Rh sensitization in abortion care: where we've been and where we're going.

PURPOSE OF REVIEW: The purpose of this review is to summarize the historical context and recent literature that contribute to the debate about preventive strategies for Rhesus (Rh)-alloimmunization in abortion are. RECENT FINDINGS: Recent studies repeatedly demonstrate that the risk of Rh-alloimmunization in first trimester abortion care is very low. SUMMARY: Recent high-quality studies have demonstrated the physiologic presence of fetal red blood cells in maternal circulation even prior to abortion. Thus, establishing the low utility of Rh immunoglobulin prior to abortion before 12 weeks of gestation. There is yet to exist a consensus guideline that balances the desire to prevent a rare devastating outcome and the need to create practical guidelines based on evidence-based risk assessments.

Economic analysis of foregoing Rh immunoglobulin for bleeding in pregnancy <12 weeks gestation.

OBJECTIVES: To perform cost analyses of foregoing RhD blood type testing and administration of Rh immunoglobulin (RhIg) for bleeding in pregnancy at <12 weeks gestation in the United States. STUDY DESIGN: We created a decision-analytic model comparing the current standard treatment pathway for patients who have threatened, spontaneous, or induced abortion in the United States, with a new pathway foregoing RhD testing and administration of RhIg for those who are RhD-negative at <12 weeks gestation, assuming that the risk of sensitization is 0%. We derived population and cost estimates from the current literature and calculated the number needed to treat (NNT) and number needed to screen to avoid one case of fatal hemolytic disease of the fetus and newborn. We performed sensitivity analyses assuming Rh-sensitization risks of 1.5% and 3% and varying the subsequent pregnancy rates from 44% to 100%. RESULTS: The annual savings to health care payers in the United States of foregoing RhD testing and RhIg administration with bleeding events at <12 weeks are $5.5 million/100,000 total pregnancies, assuming the sensitization risk is 0%. In sensitivity analyses with a sensitization risk of 1.5% and subsequent pregnancy rate of 84.3% foregoing Rh testing and RhIg administration would save $2.8 million/100,000 pregnancies, with a NNT of 7322 and a number needed to screen of 48,816. At a 3% sensitization rate, the current standard treatment pathway is most economical. CONCLUSIONS: There is an opportunity to save as much as $5.5 million/100,000 pregnancies by withholding RhIg in specific situations and conserving it for use later in pregnancy. IMPLICATIONS: Cost analyses support foregoing RhD blood type screening and RhIg administration at <12 weeks gestation if the sensitization rate is <3%. By deimplementing this low-value care, payers in the United States can save as much as $5.5 million/100,000 pregnancies and conserve RhIg for use later in pregnancy.

Antenatal RHD screening to guide antenatal anti-D immunoprophylaxis in non-immunized D- pregnant women.

In pregnancy, D- pregnant women may be at risk of becoming immunized against D when carrying a D+ fetus, which may eventually lead to hemolytic disease of the fetus and newborn. Administrating antenatal and postnatal anti-D immunoglobulin prophylaxis decreases the risk of immunization substantially. Noninvasive fetal RHD genotyping, based on testing cell-free DNA extracted from maternal plasma, offers a reliable tool to predict the fetal RhD phenotype during pregnancy. Used as a screening program, antenatal RHD screening can guide the administration of antenatal prophylaxis in non-immunized D- pregnant women so that unnecessary prophylaxis is avoided in those women who carry a D- fetus. In Europe, antenatal RHD screening programs have been running since 2009, demonstrating high test accuracies and program feasibility. In this review, an overview is provided of current state-of-the-art antenatal RHD screening, which includes discussions on the rationale for its implementation, methodology, detection strategies, and test performance. The performance of antenatal RHD screening in a routine setting is characterized by high accuracy, with a high diagnostic sensitivity of ≥99.9 percent. The result of using antenatal RHD screening is that 97-99 percent of the women who carry a D- fetus avoid unnecessary prophylaxis. As such, this activity contributes to avoiding unnecessary treatment and saves valuable anti-D immunoglobulin, which has a shortage worldwide. The main challenges for a reliable noninvasive fetal RHD genotyping assay are low cell-free DNA levels, the genetics of the Rh blood group system, and choosing an appropriate detection strategy for an admixed population. In many parts of the world, however, the main challenge is to improve the basic care for D- pregnant women.

Estimating the cost of Rh testing and prophylaxis in early pregnancy: A time-driven activity-based costing study.

