Evaluating automated titre score as an alternative to continuous flow analysis for the prediction of passive anti-D in pregnancy.

OBJECTIVES: To evaluate the potential of the automated titre score (TS) as an alternative method to continuous flow analysis (CFA) for the prediction of the nature of anti-D in pregnancy. BACKGROUND: The 2016 revised British Society for Haematology (BSH) antenatal guidelines recommended a measurement of anti-D concentration by CFA to ensure the detection of potential immune anti-D. Due to high referral costs and resource pressures, uptake has been challenging for hospital laboratories. Serious Hazards of transfusion (SHOT) data have previously shown that this has contributed to missed antenatal follow ups for women with immune anti-D and neonates affected by haemolytic disease of the fetus/newborn. METHODS/MATERIALS: In this multicentre comparative study, samples referred for CFA quantification were also tested by an ORTHO VISION automated anti-D indirect antiglobulin test (IAT) serial dilution and then converted to TS. CFA results and history of anti-D prophylaxis were used to categorise samples as passive or immune, with the aim of determining a potential TS cut-off for CFA referral of at risk patients. RESULTS: Five UK National Health Service (NHS) trusts generated a total of 196 anti-D TS results, of which 128 were classified as passive and 68 as immune. Diagnostic testing of CFA and TS values indicated a TS cut-off of 35 to assist in distinguishing the nature of anti-D. Using this cut-off, 175 (89%) results were correctly assigned into the passive or immune range, giving a specificity of 92.19% and a negative predictive value of 91.47%. CONCLUSION: TS in conjunction with clinical and anti-D prophylaxis history can be used as a viable and cost-effective alternative to CFA in a hospital laboratory setting.

Cell free fetal DNA to triage antenatal rhesus immune globulin: Is it really cost-effective in the United States?

OBJECTIVE: To compare the efficacy and costs of three different strategies of antenatal rhesus immune globulin (RhIG) administration in a US population. METHODS: A decision tree analysis was undertaken for universal antenatal RhIG administration based on RhD serologic paternity testing, universal administration without paternity, and selective antenatal RhIG administration using cell free fetal DNA (cfDNA) for RHD fetal typing. Rates of alloimmunization were calculated. Charges were determined for laboratory testing and obstetrical and neonatal treatments for the first pregnancy and cases of alloimmunization in the following pregnancy. RESULTS: The largest number of new RhD alloimmunization cases resulted from a strategy of universal RhIG that included paternity. Fewer cases resulted from a selective strategy; the least number of cases were associated with a universal approach that discounted paternity. When the costs of first pregnancies and alloimmunized second pregnancies were combined, a universal strategy that excludes paternity had the least costs followed by a selective strategy followed by a universal strategy that included paternity. CONCLUSION: The use of cfDNA to determine the selective use of antenatal RhIG would not be cost-effective in the United States. Universal antenatal RhIG without paternity is more effective in preventing new cases of alloimmunization than the current ACOG guideline.

High-throughput, non-invasive prenatal testing for fetal Rhesus D genotype to guide antenatal prophylaxis with anti-D immunoglobulin: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of high-throughput, non-invasive prenatal testing (HT-NIPT) for fetal Rhesus D (RhD) genotype to guide antenatal prophylaxis with anti-D immunoglobulin compared with routine antenatal anti-D immunoglobulin prophylaxis (RAADP). DESIGN: Cost-effectiveness decision-analytic modelling. SETTING: Primary care. PARTICIPANTS: A simulated population of 100 000 RhD-negative women not known to be sensitised to the RhD antigen. METHODS: A decision tree model was used to characterise the antenatal care pathway in England and the long-term consequences of sensitisation events. The diagnostic accuracy of HT-NIPT was derived from a systematic review and bivariate meta-analysis; estimates of other inputs were derived from relevant literature sources and databases. Women in whom the HT-NIPT was positive or inconclusive continued to receive RAADP, whereas women with a negative result received none. Five alternative strategies in which the use of HT-NIPT may affect the existing postpartum care pathway were considered. MAIN OUTCOME MEASURES: Costs expressed in 2015GBP and impact on health outcomes expressed in terms of quality-adjusted life-years over a lifetime. RESULTS: The results suggested that HT-NIPT appears cost saving but also less effective than current practice, irrespective of the postpartum strategy evaluated. A postpartum strategy in which inconclusive test results are distinguished from positive results performed best. HT-NIPT is only cost-effective when the overall test cost is £26.60 or less. CONCLUSIONS: HT-NIPT would reduce unnecessary treatment with routine anti-D immunoglobulin and is cost saving when compared with current practice. The extent of any savings and cost-effectiveness is sensitive to the overall test cost. TWEETABLE ABSTRACT: HT-NIPT is cost saving compared with providing anti-D to all RhD-negative pregnant women.

Cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal anti-D prophylaxis in RhD-negative pregnant women: a model-based analysis.

OBJECTIVE: To estimate the cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal versus no routine antenatal anti-D prophylaxis (RAADP) or versus non-targeted RAADP. DESIGN: Model based on a population-based cohort study. SETTING: The Swedish health service. POPULATION: Intervention subjects in the underlying cohort study were RhD-negative pregnant women receiving first trimester fetal RHD screening followed by targeted anti-D in 2010-2011 (n = 6723). Historical comparators were RhD-negative women who delivered in 2008-2009 when standard care did not include RAADP (n = 7099). METHODS: Healthcare costs for the three strategies were included for the first and subsequent pregnancies. For the comparison with non-targeted RAADP, the immunisation rate was based on the observed rate for targeted therapy and adjusted downwards by removing the influence of false negatives. MAIN OUTCOME MEASURE: Additional cost per RhD immunisation averted. RESULTS: Compared with RAADP, targeted prophylaxis was associated with fewer immunisations (0.19 versus 0.46% per pregnancy) and lower costs (cost-savings of €32 per RhD-negative woman). The savings were from lower costs during pregnancy and delivery, and lower costs of future pregnancies through fewer immunisations. Non-targeted anti-D was estimated to result in 0.06% fewer immunisations and an additional €16 in cost-savings per mother, compared with targeted anti-D. CONCLUSION: Based on effect data from a population-based cohort study, targeted prophylaxis was associated with lower immunisation risk and costs versus no RAADP. Based on effect data from theoretical calculations, non-targeted RAADP was predicted to result in lower costs and immunisation risk compared with targeted prophylaxis. TWEETABLE ABSTRACT: Fetal RHD screening and targeted prophylaxis resulted in lower immunisation risk and costs compared with no RAADP.

Costs and benefits of non-invasive fetal RhD determination.

OBJECTIVE: Non-invasive fetal Rhesus (Rh) D genotyping, using cell-free fetal DNA (cffDNA) in the maternal blood, allows targeted antenatal anti-RhD prophylaxis in unsensitized RhD-negative pregnant women. The purpose of this study was to determine the cost and benefit of this approach as compared to routine antenatal anti-RhD prophylaxis for all unsensitized RhD-negative pregnant women, as is the current policy in the province of Alberta, Canada. METHODS: This study was a decision analysis based on a theoretical population representing the total number of pregnancies in Alberta over a 1-year period (n = 69 286). A decision tree was created that outlined targeted prophylaxis for unsensitized RhD-negative pregnant women screened for cffDNA (targeted group) vs routine prophylaxis for all unsensitized RhD-negative pregnant women (routine group). Probabilities at each decision point and costs associated with each resource were calculated from local clinical and administrative data. Outcomes measured were cost, number of women sensitized and doses of Rh immunoglobulin (RhIG) administered. RESULTS: The estimated cost per pregnancy for the routine group was 71.43 compared with 67.20 Canadian dollars in the targeted group. The sensitization rates per RhD-negative pregnancy were equal, at 0.0012, for the current and targeted programs. Implementing targeted antenatal anti-RhD prophylaxis would save 4072 doses (20.1%) of RhIG over a 1-year period in Alberta when compared to the current program. CONCLUSIONS: These data support the feasibility of a targeted antenatal anti-RhD prophylaxis program, at a lower cost than that of the existing routine prophylaxis program, with no increased risk of sensitization.

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.

Development of a transparent interactive decision interrogator to facilitate the decision-making process in health care.

BACKGROUND: Decisions about the use of new technologies in health care are often based on complex economic models. Decision makers frequently make informal judgments about evidence, uncertainty, and the assumptions that underpin these models. OBJECTIVES: Transparent interactive decision interrogator (TIDI) facilitates more formal critique of decision models by decision makers such as members of appraisal committees of the National Institute for Health and Clinical Excellence in the UK. By allowing them to run advanced statistical models under different scenarios in real time, TIDI can make the decision process more efficient and transparent, while avoiding limitations on pre-prepared analysis. METHODS: TIDI, programmed in Visual Basic for applications within Excel, provides an interface for controlling all components of a decision model developed in the appropriate software (e.g., meta-analysis in WinBUGS and the decision model in R) by linking software packages using RExcel and R2WinBUGS. TIDI's graphical controls allow the user to modify assumptions and to run the decision model, and results are returned to an Excel spreadsheet. A tool displaying tornado plots helps to evaluate the influence of individual parameters on the model outcomes, and an interactive meta-analysis module allows the user to select any combination of available studies, explore the impact of bias adjustment, and view results using forest plots. We demonstrate TIDI using an example of a decision model in antenatal care. CONCLUSION: Use of TIDI during the NICE appraisal of tumor necrosis factor-alpha inhibitors (in psoriatic arthritis) successfully demonstrated its ability to facilitate critiques of the decision models by decision makers.

