The widespread use of anti-D immune globulin through established protocols has led to a significant decrease in the number of sensitized pregnancies in the past few decades. With the advent of routine postnatal prophylaxis with anti-D immune globulin in the 1970s, the rate of alloimmunization for at-risk pregnancies decreased from 14% to 1.5%.1 After expansion of the use of anti-D immune globulin into the antepartum realm, rates further decreased to as low as 0.2–0.4%.1
Studies examining compliance with anti-D immune globulin protocols have estimated numbers as high as 98%;2 however, there are several issues related to universal administration. All current preparations are derived from pooled human plasma, and thus there is a risk of transmission of blood-borne infection with viruses such as human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and parvovirus B19.3 An outbreak of hepatitis C related to anti-D immune globulin was reported in Ireland in the 1970s,4 and the potential for infection attributable to a yet-undiscovered agent remains a possibility.5 It should be noted that, to date, there has been no evidence of viral transmission from any product licensed in the United States.3 Additionally, the supply of anti-D immune globulin is limited, leading some countries to restrict its use rather than to adopt the protocols that are currently used in the United States.1
Landmark work by Lo et al6 in 1997 found that approximately 3–6% of cell-free DNA in the plasma of pregnant women is fetal in origin. Soon after this discovery, Lo et al.7 reported that fetal RhD genes were detectable in RhD-negative women using this technology. The 2006 American College of Obstetricians and Gynecologists practice bulletin8 briefly addresses the use of maternal plasma for RhD typing but states that “this is not a widely used clinical tool.”
The current RhD typing test used in the United States (Sequenom) examines 92 DNA polymorphisms to aid in diagnosis for pregnancies in which the fetus is female and RhD-negative.5 In a clinical validation study that included both first-trimester and second-trimester samples and incorporated the use of this fetal identifier single-nucleotide polymorphism assay, Bombard et al5 demonstrated that all fetuses in this sample thought to be RhD-negative were confirmed to be RhD-negative, providing a negative predictive value of 100%. Of less consequence was one false-positive result in the population,5 clinically equating to unnecessary administration of anti-D immune globulin in a single pregnancy. A 2012 study by Moise9 examined the use of this test in 120 RhD-negative nonalloimmunized women across all three trimesters; they found a total of three false-positive results and one false-negative result in more than 300 samples.
Szczepura et al studied the cost and benefits of mass testing to target antenatal anti-D prophylaxis in England and Wales.10 Their analysis found that universal noninvasive determination of fetal RhD status in all RhD-negative women was not cost-saving and, in fact, would generate a significant number of additional sensitizations unless the test sensitivity exceeded 99.9%. The authors concluded that even assuming minimal cost of noninvasive testing, universal testing still was not cost-effective because of these additional sensitizations.10 It is important to highlight that test characteristics and prophylaxis algorithms differed from those used in the United States.10
Despite an urgent need to evaluate the economic aspects of this emerging technology, a cost benefit analysis has yet to be performed using costs specific to testing and treatment for alloimmunization in the United States. This analysis examines the cost benefits of implementation of noninvasive RhD genotyping using characteristics specific to the tests available in the United States, U.S. cost of anti-D immune globulin prophylaxis, and cost of management of future sensitized pregnancies. We designed a decision tree that allowed us to follow three theoretical cohorts of one million nonalloiummunized women through pregnancy and delivery: 1) routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing; 2) noninvasive fetal RhD typing with prophylaxis guided by test results; and 3) no screening or prophylaxis. We calculated the number of sensitized women with each approach, fetal and neonatal morbidity and mortality, total number of anti-D immune globulin administrations, and costs involved in each strategy.
MATERIALS AND METHODS
Costs were estimated for the three strategies (Fig. 1). Strategy 1 consisted of routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing for all RhD-negative patients. Large studies have estimated the occurrence of first-trimester bleeding as 19–33%11,12; therefore, we estimated that 25% of patients would require two doses of prophylaxis because of bleeding or an invasive procedure necessitating its administration. The remainder (75%) was assumed to require antepartum prophylaxis only once. With this approach, cord blood typing was utilized to assess the need for additional maternal prophylaxis. Our analysis assumed cord blood serology to be the gold standard for RhD genotyping, with an accuracy of 100%.13 Those who were found to have an RhD-positive fetus received postpartum prophylaxis with anti-D immune globulin.