OBJECTIVE: To estimate the cost of Rhesus (Rh) testing and prophylaxis for first-trimester vaginal bleeding in the ambulatory setting. STUDY DESIGN: We used time-driven, activity-based costing to analyze tasks associated with Rh testing and prophylaxis of first-trimester vaginal bleeding at one hospital-based outpatient and two independent reproductive health clinics. At each site, we observed 10 patients undergoing Rh-typing and two patients undergoing Rh prophylaxis. We computed the costs of blood Rh-typing by both fingerstick and phlebotomy, cost of locating previous blood type in the electronic health record (available for 69.8% of hospital-based patients), and costs associated with Rh immune globulin prophylaxis. All costs are reported in 2021 US dollars. RESULTS: The hospital-based clinic reviewed the electronic health record to confirm Rh-status (cost, $26.18 per patient) and performed a phlebotomy, at $47.11 per patient, if none was recorded. The independent clinics typed blood by fingerstick, at a per-patient cost of $4.07. Rh-immune globulin administration costs, including the medication, were similar across facilities, at a mean of $145.66 per patient. Projected yearly costs for testing and prophylaxis were $55,831 for the hospital-based clinic, which was the lowest-volume site, $47,941 for Clinic A, which saw 150 patients/month, and $185,654 for Clinic B, which saw 600 patients/month. CONCLUSIONS: Rh testing and prophylaxis for first-trimester vaginal bleeding generates considerable costs for outpatient facilities, even for Rh-positive patients with a prior blood type on record. IMPLICATIONS: Rh testing and prophylaxis for first-trimester bleeding generate considerable costs even for Rh-positive patients and those with a previously known blood type. These findings highlight the need to reconsider this practice, which is no longer supported by evidence and already safely waived in multiple medical settings in the United States and around the world.

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.

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.

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.

Application of anti-D immunoglobulin in D-negative pregnant women in China.

This article summarizes the current situation of anti-D immunoglobulin (anti-D-Ig) use in RhD-negative pregnant women at home and abroad. The article describes the concept, research and development history, and domestic and foreign applications of anti-D-Ig and points out that anti-D-Ig has not been widely used in China, mainly due to reasons such as unavailability in the domestic market and non-standard current application strategies. The article focuses on analyzing the genetic and immunological characteristics of RhD-negative populations in China. The main manifestations were that the total number of hemolytic disease of the newborn (HDN) relatively high and D variant type. In particular, there are more Asian-type DEL, the importance of clinical application of anti-D-Ig was pointed out, and its antibody-mediated immunosuppressive mechanism was analyzed, which mainly includes red blood cell clearance, epitope blocking/steric hindrance, and Fc γ R Ⅱ B receptor mediated B cell inhibition, anti-D-Ig glycosylation, etc.; clarify the testing strategies of RhD blood group that should be adopted in response to the negative initial screening of pregnant and postpartum women; this article elaborates on the necessity of using anti-D-Ig in RhD-negative mothers after miscarriage or miscarriage, as well as the limitations of its application both domestically and internationally. It also proposes a solution strategy for detecting RhD blood group incompatibility HDFN as early as possible, diagnosing it in a timely manner, and using anti-D-Ig for its prevention and treatment. If the DEL gene is defined as an Asian-type DEL, anti-D-Ig prophylaxis in women would be unnecessary. Finally, based on the specificity of RhD-negative individuals, the article looks forward to the application trend of anti-D-Ig in China. It also called for related drugs to be listed in China as soon as possible and included in medical insurance.

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.

Terminating Routine Cord Blood RhD Typing of the Newborns to Guide Postnatal Anti-D Immunoglobulin Prophylaxis Based on the Results of Fetal RHD Genotyping.

INTRODUCTION: Targeted routine antenatal prophylaxis with anti-D immunoglobulin (Ig) only to RhD-negative pregnant women who carry RhD-positive fetuses (determined by fetal RHD genotyping) has reduced D-alloimmunization significantly when administered in addition to postnatal prophylaxis. Achieving high analysis sensitivity and few false-negative fetal RHD results will make RhD typing of the newborn redundant. Postnatal prophylaxis can then be given based on the result of fetal RHD genotyping. Terminating routine RhD typing of the newborns in cord blood will streamline maternity care. Accordingly, we compared the results of fetal RHD genotyping with RhD typing of the newborns. METHODS: Fetal RHD genotyping was performed, and antenatal anti-D Ig was administered at gestational week 24 and 28, respectively. Data for 2017-2020 are reported. RESULTS: Ten laboratories reported 18,536 fetal RHD genotypings, and 16,378 RhD typing results of newborns. We found 46 false-positive (0.28%) and seven false-negative (0.04%) results. Sensitivity of the assays was 99.93%, while specificity was 99.24%. CONCLUSION: Few false-negative results support the good analysis quality of fetal RHD genotyping. Routine cord blood RhD typing will therefore be discontinued nationwide and postnatal anti-D Ig will now be given based on the result of fetal RHD genotyping.