Is the management of Rh-Rh incompatibility with noninvasive fetal Rh genotyping for targeted prophylaxis cost-effective in the Turkish population?

Background/aim: The aim of this study was to assess unnecessary immunization rates and compare the cost-effectiveness of targeted prophylaxis with fetal Rh genotyping with that of traditional management of Rh-Rh incompatibility in a virtual economic model. Materials and methods: This retrospective data analysis was conducted at two tertiary centers between 2011 and 2015. The data of 1135 pregnant women were analyzed. The main outcome measure was to determine the unnecessary immunization rate among the whole Rh-Rh incompatibility group. The second outcome measure was to compare the cost-effectiveness of universal immunization with that of targeted prophylaxis with fetal Rh genotyping in a virtual economic model. Results: Average cost per patient was found as $259.20 with universal prophylaxis and the total cost was $177,344, whereas if targeted prophylaxis had been applied to these patients the total cost would have been $263,392 and cost per patient would have been $385. Universal prophylaxis was more cost-effective than targeted prophylaxis in terms of both total cost and cost per patient (P < 0.0001). Conclusion: Unless the cost of noninvasive fetal Rh genotyping is reduced, a universal approach of anti-D immune globulin prophylaxis is more cost-effective than noninvasive determination of fetal Rh genotyping with targeted prophylaxis.

Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura.

AIMS: Real-world evidence on the safety profile and costs associated with immune thrombocytopenic purpura (ITP) treatment in adults is lacking. This study quantifies and compares adverse event (AE) crude rates and costs associated with ITP treatments as found in claims data. MATERIALS AND METHODS: A retrospective claims-based analysis was conducted using IMS Pharmetrics Plus database. Included patients were ≥18 years old, with a diagnosis of ITP (2007-2012); an ITP-related claim for anti-D, intravenous immunoglobulin (IVIG), rituximab, romiplostim, or eltrombopag; and 1-year continuous enrollment (3-years for rituximab) during follow-up. AEs and event costs were identified during active treatment, defined from the first claim of each drug to a pre-defined treatment gap or end of study period. Descriptive statistics were reported with Wilcoxon rank-sum significance tests. RESULTS: A total of 2,518 patients were identified (mean age = 50.8 (±16.3 years); 55.8% male). Of all patients, 22.8% experienced any AE. Significantly fewer anti-D patients had any AE (13.8% vs IVIG: 21.1%, rituximab: 29.4%, romiplostim: 28.1%, eltrombopag: 22.4%). Nausea/vomiting and arthralgia/musculoskeletal pain were most common across treatments, and hemolytic events did not differ significantly across treatments. Most costly AEs were urinary tract infection, aseptic meningitis, and fever ($5000+/case); headache, nasal congestion, and hemolytic event were $4,000-5,000/case. Cost per AE did not differ by treatment. LIMITATIONS AND CONCLUSIONS: Although lower than trial-based AE rates, claims for ITP treatment-related AEs are common, with higher numbers for rituximab and lower numbers for anti-D. This disparity suggests a possible differential cost burden overall that future analysis should explore.

[Economic analysis of the prevention of anti-D immunization]. / Analyse économique de la prévention de l'immunisation anti-D.

Any prevention policy has a cost. For anti-D immunization, the main questions concern the cost of a change in the prevention policy by the health insurance fund and more globally by the society in general. Furthermore, the analysis must also examine the cost effectiveness of systematic prevention extended to all Rhesus negative women in comparison with targeted prevention or no prevention. Studies published in Great Britain, Canada, and The United States have generally concluded that the raw cost of systematic prevention is high compared with targeted prevention. On the other hand, the cost-effectiveness would favor the systematic approach. These data are difficult to apply to the French situation because health care costs are different and because of the lack of perfectly reliable epidemiological data on the frequency and consequences of severe forms of allo-immunization. Technological advances, particularly concerning genotyping of fetal Rhesus from maternal blood samples, could have an important impact on the cost factor if a systematic approach is adopted.

