Objective
We analyzed the cost-effectiveness (CE) and performances of commonly used prenatal Down syndrome (DS) screening strategies.
Study Design
We performed computer simulations to compare 8 screening options by applying empirical data from Serum, Urine, and Ultrasound Screening Study trials on the population of 110,948 pregnancies. Screening strategies outcomes, CE ratios, and incremental CE ratios were measured.
Results
The most CE DS screening strategy was the contingent screening method (CE ratio of Can$26,833 per DS case). Its incremental CE ratio compared to the second-most CE strategy (serum integrated screening) was Can$3815 per DS birth detected. Among the procedures respecting guidelines, our results identified the combined test as the screening strategy with the highest CE ratio (Can$47,358) and the highest number of procedure-related euploid miscarriages (n = 71).
Conclusion
In regard to CE, contingent screening is the best choice. The combined test, which is the most popular screening strategy, shows many limitations.
In the last 15 years, major advancements have been made in Down syndrome (DS) prenatal screening. However, there is still no consensus on the optimal strategy that should be offered to pregnant women. Actually, neither Canada nor the United States has adopted a national strategy and screening practices largely differ across North America. Matched to worldwide-advised procedures, 6 screening options respecting guidelines in Canada and the United States are available: quadruple, combined, integrated, and serum integrated tests, and stepwise sequential (sequential) and contingent sequential (contingent) screenings.
Whereas pretest counseling should be available to patients so that they can make an informed choice for screening procedures, the literature is insufficient to help clinicians choose among the options proposed. The risks and benefits of each strategy have been partially reported on different populations and a detailed analysis of the cost-effectiveness (CE) of these options on the same model is lacking. So far, most analyses published have not used empirical data, have applied inappropriate statistical approaches, or have compared the CE of invasive tests vs no diagnosis. Evaluation of 3 strategies combining first- and second-trimester analyses (contingent, sequential, and integrated screenings) has been reported with limited and contradictory results: Ball et al demonstrated that contingent screening dominated the integrated test, whereas Wald et al concluded that integrated screening had the best screening performance. Many authors have addressed concerns regarding the lack of data about these 3 screening strategies. Given the numerous screening options available, it is unlikely that any single empirical or clinical study could compare all the strategies available with acceptable external validity. Computer simulations are an elegant alternative to identify which strategy is likely to be the most CE. We recently reported the impact of various risk cutoffs in first trimester on their CE. The objective of the current study is to compare all commonly used screening strategies including the quadruple and the serum integrated tests, but also the combined test, since first-trimester screening has become the de facto standard of care in the United Kingdom, France, and the United States, while the rest of North America may follow suit.
Materials and Methods
Design
Using the modeling approach previously developed, a decision analysis was performed through the computation of expected outcomes resulting from the DS screening options tested. Data simulations were performed on a virtual population of 110,948 pregnancies with demographic (maternal age distribution), genetic, and phenotypic (regarding DS) characteristics of the Quebec, Canada, population. By this approach we simulated the costs and outcomes of all options considered. The Figure presents a simplified version of the decision model.
Screening options and endpoints
Analyses were run to analyze the CE (global costs, CE ratios [costs per DS diagnosed], and the incremental CE ratios [ICER]) of 8 screening options (quadruple, combined, integrated, and serum integrated tests; sequential and contingent screenings; maternal age alone [≥35 years]; and the triple test) from a public health perspective and to compare their performance estimates for an overall 90% detection rate by evaluating 7 other relevant endpoints that cover the main outcomes in DS prenatal screening: the false-positive rate, which defines the number of scheduled amniocentesis procedures; the number of procedure-related euploid miscarriages; the number of DS live births; the number of unnecessary terminations; the proportion of DS pregnancies screened by a first-trimester test; the proportion of patients reassured in early gestation through first-trimester testing; and the proportion of continuing pregnancies that proceed to second-trimester testing. The ICER represents the ratio of the difference in the cost of 2 screening strategies divided by the difference in outcome (additional DS case diagnosed) of the 2 techniques.
Sequential and contingent screenings
Given the published data for sequential and contingent screenings, the first-trimester high-risk cutoff we applied was 1 in 30, and in the contingent screening approach, the lower risk cutoff used on the first test was 1 in 2000.
Diagnosis tests
Simulated diagnostic procedures are contingent on the timing of the screening test results. To evaluate the impacts of screening tests based on the gold standard of prenatal care, only amniocentesis was used in prenatal diagnosis following second-trimester screenings results. However, for women who tested positive in the first-trimester screening, transabdominal chorionic villous sampling (CVS) karyotyping was considered. Timing and rate of procedure-related euploid miscarriages depends on the tests undergone. The model also takes into account diagnostic test performance characteristics (amniocentesis and CVS).
Data
The screening markers and procedures used are shown in Table 1 . All input variables and their sources are presented in Table 2 .
| Combined test | First-trimester test based on combining NT measurement (NT, ultrasound measurement of width of area of translucency at back of fetal neck early in pregnancy) with free β-hCG, PAPP-A, and maternal age. |
| Triple test | Second-trimester test based on measurement of AFP, uE3, and hCG (either total hCG or free β-hCG) together with maternal age. |
| Quadruple test | Second-trimester test based on measurement of AFP, uE3, free β-hCG (or total hCG), and inhibin-A together with maternal age. |
| Integrated test | Integration of measurements performed at different times of pregnancy into single test result. Unless otherwise qualified, “integrated test” refers to integration of NT and PAPP-A in first trimester with quadruple test markers in second. First-trimester screening marker results are not analyzed until second-trimester markers are evaluated, at which point they are both assessed together. |
| Serum integrated test | Variant of integrated test without NT (using PAPP-A in first trimester and quadruple test markers in second trimester). |
| Sequential screening | Screening in which first-trimester test is performed (NT, free β-hCG, and PAPP-A) and result is interpreted immediately. If this is positive, diagnostic test is offered (CVS), but if it is not positive, second-trimester serum markers are measured (quadruple test markers) and first-trimester markers are reused to form integrated test. |
| Contingent screening | Screening in which first-trimester test (NT, free β-hCG, and PAPP-A) is used to triage population of women screened into 3 groups: 1 group (high-risk screen-positive) that is immediately offered diagnostic test (CVS), second group (screen-negative) that receives no further screening, and third intermediate group (or lower-risk screen-positive) that has second-trimester markers measured (quadruple test markers) and first-trimester measurements reused to form integrated test. |
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