Management and Follow-up of Massive Fetomaternal Hemorrhage Requiring High-Dose Rh Immune Globulin: A Case Report.

OBJECTIVES: Massive fetomaternal hemorrhage (FMH) is rare and reported to be the cause in approximately 3% of all fetal deaths. Maternal management of massive FMH includes prevention of Rh(D) alloimmunization in Rh(D)-negative mothers by administration of Rh(D) immune globulin (RhIG). METHODS: We describe a case of a 30-year-old O-negative, primigravida woman who presented at 38 weeks of gestation with decreased fetal movements. She underwent an emergency cesarean section and delivered an O-positive baby girl who died shortly after birth. RESULTS: The patient's FMH screen was positive, with a Kleihauer-Betke test demonstrating 10.7% fetal blood in maternal circulation. The calculated dose of 6,300 µg RhIG was given prior to discharge over 2 days using an intravenous (IV) preparation. Antibody screening a week after discharge showed anti-D and anti-C. The anti-C was attributed to acquired passive immunity from the large dose of RhIG. Anti-C reactivity waned and was negative at 6 months, but the anti-D pattern persisted at 9 months postdelivery. Negative antibody screens were noted at 12 and 14 months. CONCLUSIONS: This case highlights the immunohematology challenges of IV RhIG as well as the success in preventing alloimmunization with IV RhIG given the patient's complete resolution of anti-C and no anti-D formation, with a subsequent healthy pregnancy.

Cases of RhD variants RhD*DAU2/DAU6 and RhD*weak D type 4.1 in pregnant women in Saudi Arabia.

The D antigen is one of the most immunogenic and clinically significant antigens of the Rh blood group system due to its various genotypes that encode for more than 450 different variants. Accurate RhD typing and D variant identification is crucial specially in prenatal screening during pregnancy. Women with RhD -ve phenotype are eligible to Rh immune globulin (RhIG) prophylaxis for the prevention of anti-D alloimmunization and hemolytic disease of the fetus and newborn (HDFN). However, there are some women who possess RhD variant alleles, who are mistakenly grouped as RhD positive and considered not eligible for RhIG prophylaxis, putting them at risk of anti-D alloimmunization and consequently leading to HDFN during subsequent pregnancies. Here, we describe  two cases of RhD variants DAU2/DAU6 and Weak D type 4.1 in obstetric patients who were grouped as RhD +ve with negative antibody screening during routine serologic  testing. Weak/Partial D molecular analysis using genomic DNA Red Cell Genotyping (RCG) revealed that both patients had RhD variants, one of which DAU2/DAU6 allele associated with anti-D alloimmunization. According to routine testing neither patients received RhIG or transfusion. In this case report we document to our knowledge the first reported cases of RhD variants among pregnant women in Saudi Arabia.

Obstetric and Newborn Weak D-Phenotype RBC Testing and Rh Immune Globulin Management Recommendations: Lessons From a Blinded Specimen-Testing Survey of 81 Transfusion Services.