The other clinical strategy consisted of noninvasive screening using cell-free fetal DNA to determine fetal RhD status. For the purposes of this analysis, we assumed the test was performed early enough to avoid administration of anti-D immune globulin to the 25% of women experiencing any first-trimester bleeding. Several studies5,14 have supported the use of noninvasive RhD status determination during the first trimester. Thus, the finding of an RhD-negative fetus resulted in avoidance of all antepartum and postpartum prophylaxis. Our initial analysis assumed that no cord blood typing would be performed for neonates presumed to be RhD-negative on the basis of noninvasive screening; however, we later examined the effect of adding this evaluation to this group. With this strategy, those pregnant women found to have an RhD-positive fetus (60%) received either one or two antepartum anti-D immune globulin administrations as well as postpartum prophylaxis. Here, the cost of cord blood typing was omitted because we assumed fetal evaluation to be unnecessary given performance of the noninvasive test. The third strategy involved neither maternal screening nor prophylaxis.
Costs were ascertained for the following: noninvasive fetal RhD genotyping (cost obtained from Sequenom, adjusted for Medicaid and Medicare reimbursement); anti-D immune globulin (both medication and cost of administration); and newborn RhD evaluation. The costs of the latter two were derived from hospital billing records; both had cost-to-charge assumption of 37% (standard in South Carolina) applied. We then estimated costs of management of a sensitized pregnancy. To account for the various aspects of management, we included the cost of an initial ultrasonogram with middle cerebral artery Doppler studies and estimated based on experience in our tertiary referral center that a sensitized pregnancy would require eight follow-up ultrasonograms to evaluate middle cerebral artery Doppler studies. The cost of percutaneous umbilical cord blood sampling and intravascular transfusion was estimated for our hospital based on billing records. These costs were examined both in terms of facility and professional fees, and had a cost-to-charge assumption of 37% applied. We estimated based on experience at our institution and reports in the literature15 that a sensitized pregnancy with evidence of fetal anemia severe enough to require transfusion would require an average of three percutaneous umbilical cord blood sampling and transfusion procedures during the course of a pregnancy. Cost data are represented in Table 1.
To account for the cost of false-negative fetal RhD typing and subsequent alloimmunization, we performed a sensitivity analysis varying the false-negative rate from 0% (0.0000001 for purposes of statistical analysis) to 1.9%, which are the reported rates for the test used in the United States.5 It should be noted that the false-negative rate of 1.9% was found in the cohort of the clinical validation study by Bombard et al5 that did not use the fetal identifier single-nucleotide polymorphism assay. The two published studies (the clinical validation study and the test performance in a clinical cohort by Moise et al9) using the fetal identifier single-nucleotide polymorphism assay found false-negative rates of 0% and 0.45%, respectively.5 We assumed the average pregnancy rate in the United States to be 1.9 pregnancies per woman,16 thus putting the actual number of future “at-risk” pregnancies at 0.54 using the assumption that an RhD-negative woman has a 60% chance of carrying an RhD-positive fetus. We assumed a sensitization rate for base case analysis of 14%, but varied this from 0.2% to 14% in our sensitivity analyses; the high end of this range represents the percentages of sensitized pregnancies noted without either antepartum or postpartum anti-D immune globulin prophylaxis.1 The risk of hemolytic disease severe enough to necessitate intrauterine transfusion was derived from the landmark work of Mari et al,17 supported by previous studies by Bowman,18 and set at 10% for purposes of analysis. Published data regarding morbidity and mortality of fetal hydrops were used to provide a risk of 25%.15,18 This was thought to be a conservative estimate, given that as many as 50% of live births affected by untreated hemolytic disease result in death or brain damage.19 We assumed the 1–2% risk of severe complications involved with percutaneous umbilical cord blood sampling20 could be reasonably incorporated into this figure without substantially affecting the analysis. Finally, we set the cost for loss of life or severe disability at $5 million.21
Microsoft Excel was used to construct the model, which was designed in a decision tree format as outlined. Sensitivity analyses also were performed with Excel; probability estimates in support of the model are represented in Table 2. Multilevel sensitivity modeling was performed in circumstances in which both test specificity and costs required adjusting. After determination that the noninvasive screening arm was not cost-saving under any circumstances, threshold analyses were performed to determine at what cost the noninvasive fetal RhD testing must be set to incur no additional cost of testing. Given the nature of the analysis, qualifications for Institutional Review Board exemption at the Medical University of South Carolina were met.
