Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At‐Risk Couples

Abstract

Expanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes to determine reproductive risk. Data on the clinical utility of screening conditions beyond professional guidelines are scarce. Individuals underwent ECS for up to 110 genes. Five-hundred thirty-seven at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to participate in a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results. Sixty-four eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n = 28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. Twenty-nine percent (n = 13) were not planning to alter reproductive decisions. The remaining 9% (n = 4) of responses were unclear. Of 19 pregnant respondents, 42% (n = 8) elected PNDx, 11% (n = 2) planned amniocentesis but miscarried, and 47% (n = 9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. Two of 3 affected pregnancies were terminated. Disease severity was found to have significant association (p = 0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p = 0.284). Most ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.Electronic supplementary materialThe online version of this article (10.1007/s10897-017-0160-1) contains supplementary material, which is available to authorized users.

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

“…Our previous study of carrier rates in 346 790 patients showed that an ECS panel was expected to identify more pregnancies at risk for serious conditions than ethnic-based panels spanning far fewer genes (4 ), and the American College of Obstetricians and Gynecologists recently recognized ECS as an acceptable strategy for preconception and prenatal carrier screening (5 ). To the extent that these guidelines increase ECS usage, they will have a large clinical impact because it has recently been shown in clinical-utility studies that approximately 80% of couples found to be at risk for severe conditions pursue alternative reproductive options (6,7 ).…”

Clinical Impact and Cost-Effectiveness of a 176-Condition Expanded Carrier Screen

“…While many couples undergo prenatal ECS, preconception screening was the focus of our model because it has well established utility and confers greater patient autonomy 2 . We expect similar results at either stage but with a reduced rate of reproductive interventions for prenatal screening 10 . Importantly, even if the intervention rate were to drop from its 76% preconception value to 50% in the prenatal period (as was observed in the post-conception cohort in 10 ), our one-way sensitivity analysis demonstrated that ECS would still avert 150 births affected with severe disease and $2,000 in lifetime cost per birth.…”

“…Second, we assume that the detection rate for each condition is 100% (see Discussion), so that couples deemed "not at risk" have zero chance of having a child affected with a screened condition (see Discussion). Third, at-risk couples (ARCs; defined below) have a fixed probability of choosing a reproductive intervention that is assumed to avert any possibility of a child affected by a screened condition; this fixed probability (76%) is estimated from survey-based clinical utility studies of ARCs 10,11 .…”

“…Due to the high mortality associated with ECS conditions, the per-birth rate of lost life-years was 0.017, or 0.078 without discounting ( Table 2). In clinical practice where screening is performed, approximately 76% of patients would intervene 10,11 to avoid an affected birth (via, e.g., in vitro fertilization with preimplantation genetic diagnosis, use of donor gamete, adoption, or decision to avoid pregnancy), meaning that ECS would avert 230 affected births per 100,000 pregnancies ( Table 2: "76% Intervention ECS"). Finally, the model also estimated the incremental gain of ECS over minimal screening ("76% Intervention CF23+SMA" in Table 2), showing that ECS averts an additional 200 births per 100,000 pregnancies.…”

“…Among only affected births, the average lifetime cost per affected birth was $1,300,000. Considering a more realistic comparison wherein 76% of ARCs intervene to avoid an affected birth 10 and CF23+SMA is used as a baseline, ECS still showed large incremental cost savings when averaged over all births: approximately $2,100 over a lifetime, $230 in years 0-3, and $70 in years 0-1.…”