Second-line therapies in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a rare, acquired autoimmune condition characterized by a low platelet count and an increased risk of bleeding. Although many children and adults with ITP will not need therapy beyond historic first-line treatments of observation, steroids, intravenous immunoglobulin (IVIG), and anti-D globulin, others will have an indication for second-line treatment. Selecting a second-line therapy depends on the reason for treatment, which can vary from bleeding to implications for health-related quality of life (HRQoL) to likelihood of remission and patient preference with regard to adverse effects, route of administration, and cost. Published studies of these treatments are limited by lack of comparative trials, in addition to inconsistent outcome measures, definitions, and efficacy endpoints. This article provides an up-to-date comparison of the second-line treatments, highlighting important outcome measures including bleeding, HRQoL, fatigue, and platelet counts, which influence treatment selection in a shared decision-making model.

Rh(O)D immune globulin products for prevention of alloimmunization during pregnancy.

PURPOSE: The pharmacologic properties of Rhesus (Rh) immune globulin (RhIG) and clinical data on its effectiveness in preventing Rh-antigen alloimmunization in pregnant women are reviewed. SUMMARY: RhIG is a human plasma derivative that targets red blood cells (RBCs) positive for Rh(O) antigen (also called D antigen). In the United States and other countries, the widespread use of RhIG has markedly reduced the occurrence of hemolytic disease of the fetus and newborn (HDFN), a devastating condition caused by D-antigen sensitization of a pregnant woman via exposure to fetal RBCs (usually during detachment of the placenta in labor) that results in a maternal immune response leading to severe hemolysis in the fetus. Routine administration of RhIG at 26-30 weeks' gestation and again within 72 hours of delivery has been shown to be highly effective in preventing maternal Rh alloimmunization, with very low rates of D-antigen sensitization (in the range of 0-2.2%) reported in multiple studies of at-risk women. The four RhIG products currently available in the United States have common clinical indications but differ in certain attributes. Pharmacists can play an important role in guiding other clinicians on the rationale for the use of RhIG, important differences between products, and appropriate timing of RhIG therapy. CONCLUSION: Routine administration of RhIG to women at risk for Rh alloimmunization is clinically effective and has made HDFN a rare clinical event. The available RhIG products are not the same and should be carefully reviewed to ensure that they are administered safely.

Idiopathic thrombocytopenia purpura: Treatment patterns and an analysis of cost associated with intravenous immunoglobulin and anti-D therapy.

A retrospective study was conducted to determine treatment patterns for idiopathic thrombocytopenia purpura (ITP) across the US and to determine the cost of its treatment with high-dose intravenous immunoglobulin (IVIg) and anti-D therapy. Information on the incidence, treatment patterns, hospital care, and costs for ITP was derived from three data bases and supplemented by in-depth case studies from five hospital centers in the US. Data collection forms were developed to collect data on treatment patterns and costs at the five hospital centers. Treatment patterns were analyzed and used to model the comparative costs of IVIg and anti-D therapy. Cost estimations were based on a process and cost-finding analysis reflecting current practice patterns for the use of IVIg and anti-D therapy in an outpatient clinic. The incidence of ITP was estimated at 65 per 10,000 in human immunodeficiency virus (HIV)-positive individuals and 1.5 per 10,000 in HIV-negative individuals. Hospital discharge data from all 1991 and 1992 hospital discharges in Maryland revealed that both Medicare patients and patients who had other payment options spent less time in hospital compared to Medicaid patients. The limited case study data indicate that anti-D therapy increased platelet counts to greater than 25,000/microL in 82% of evaluable episodes and that IVIg-treated patients reached 25,000/microL in 48% of treated episodes. The estimated cost per treated episode of ITP was $4,269 for IVIg and $2,716 for anti-D therapy, reflecting a cost savings of $1,553 per episode. This retrospective study has shown that the use of anti-D therapy is associated with lower costs compared with IVIg treatment in patients with ITP. The shorter infusion time required for anti-D therapy may also contribute to a better quality of life for patients.

ACOG practice bulletin. Prevention of Rh D alloimmunization. Number 4, May 1999 (replaces educational bulletin Number 147, October 1990). Clinical management guidelines for obstetrician-gynecologists. American College of Obstetrics and Gynecology.

The reduction in the incidence of Rh D alloimmunization is a prototype for the effectiveness of preventive medicine. Some controversies remain, however, such as the use of anti-D immune globulin in patients with either threatened abortion or antenatal hemorrhage. Similarly, it may not be cost-effective either to screen all Rh D-negative patients with an indirect Coombs test at 24-28 weeks of gestation or to screen all postpartum patients for excessive fetomaternal hemorrhage.