The cost per pregnancy in the current approach to prevent alloimmunization (one to two antepartum administrations of anti-D immune globulin, fetal evaluation for blood type and RhD typing, and postpartum prophylaxis when indicated) is $351. Our initial analysis revealed that with a current noninvasive test cost and reimbursement rate of $450, assuming an essentially perfect test (false-negative rate=0.0000001), and sensitization rate of 14%, the noninvasive testing strategy would be $331 more expensive ($682 per pregnancy). A threshold analysis was performed to find the break-even cost of noninvasive fetal RhD testing; holding these variables constant, the fetal RhD typing test would need to cost $119. Again, fixing these variables as noted, we calculated that the cost of anti-D immune globulin must increase to $825 (from a baseline of $172 including cost of administration) for the two strategies to be cost-equivalent.
Use of noninvasive testing would avoid 500,000 unnecessary administrations of anti-D immune globulin per 1 million pregnancies and save $85 million in anti-D immune globulin expense. The cost of the noninvasive testing strategy is dependent on test characteristics (false-positive and positive rates of test, cost of test, cost of management of sensitized pregnancies, and the cost for loss of life or severe neurologic impairment in a future pregnancy as a result of sensitization). These costs under varying assumptions are represented in Table 3.
Given the knowledge that the majority of sensitization occurs at the time of delivery, we examined the effect of performing cord blood typing in all pregnancies previously found to be RhD-negative by noninvasive testing, assuming a false-negative rate of 0.45%.9 We anticipated this would “catch” most of those women who were missed and allow them to receive appropriate postpartum prophylaxis with anti-D immune globulin. For this analysis, the sensitization rate thus was decreased from 14% to 1.5%. Although it did not change costs appreciably given both low cost of cord blood typing and overall low number of sensitized pregnancies with noninvasive testing, this additional evaluation decreased the number of sensitizations leading to severe fetal morbidity and mortality from 34 to 4 per 1 million women.
Sensitivity analyses with varying test characteristics were performed; however, given the lack of economic benefit seen even with a false-negative rate of 0.0000001, increasing the false-negative rate of the test only served to widen the cost gap between the two strategies. Given the varying performances with different tests used outside of the United States (false-negative rates ranging from 0% [in a 4-year study performed in Belgium22] to 1.9%), we explored the effect that this would have if those tests were to be adopted for use in the United States. A single-exon RhD test used in Sweden has been shown to have a false-negative rate of 1.1% in a large study of 4,118 pregnancies.1 Assuming a test cost of $450 and false-negative rate of 1.1% with a sensitization risk set at 14%, the noninvasive arm would result in an increase in the number of clinically significant sensitizations from 34 to 83, and a subsequent increase in cost to $787 per pregnancy.
Sensitivity analyses also were performed at fixed test costs to examine the effect of changing the rate of sensitization from the base rate of 14% to as low as 0.2%. This did not affect the results given the extremely low prevalence of sensitization using a test with essentially zero false-negative results. Even using a false-negative rate of 0.45% and sensitization of 0.2%, noninvasive testing was not found to be cost-beneficial. Sensitivity analyses were performed to assess the effect of changing the number of middle cerebral artery Doppler studies and percutaneous umbilical cord blood sampling required in a sensitized pregnancy, because these can be highly variable and were found to have minimal effect on the overall cost differential of the two strategies. To ensure that the 37% cost-to-charge assumption did not change the overall results appreciably, we examined the model without this assumption. We found only a minimal effect on the overall cost differential between routine prophylaxis and noninvasive testing, as might be expected assuming the high negative predictive value of noninvasive testing. To assess what would occur with a lower rate of RhD-negativity as seen in other ethnic populations, we again tested the model and discovered this only served to widen the cost differential in favor of the strategy using routine prophylaxis.
The major determinants of costs included the cost of noninvasive screening, cost of anti-D immune globulin, and test accuracy. Once the test accuracy was fixed at a 0.0000001 false-negative rate, the costs of management of a sensitized pregnancy (ultrasound and Doppler monitoring, cost of percutaneous umbilical cord blood sampling, and cost attributable to loss of life) became insignificant because of such low prevalence.
