1. What is the decision or change (e.g. clinical topic, practice guideline, system design, delivery of care) you are facing or struggling with where a summary of the evidence would be helpful?
Question: What is the effectiveness of non-invasive prenatal cell-free DNA screening (NIPS) for detection of microdeletions/microduplications?
Population: individuals with first- and second-trimester singleton pregnancy or multiple pregnancies
Intervention: NIPS using analysis of cell-free fetal DNA for detection of fetal microdeletions/microduplications is the intervention. Genetic counseling may also be necessary.
Comparator: conventional serum and ultrasound screening followed by invasive diagnostic testing in select cases when ultrasound indicates anomalies (eg, heart defects, cleft palate) that could be associated with a particular microdeletion/microduplication syndrome, as well as standard of care without screening
Outcomes: The primary outcomes of interest are test accuracy and validity, reductions in miscarriages associated with invasive confirmatory testing, and reduction in the use of other noninvasive and invasive tests received by the pregnant individuals.
2. Why are you struggling with this issue?
Non-invasive prenatal screening tests have high market demand. Yet, it is difficult to assess the effectiveness and safety of the tests individually due to laboratory factors and limited published data.
Laboratory factors include that none of the commercially available NIPS tests are FDA approved and there is no regulatory oversight. There are a number of labs offering varying NIPS tests with different underlying methodologies. There are even laboratory developed NIPS testing kits and equipment for purchase and use by any lab; while this provides in-house NIPS and faster turn-around, the effectiveness and safety of these tests in the lab of origin let alone in any purchasing lab is unknown.
The published clinical validity and clinical utility of testing for microdeletions is limited, as there are missing data on confirmatory testing, false-negatives, and there is no widely accepted clinical use for screening for microdeletions and microduplications. Although there is potential for clinical utility in screening for some syndromes associated with microdeletions early in pregnancy, the clinical management changes that would be associated with early diagnosis of these syndromes are not well-established, and the potential for outcome improvements associated with early diagnosis (ie, before the diagnosis would be suspected on the basis of physical exam findings or findings on routine imaging) is not well-established.
The potential low positive predictive value of NIPS tests for rare microdeletions was recently highlighted in a 2022 New York Times article. The article described how clinical decisions are being made based on the results of these tests in contradiction to guideline recommendations.
The American College of Obstetricians and Gynecologists does not recommend the use of NIPS to detect microdeletions or microduplications. A recent systematic review by the America College of Medical Genetics also reports that no conclusions can be made as to the use of NIPS for microdeletions. Yet, ACMG’s systematic review further reports the cost-effectiveness of adding microdeletion screening to NIPS for common aneuploidies based on quality adjusted life years, decreased overall costs, and fewer neonatal deaths and second trimester miscarriages. While the ACMG clinical guidelines forthcoming from their systematic review is not yet published, it is important that those recommendations be based on net health outcomes.
When NIPS results are positive, even for those who receive professional guidance and assurance that NIPS is a screening test and that most positive results are false positives, the ramifications of false positive results can be emotional and financial. The New York Times article highlighted examples including a mother who despite reassurance could not stop thinking about the screening results, crying through the ultrasound thinking how she might never see her baby, and who spent thousands of dollars on follow-up tests to eventually learn that the NIPS positive result was false. Others do not have time for follow-up testing after positive NIPS considering legal timelines for elective pregnancy termination, and then face the enormous decision of elective termination of a potentially healthy pregnancy. Similarly, some parents try to have follow-up testing, only to not have results returned soon enough. They too must make termination decisions without full information, and some find out after the termination that follow-up results were normal.
The mental health impacts and disruption in family dynamics that can come from false NIPS results then cannot be overlooked. Indeed, the uncertainty of the accuracy of any commercially available NIPS test is such that the FDA released a safety communication warning patients and health care providers about the risks of false results with NIPS and the importance of confirmatory testing. Yet, widespread use of unregulated NIPS is expected only to grow, with predictions of future test volume to double by 2025. In this landscape of unregulated testing and growing demand, an AHRQ report could provide objective clarity.
3. What do you want to see changed? How will you know that your issue is improving or has been addressed?
While federal oversight of laboratory developed tests (LDTs) is yet to happen, it is important that patients and providers be able to make evidence-based testing decisions, and payers be able to make evidence-based coverage determinations. An objective evidence review by AHRQ could advise patients, providers, professional societies, and payers. While payers can have evidence-based medical coverage policies, it is difficult to implement in the landscape of patient and provider demand largely generated from laboratory marketing efforts. An AHRQ review could lend credibility as to the state of the evidence and reduce inappropriate use of NIPS and potential associated harms.
4. When do you need the evidence report?
Sun, 06/02/2024
5. What will you do with the evidence report?
Given the extensive marketing from NIPS laboratories competing in a billion-dollar industry and the expected growth in test uptake in the face of much uncertainty about test performance, a full systematic review and evidence report is needed to inform patients, providers, professional societies, payers, and other decision-makers as to the evidence base of commercially available NIPS tests. Reliance on Congress and a federal oversight of LDTs is a potential, but longer-term solution.
An evidence report could be used to inform patients and providers in making NIPS testing decisions, help professional societies in making practice guidelines, and help payers with coverage decisions. The timing is critical, as demand for answers has been currently heightened.
Supporting Documentation
ACMG Systematic Evidence Review for NIPS 2022 (PDF, 608 KB)
Optional Information About You
What is your role or perspective? Medical Director
If you are you making a suggestion on behalf of an organization, please state the name of the organization? Blue Cross Blue Shield Association
May we contact you if we have questions about your nomination? Yes