[Anti-Rh(D): an efficacious therapeutic alternative in autoimmune hemocytopenias]. / Gli anti-Rh(D): una efficace alternativa terapeutica nelle emocitopenie autoimmuni.

In the last years high dose intravenous immunoglobulin (i.v.IG) has clearly modified the therapeutic approach toward autoimmune hemocytopenia. Their introduction has promoted the studies on the i.v.IG mechanisms of action: the hypothesis most widely accepted is the blockade of Fc-receptors in the reticuloendothelial system. It was hypothesized that low levels of anti-red blood cell antibodies contained in the i.v.IG preparations might be responsible for the Fc-receptor blockade. On this basis, anti-Rh(D) immunoglobulin has been successfully tested in Rh-positive patients with idiopathic thrombocytopenic purpura (ITP). The present paper describes the presumed mechanisms of action, clinical indications, side effects and cost of the anti-Rh(D) immunoglobulin. Until now, anti-Rh(D) has been chiefly employed in patients with ITP and human immunodeficiency virus-related ITP. However, at present, new clinical indications are emerging from studies in patients with autoimmune neutropenia, both using the intravenous and the intramuscular route. Anti-Rh(D) immunoglobulin has proved, in our and in other Authors' experience, a safe and easy to be administered treatment, at low cost and slightly lower in efficacy compared with i.v.IG.

Cost-benefit analysis of indirect antiglobulin screening in Rh(D)-negative women at 28 weeks of gestation.

OBJECTIVE: To estimate the potential economic benefit of reduced indirect antiglobulin screening for Rh(D)-negative pregnant women. METHODS: A chart review of all Rh(D)-negative mothers delivering at the University of Washington from 2002 to 2012 was conducted to determine the rate of gestational seroconversion to anti-D antibodies before 28 weeks of gestation. A decision tree was constructed to estimate the economic effects of eliminating the indirect antiglobulin screen at 28 weeks of gestation and instead immunizing all Rh(D)-negative, anti-D antibody-negative women with anti-D immune globulin at that time. A theoretical cohort of 100,000 women was modeled. Probabilities and costs were derived from published literature, chart review, and expert opinion. Univariate sensitivity analyses followed by a Monte Carlo analysis examined assumptions and uncertainties in our model across entire distributions. RESULTS: The seroconversion rate of development of anti-D antibodies before 28 weeks of gestation in the cohort analyzed was 0.099% (2/2,029 women). From a societal perspective, the expected cost savings from implementing the reduced indirect antiglobulin screening strategy, per 100,000 women, ranged from $6 to $7.7 million. The overall cost savings for implementing this strategy in the United States for 1 year ranged from $34.7 to $35.6 million. This strategy remained cost-beneficial when varying our parameters (eg, anti-D immune globulin, antibody test cost) to their logical extremes. The Monte Carlo analysis verified the cost savings of our strategy. CONCLUSION: The updated seroconversion rate and our model suggest that eliminating the 28-week antibody screen would be cost-beneficial from a societal perspective while posing minimal potential harm to the recipients.

Costs and clinical outcomes of noninvasive fetal RhD typing for targeted prophylaxis.

OBJECTIVE: To examine the cost and clinical outcomes of noninvasive RhD typing with cell-free fetal DNA to selectively deliver antenatal and postnatal prophylaxis with anti-D immune globulin for prevention of alloimmunization in RhD-negative women. METHODS: We developed a decision tree to compare the costs and clinical outcomes of three strategies in an RhD-negative nonalloimmunized population as follows: 1) routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing (the current approach in most of the United States); 2) noninvasive fetal RhD typing with prophylaxis guided by test results; and 3) no screening or prophylaxis. Costs were estimated for testing and treatment algorithms using hospital billing records and information from the manufacturer of the fetal RhD genotyping test. Probability estimates were derived from published literature. The decision tree and sensitivity analyses were constructed and performed with Microsoft Excel. RESULTS: We estimated the cost of the current approach to prevention of alloimmunization to be $351 per pregnancy, and we estimated the cost of noninvasive determination of fetal RhD status to be $682. Assuming essentially perfect test performance, threshold analysis found the cost must decrease to $119 to break even. The gap widened in favor of routine prophylaxis in most other circumstances (increased false-negative test rate and decreasing prevalence of RhD negativity). CONCLUSION: Unless the cost of noninvasive fetal RhD typing is reduced substantially, routine antenatal anti-D immune globulin prophylaxis with postpartum prophylaxis guided by cord blood typing is less costly than noninvasive determination of fetal RhD status.