CONTEXT.­: Modern RHD genotyping can be used to determine when patients with serologic weak D phenotypes have RHD gene variants at risk for anti-D alloimmunization. However, serologic testing, RhD interpretations, and laboratory management of these patients are quite variable. OBJECTIVE.­: To obtain interlaboratory comparisons of serologic testing, RhD interpretations, Rh immune globulin (RhIG) management, fetomaternal hemorrhage testing, and RHD genotyping for weak D-reactive specimens. DESIGN.­: We devised an educational exercise in which 81 transfusion services supporting obstetrics performed tube-method RhD typing on 2 unknown red blood cell challenge specimens identified as (1) maternal and (2) newborn. Both specimens were from the same weak D-reactive donor. The exercise revealed how participants responded to these different clinical situations. RESULTS.­: Of reporting laboratories, 14% (11 of 80) obtained discrepant immediate-spin reactions on the 2 specimens. Nine different reporting terms were used to interpret weak D-reactive maternal RhD types to obstetricians. In laboratories obtaining negative maternal immediate-spin reactions, 28% (16 of 57) performed unwarranted antiglobulin testing, sometimes leading to recommendations against giving RhIG. To screen for excess fetomaternal hemorrhage after a weak D-reactive newborn, 47% (34 of 73) of reporting laboratories would have employed a contraindicated fetal rosette test, risking false-negative results and inadequate RhIG coverage. Sixty percent (44 of 73) of laboratories would obtain RHD genotyping in some or all cases. CONCLUSIONS.­: For obstetric and neonatal patients with serologic weak D phenotypes, we found several critical problems in transfusion service laboratory practices. We provide recommendations for appropriate testing, consistent immunohematologic terminology, and RHD genotype-guided management of Rh immune globulin therapy and RBC transfusions.

Rh Immune Globulin After the Transfusion of RhD-Positive Blood in a Patient with a Partial D Antigen.

BACKGROUND: Patients with a serologic weak D phenotype may demonstrate variable RhD expression. We present a case in which clinical management would have been simplified if RHD genotyping had been performed previously. CASE: A 33-year-old patient, G11P4155, presented with an incomplete miscarriage and was transfused RhD-positive packed red blood cells after typing RhD-positive. The patient had been historically typed RhD-negative by a different testing methodology. Indirect antiglobulin testing was performed, which revealed a serologic weak D phenotype. The patient was given 9,600 micrograms of Rh immune globulin. Molecular testing revealed a partial D antigen, which was originally thought to be at risk for alloimmunization; however, this has since been disproven. CONCLUSION: Although not yet universal practice, prenatal RHD genotyping for partial D antigen could have prevented the characterization of this patient as RhD-positive at the time of transfusion.

Fetomaternal hemorrhage assessment in Rh-negative patients undergoing dilation and evacuation between 20 and 24 weeks' gestational age: A retrospective cohort study.

OBJECTIVE: To estimate the rate of requiring more than one 300-mcg Rh D immune globulin dose for fetomaternal hemorrhage (FMH) at the time of second-trimester dilation and evacuation (D + E). STUDY DESIGN: We performed a retrospective cohort analysis of patients at greater than 20 weeks' gestation who underwent D + E, had Rh D-negative blood type, and received FMH quantification testing. RESULTS: Of 25 eligible patients, 24 had negative quantification of FMH; one had positive quantification that did not meet the clinical threshold for additional dosing. CONCLUSIONS: The absolute risk of requiring additional Rh D immune globulin after D+E for pregnancies greater than 20 weeks' gestation was 0%.

Following targeted routine antenatal anti-D prophylaxis, almost half of the pregnant women had undetectable anti-D prophylaxis at delivery.

INTRODUCTION: In September 2016, a nationwide targeted routine antenatal anti-D prophylaxis program was implemented in Norway. The prophylaxis (anti-D immunoglobulin) aims to cover the whole third trimester and is administered in gestational week 28 to RhD-negative women who carry RhD-positive fetuses. However, in many women, antibody screening at delivery does not detect anti-D immunoglobulin. The goal of this study was to investigate the presumable role of dose and timing of antenatal anti-D immunoglobulin administration in non-detectable prophylaxis at the time of delivery. MATERIAL AND METHODS: In this retrospective observational study, RhD-negative pregnant women who gave birth at Oslo University Hospital and Akershus University Hospital between January 2017 and December 2019 were analyzed. Women who received antenatal anti-D immunoglobulin (1500 IU at Oslo University Hospital and 1250 IU at Akershus University Hospital) when fetal RHD genotyping at gestational week 24 predicted an RhD-positive fetus were included if an antibody screen at delivery was available. Data from the blood bank, maternity information systems, and electronic patient records were used. RESULTS: Analysis of the 984 RhD-negative women at the two hospitals revealed that 45.4% had non-detectable anti-D at delivery. A significant difference between the two hospitals was observed: 40.5% at Oslo University Hospital (n = 509) and 50.7% at Akershus University Hospital (n = 475) (p = 0.001). The proportion with non-detectable anti-D increased to 56.0 and 75.3%, respectively (p = 0.008) in the group of women who gave birth 12 weeks after routine antenatal anti-D prophylaxis. Significantly fewer women had detectable anti-D at delivery when the lower anti-D immunoglobulin dose (1250 IU) was administered antenatally. Multiple logistic regression indicated that the time interval between routine antenatal anti-D prophylaxis and delivery, in addition to anti-D dose, were significantly associated with detectable anti-D at delivery (p < 0.001). CONCLUSIONS: We do not know which RhD-negative pregnant women, despite antenatal anti-D prophylaxis, are at risk of RhD alloimmunization, when antibody screening is negative at delivery. Administration of antenatal prophylaxis should probably be moved closer to delivery, since the risk of fetomaternal hemorrhage is higher during the last weeks of the third trimester.

Cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies.

BACKGROUND: We sought to determine the cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies in Canada. STUDY DESIGN AND METHODS: We developed two probabilistic state-transition (Markov) microsimulation models to compare fetal genotyping followed by targeted management versus usual care (i.e., universal Rh immunoglobulin [RhIG] prophylaxis in nonalloimmunized RhD-negative pregnancies, or universal intensive monitoring in alloimmunized pregnancies). The reference case considered a healthcare payer perspective and a 10-year time horizon. Sensitivity analysis examined assumptions related to test cost, paternal screening, subsequent pregnancies, other alloantibodies (e.g., K, Rh c/C/E), societal perspective, and lifetime horizon. RESULTS: Fetal genotyping in nonalloimmunized pregnancies (at per-sample test cost of C$247/US$311) was associated with a slightly higher probability of maternal alloimmunization (22 vs. 21 per 10,000) and a reduced number of RhIG injections (1.427 vs. 1.795) than usual care. It was more expensive (C$154/US$194, 95% Credible Interval [CrI]: C$139/US$175-C$169/US$213) and had little impact on QALYs (0.0007, 95%CrI: -0.01-0.01). These results were sensitive to the test cost (threshold achieved at C$88/US$111), and inclusion of paternal screening. Fetal genotyping in alloimmunized pregnancies (at test cost of C$328/US$413) was less expensive (-C$6280/US$7903, 95% CrI: -C$6325/US$7959 to -C$6229/US$7838) and more effective (0.19 QALYs, 95% CrI 0.17-0.20) than usual care. These cost savings remained robust in sensitivity analyses. DISCUSSION: Noninvasive fetal RhD genotyping saves resources and represents good value for the management of alloimmunized pregnancies. If the cost of genotyping is substantially decreased, the targeted intervention can become a viable option for nonalloimmunized pregnancies.

Risk factors for RhD immunisation in a high coverage prevention programme of antenatal and postnatal RhIg: a nationwide cohort study.

OBJECTIVE: To evaluate which risk factors for RhD immunisation remain, despite adequate routine antenatal and postnatal RhIg prophylaxis (1000 IU RhIg) and additional administration of RhIg. The second objective was assessment of the current prevalence of RhD immunisations. DESIGN: Prospective cohort study. SETTING: The Netherlands. POPULATION: Two-year nationwide cohort of alloimmunised RhD-negative women. METHODS: RhD-negative women in their first RhD immunised pregnancy were included for risk factor analysis. We compared risk factors for RhD immunisation, occurring either in the previous non-immunised pregnancy or in the index pregnancy, with national population data derived from the Dutch perinatal registration (Perined). RESULTS: In the 2-year cohort, data from 193 women were eligible for analysis. Significant risk factors in women previously experiencing a pregnancy of an RhD-positive child (n = 113) were: caesarean section (CS) (OR 1.7, 95% CI 1.1-2.6), perinatal death (OR 3.5, 95% CI 1.1-10.9), gestational age >42 weeks (OR 6.1, 95% CI 2.2-16.6), postnatal bleeding (>1000 ml) (OR 2.0, 95% CI 1.1-3.6), manual removal of the placenta (MRP) (OR 4.3, 95% CI 2.0-9.3); these factors often occurred in combination. The miscarriage rate was significantly higher than in the Dutch population (35% versus 12.-5%, P < 0.001). CONCLUSION: Complicated deliveries, including cases of major bleeding and surgical interventions (CS, MRP), must be recognised as a risk factor, requiring estimation of fetomaternal haemorrhage volume and adjustment of RhIg dosing. The higher miscarriage rate suggests that existing RhIg protocols need adjustment or better compliance. TWEETABLE ABSTRACT: Complicated delivery (caesarean section, manual removal placenta, major bleeding) is the most valid risk factor for RhD immunization despite antenatal and postnatal RhIg.