Our results show that at the current cost of noninvasive fetal RhD testing, even assuming essentially perfect test performance, the test would not be of any economic benefit for management of all RhD-negative patients. Similar to Szczepura et al10, we also found that the major determinant of cost is the cost of testing. At first, it would seem that the cost of noninvasive determination ($450) would be similar to that of two administrations of anti-D immune globulin and fetal evaluation ($162+$9.60+$162+$9.60+$90=$377). One must note, however, that 60% of those who undergo noninvasive testing will still require administration of anti-D immune globulin. The cost-savings associated with the 40% of patients who have RhD-negative fetuses cannot offset the majority who will incur the cost of both noninvasive testing and prophylaxis.
From a purely economic point of view, routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing remains the most cost-beneficial option for management of RhD-negative women. However, one must consider the following scenarios: women opposed to the use of blood-derived products; ethical issues surrounding intentional alloimmunization for production of anti-D immune globulin; and the concern of product supply. In the Netherlands, decreased use of anti-D immune globulin has been viewed as an ethical benefit because of the fact that their supply is limited and derived from intentional alloimmunization of their own citizens.10 Although development of a monoclonal antibody to replace the plasma-derived product is in phase two clinical trials, it likely will be more expensive as a newly developed drug than human-derived anti-D immune globulin. An increased expense of prophylaxis could serve to shift the noninvasive testing option to a cost-saving option.9
Our study has several weaknesses. We did not account for any of the adverse reactions associated with use of anti-D immune globulin. Not considering reactions such as pain, tenderness, erythema, swelling, and hypersensitivity might create bias in the analysis toward the routine prophylaxis strategy. We used a 37% cost-to-charge assumption, which is standard in South Carolina. Likewise, the costs of management of a sensitized pregnancy were based on our hospital charges at a state-funded public university hospital; different costs might be incurred elsewhere.
For the sake of analyses, we assumed an RhD-negative rate of 15%; therefore, rates of fetal RhD-positivity were applicable only to Caucasian-only unions.1 These percentages would be expected to differ based on the ethnicity of the population studied. We did not consider the percentage of either false-positive or inconclusive results in the noninvasive testing arm. Management of false-positive results with middle cerebral artery Doppler studies with their own attendant risks of false-positive results and thus unnecessary percutaneous umbilical cord blood sampling might be expected to significantly increase the cost of the noninvasive testing arm. The Clinical Laboratory Improvement Amendments program reports that the percentage of tests that return as inconclusive or “not reported” is approximately 7.6%, the largest fraction of which are attributable to the presence of an RhD psi-pseudogene (personal communication with Bombard on February 8, 2013). This pseudogene has been described in 21% of African Americans,20 underlining the importance of further cost-benefit analyses in an ethnically diverse population. Weak D and partial D phenotypes (formerly referred to as Du) also have the potential to type as either RhD-positive or RhD-negative with noninvasive polymerase chain reaction–based methods.23
Strengths of this analysis include the fact that it is one of few cost-benefit models to examine the use of noninvasive RhD testing in a general population of nonsensitized RhD-negative women. We used the only published data regarding test characteristics of the single test currently available in the United States. The validation study was conducted on an ethnically diverse population of women, making it more generalizable. Our sensitivity analyses specifically addressed the 0.45% false-negative rate reported in the 2012 study by Moise.9 We accounted for varying schedules of prophylaxis based on an estimated value of 25% of women experiencing first-trimester bleeding. Finally, we addressed the novel use of targeted cord blood evaluation to theoretically decrease sensitizations occurring at the time of delivery for false-negative test results. The decrease in morbidity and mortality from 34 to 4 cases per 1 million pregnancies is of clinical significance with minimal overall cost difference, providing another possibility for future noninvasive testing-based algorithms.
In conclusion, our analysis reveals that the use of noninvasive testing for fetal RhD genotype in the population of nonalloimmunized RhD-negative women does not offer any economic benefit at the current test cost. It is likely that as more tests become available that can accurately verify the presence of fetal DNA and thus ensure a test will generate no additional sensitizations, the costs of these tests will decrease because of market competition. Our analysis revealed that at $119, universal noninvasive fetal RhD assessment would be equivalent in cost to routine prophylaxis. With cost equivalency, noninvasive fetal RhD typing might be the preferred strategy based on patient preference, supply of anti-D immune globulin, and other factors; true cost-saving might not be necessary to move to such an algorithm.
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