fue dado de alta a las 72 horas con evolución satisfactoria. Discusión. Las gestantes con isoinmunización Rh bajas respondedoras se sensibilizan con altos volúmenes sanguíneos sin repercusión hemodinámica in utero, produciendo una enfermedad hemolítica fetal leve. Esta respuesta inmune es poco frecuente y está asociada a factores protectores; sin embargo, son necesarios más estudios que sustenten esta condición. Conclusiones. El control prenatal y el Coombs indirecto cuantitativo seriado son las principales herramientas para la prevención de la isoinmunización. El conocimiento de la respuesta inmunológica permite identificar el subgrupo de las bajas respondedoras que tienen una evolución clínica más leve y menor morbilidad neonatal. Palabras clave: Embarazo; Isoinmunización Rh; Eritroblastosis Fetal; Globulina Inmune RHO(D); Hidropesía Fetal.

Introduction. Rh isoimmunization consists of a Rh-negative pregnant woman producing maternal antibodies against the antigens of fetal Rh-positive erythrocytes due to fetomaternal hemorrhage. 15% of the pregnant population is Rh negative, and the severity of fetal effects is related to a series of immunological processes and the obstetric history. If a Rh-negative pregnant woman at risk of isoimmunization does not receive a prophylaxis of Anti-D immunolobulin, 16% are immunized in the first pregnancy, 30% in the second and 50% after the third. In this case report we will describe the subgroup of low responder pregnant patients with Rh isoimmunization. Case Presentation. G9P5C1A2Gem1V7, 43 years old, referred on the 30th week of pregnancy due to Rh isoimmunization. She did not receive Anti-D immunolobulin during this pregnancy, nor in her previous pregnancies, nor during postpartum. Indirect Coombs report of 1/4, which increases to 1/16. Ultrasound monitoring is normal. At week 35.3 she presented mild fetal anemia, and because the pregnancy was near its term, it was ended by cesarean section. Newborn with adequate weight considering the gestational age, who was then discharged after 72 hours with satisfactory evolution. Discussion. Low responder pregnant women with Rh isoimmunization are sensitized with high blood volumes but without hemodynamic repercussions in utero, producing a mild fetal hemolytic disease. This immune response is infrequent and is associated with protective factors; however, further studies are required to support this condition. Conclusions. Prenatal control and serialized quantitative indirect Coombs testing are the main tools for the prevention of isoimmunization. Knowledge of the immunological response enables identifying the subgroup of low responders who present a milder clinical evolution and lower newborn morbidity. Keywords: Pregnancy; Rh Isoimmunization; Erythroblastosis, Fetal; RHO(D) Immune Globulin; Hydrops Fetalis.

Introdução. A isoimunização Rh consiste na produção de anticorpos maternos em uma gestante Rh negativa contra os antígenos dos eritrócitos fetais Rh positivos causados por hemorragia fetomaterna. Na população gestante, 15% são Rh negativos e a gravidade do envolvimento fetal está relacionada a uma série de processos imunológicos e ao histórico obstétrico. Se uma gestante Rh negativa com risco de isoimunização não receber profilaxia com imunoglobulina Anti-D, imuniza-se 16% na primeira gestação, 30% na segunda e 50% após a terceira. Com este relato de caso, queremos descrever o subgrupo de pacientes gestantes com isoimunização Rh de baixa resposta. Apresentação do caso. G9P5C1A2Gem1V7, 43 anos, encaminhada na 30ª semana de gestação para isoimunização Rh, não recebeu imunoglobulina Anti-D nesta gestação, nem nas anteriores nem no puerpério, laudo de Coombs indireto de 1/4 que sobe para 1/16, acompanhamento ultrassonográfico normal. Na semana 35,3, apresentou anemia fetal leve e por se tratar de uma gestação próxima ao termo, foi interrompida por cesariana. Recém-nascido com peso adequado para a idade gestacional, que recebeu alta às 72 horas com evolução satisfatória. Discussão. Gestantes com isoimunização Rh de baixa resposta são sensibilizadas com elevados volumes sanguíneos sem repercussões hemodinâmicas in utero, produzindo doença hemolítica fetal leve. Essa resposta imune é rara e está associada a fatores protetores; no entanto, mais estudos são necessários para fundamentar esta condição. Conclusões. O controle pré-natal e o Coombs indireto quantitativo seriado são as principais ferramentas para a prevenção da isoimunização. O conhecimento da resposta imunológica permite identificar o subgrupo de pacientes com baixa resposta que apresentam evolução clínica mais branda e menor morbidade neonatal. Palavras-chave: Gravidez; Isoimunização Rh; Eritroblastose Fetal; Inmunoglobulina RHO (D), Hidropisia Fetal.