Expanding access to molecular diagnostics in maternal-fetal medicine: A case study

Numerous discoveries in molecular diagnostics have driven a sudden expansion of the field, presenting significant challenges for clinical implementation. Even with robust institutional systems in place, the decision to implement or authorize new genetic testing is multi-factorial, with consideration given to the test itself, the performing laboratory, anticipated volume, clinical utility, professional society guidelines, and costs for patients and healthcare systems. Insufficient data in any of these areas may delay or prevent the adoption of innovative medicine.

The prenatal genetic testing landscape has experienced particularly rapid advancements. It has evolved from traditional karyotyping to fluorescence in situ hybridization and microarray, to noninvasive cell-free DNA screening, and now even includes advanced molecular diagnostic techniques like fetal whole exome and whole genome sequencing (fWES and fWGS, respectively). Although sequencing methods have been foundational to advancing research, the real-world clinical application of fWES and fWGS is still debated. These tools are not currently recommended for routine care, but there is increasing recognition among providers and healthcare entities that there are clinical scenarios where fWES and fWGS can improve diagnostic yield (1).

At Johns Hopkins University, we took a multidisciplinary, stewardship-based approach to identifying the most appropriate use of fWES and fWGS. Stewardship programs strive to advance healthcare delivery, high-value care, and efficient operations. Although early programs focused primarily on analytical systems, test performance represents only one component of the testing process (2). As healthcare systems evolve to become more nuanced and complex, interdisciplinary collaboration among laboratory medicine professionals, genetic counselors, clinicians, and administrators is essential to ensuring patients have access to testing that informs high-quality, individualized care (2,3). Leveraging a team-based approach to stewardship allows healthcare leaders and subject-matter experts to evaluate medical advancements, establish clinical utility, assess operational feasibility, and perform cost analyses to protect patients from financial harm.

In this article, we describe a collaborative initiative that brought together leaders in prenatal genetic counseling, maternal-fetal medicine, and laboratory medicine to develop a clinical algorithm for optimizing use of molecular diagnostics for prenatal testing at our institution.

Establishing an ordering algorithm for fWGS

To address the diagnostic needs of their patients, professionals in the division of maternal-fetal medicine at Johns Hopkins University strongly advocated for an examination of access to molecular diagnostics in prenatal care, specifically for investigating fetal anomalies detected by ultrasound.

Prior to this initiative, testing followed a tiered approach that was largely reflective of guidelines set forth by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) (4). When fetal anomalies were identified via ultrasound, patients were counseled on the potential for an underlying genetic etiology and relevant testing options. If an invasive procedure was elected, a chromosomal microarray was typically recommended as the first-line diagnostic analysis.

If the microarray results were nonexplanatory for the ultrasound findings, fWES would be offered to patients who wanted to pursue additional testing. Although the use of fWES for prenatal sequencing goes beyond the scope of ACOG and SMFM guidelines, the additive value in select cases is supported by a 2022 position statement published by the International Society for Prenatal Diagnostics (ISPD) (5). Nevertheless, there were instances when this tiered-testing paradigm fell short, highlighting a clinical need for access to fWGS.

To evaluate this need, the university established a working group comprised of prenatal genetic counselors and leaders from maternal-fetal medicine and laboratory medicine. They performed a needs assessment to define the current state of testing and highlight where it was inconclusive or precluded timely clinical intervention. The working group brought a wealth of knowledge and diverse experiences to the review of specific cases, leading to a clear determination of which patients would benefit most from fWGS (Box 1).

Box 1. Indications for direct fWGS ordering

Their work culminated in the establishment of an ordering algorithm — a framework that relies on clinical judgment while ensuring that early implementation of fWGS remains focused and appropriate (Figure 1). The team also conducted a financial review to ensure the new framework did not strain health-system resources and to help clinicians advise patients regarding the potential financial burdens of testing.

Figure 1. Institutional ordering algorithm for fWGS

Building on initial success

After the working group completed its proposal, the institution’s laboratory formulary committee reviewed and approved the new ordering algorithm and financial analysis. The algorithm was used as a key tool to define the clinical utility of fWGS, estimate projected test volumes, and perform cost assessments. The team enlisted the engagement and support of the institution’s prenatal genetic counseling team to ensure patients received appropriate guidance and felt empowered to make informed decisions.

This initiative sparked further collaboration between the maternal-fetal medicine department and the laboratory formulary committee at Johns Hopkins. In subsequent projects, we evaluated diagnostics for fetal methylation disorders and fragile X syndrome. More recently, we established a mechanism to perform fetal blood typing in order to prepare whole-blood products for neonates who require emergency cardiac surgery at delivery.

Although each new project requires a slightly different approach, we follow the same core process to ensure smooth integration: cultivating consensus among the treating team while examining clinical utility, analytical validity, regulatory compliance, and operational feasibility. In each instance, a concurrent financial review is also performed to ensure we remain responsible stewards.

As we build on these promising initial experiences, we remain committed to working in interdisciplinary teams. Such collaboration is key to promoting robust and transparent billing practices and implementing systematic improvements for integrating novel and clinically impactful genetic tests into clinical practice.
 
Ashley R. Rackow, PhD, DABCC, NRCC, is a medical director and assistant professor in the department of pathology at Johns Hopkins University in Baltimore. +EMAIL: [email protected]

Sabrina V. Southwick, MS, LCGC, is a genetic counselor in the division of maternal-fetal medicine within the department of gynecology and obstetrics at Johns Hopkins University in Baltimore. +EMAIL: [email protected]

Read the full September-October issue of CLN here.

References

1. Shreeve N, Sproule C, Choy KW, et al. Incremental yield of whole-genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2024; doi: 10.1002/uog.27491.
2. Plebani M, Laposata M, Lundberg GD. The brain-to-brain loop concept for laboratory testing 40 years after its introduction. Am J Clin Pathol 2011; doi: 10.1309/AJCPR28HWHSSDNON.
3. Hilborne LH, Chambliss AB. Diagnostic stewardship — Our past, our current status, and future promise. J Appl Lab Med 2025;10:200–4.
4. Committee on Genetics and the Society for Maternal–Fetal Medicine. Committee Opinion No. 682: Microarrays and next-generation sequencing technology: The use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol 2016; doi: 10.1097/AOG.0000000000001817. Reaffirmed 2023.
5. Van den Veyver IB, Chandler N, Wilkins-Haug LE, et al. International Society for Prenatal Diagnosis updated position statement on the use of genome-wide sequencing for prenatal diagnosis. Prenat Diagn 2022; doi: 10.1002/pd.6157.