Cost-Effectiveness of Exome Sequencing versus Targeted Gene Panels for Prenatal Diagnosis of Fetal Effusions and Non-Immune Hydrops Fetalis


      Although exome sequencing has a greater overall diagnostic yield than targeted gene panels in the evaluation of nonimmune hydrops fetalis and fetal effusions, the cost-effectiveness of this approach is not known.


      This study aimed to evaluate the costs and outcomes of targeted gene panels vs exome sequencing for prenatally diagnosed nonimmune hydrops fetalis and fetal effusions when next-generation sequencing is pursued following nondiagnostic standard nonimmune hydrops fetalis evaluations, including karyotype or chromosomal microarray.


      A decision-analytical model was designed using TreeAge Pro to compare 10 genetic testing strategies, including a single test only (RASopathy, metabolic, or nonimmune hydrops fetalis–targeted gene panel or exome sequencing), sequential testing (RASopathy panel followed by nonimmune hydrops fetalis panel, metabolic panel followed by nonimmune hydrops fetalis panel, RASopathy panel followed by exome sequencing, metabolic panel followed by exome sequencing, and nonimmune hydrops fetalis panel followed by exome sequencing), and no additional genetic testing. Our theoretical cohort included cases with normal karyotype and/or microarray and excluded cases of alloimmunization and congenital viral infections. As nonimmune hydrops fetalis and fetal effusions can present throughout gestation, whereas pregnancy management options vary depending on gestational age, outcomes were calculated for 3 time intervals: 10 to 18, 18 to 22, and >22 weeks of gestation. The primary outcome was incremental cost per quality-adjusted life year. Additional outcomes included termination of pregnancy, stillbirth, neonatal death, and neonates born with mild, moderate, and severe or profound disease phenotypes. The cost-effectiveness threshold was $100,000 per quality-adjusted life year.


      Among women <18 weeks of gestation, exome sequencing alone was the dominant strategy associated with the lowest costs ($221 million) and the highest quality-adjusted life years (10,288). Strategies with exome sequencing alone or as a sequential test resulted in more terminations but fewer stillbirths, neonatal deaths (NNDs), and affected infants than strategies without exome sequencing. Among women between 18 and 22 weeks of gestation, exome sequencing alone was also associated with the lowest costs ($188 million) and the highest quality-adjusted life years (8734), and similar trends were observed in pregnancy outcomes. Among patients >22 weeks of gestations, when termination was not available, exome sequencing was associated with lower costs ($300 million) and the highest quality-adjusted life years (8492). Exome sequencing was cost-effective up to a cost per test of $50,451 at <18 weeks of gestation, $50,423 at 18 to 22 weeks of gestation, and $9530 at >22 weeks of gestation. Targeted genetic panels and exome sequencing were cost-effective strategies compared with no additional genetic testing.


      For cases of nonimmune hydrops fetalis and fetal effusions with nondiagnostic karyotype or microarray, next-generation sequencing was cost-effective compared with a strategy without additional genetic testing. For those that undergo next-generation sequencing, exome sequencing was the cost-effective strategy compared with all other testing strategies using targeted gene panels, leading to lower costs and fewer adverse perinatal outcomes. Exome sequencing was cost-effective in a setting without the option for pregnancy termination. These data supported the routine use of exome sequencing when next-generation sequencing is pursued for establishing a genetic diagnosis underlying otherwise unexplained nonimmune hydrops fetalis and fetal effusions.


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