SUMMARY:

NIPS, a prenatal screening test based on cell free DNA technologies, has a high sensitivity and specificity for the detection of common fetal aneuploidies. However, these tests can also detect incidental findings. In rare cases, chromosomal abnormalities (typically more complex than seen in common fetal aneuploidy cases) can reflect changes in the mother’s cells, such as maternal cancer, unrelated to the pregnancy. Currently, there are no professional recommendations to assist healthcare professionals regarding what to do if a NIPS result indicates potential risk for maternal cancer. An expert review has been published that provides a suggested approach to pretest counseling for a typical pregnant patient as well as next steps in case of a NIPS report suggestive of maternal cancer (Rink et al., Obstetrics and Gynecology, 2022)

Background 

• Prenatal cfDNA screening methodologies rely on the presence of both DNA fragments from placental cells and maternal DNA fragments that circulate in a pregnant patient’s serum
• Cancer occurs in approximately 1 in 1,000 to 1,500 pregnancies
• Circulating tumor-derived cell-free DNA (ctDNA) can be detected with NIPS
  • Concern for maternal malignancy on a prenatal screening may be flagged by a lab when there is a finding of multiple aneuploidies or autosomal monosomy
  • These atypical findings occur in approximately 0.07% of cases
• NIPS is a screening and not a diagnostic test
  • Any report can suggest potential for increased risk but is not a definitive diagnosis

Pretest Counseling of Patients Prior to NIPS

• Discuss possible incidental findings including the potential to identify maternal malignancy
• Incidental findings are more likely with genome-wide vs more targeted NIPS
• Pregnant patients with a personal history of cancer or bone marrow/organ transplantation should understand that cfDNA screening for fetal aneuploidy can be confounded by the presence of donor DNA, disease progression or recurrence
  • Other methods of screening or diagnostic testing for aneuploidy may be preferred in this setting

If the NIPS Report Suggests Increased Risk for Maternal Malignancy  

• Offer fetal diagnostic testing (typically amniocentesis) to rule out fetal source of abnormality
• If fetal diagnostic testing is normal, the following data have been reported regarding maternal cancer risk based on original NIPS result
  • Single autosomal monosomy: Cancer incidence of 4%
  • Multiple aneuploidies: Cancer incidence between 20%

Note: High-risk cfDNA results for a single trisomy or monosomy X are not expected to confer an increased risk for maternal malignancy, even when fetal diagnostic testing is normal | Likely explanation related to mosaicism (placental, fetal or maternal) or co-twin demise

Additional Counseling Points

• Prenatal NIPS screening tests are not designed or validated to detect malignancies
• A low-risk NIPS result does not rule out the possibility of cancer in a pregnant patient
• There is no standard reporting method to indicate a potential risk for maternal malignancy with prenatal NIPS screening
  • Laboratories may use multiple terms like abnormal, atypical or nonreportable
  • Laboratories differ on use of telephone calls vs including the risk within the actual report
• Healthcare professionals are encouraged to contact the laboratory to discuss details of a particular case if the possible reasons for an uninformative result are not clear from the written report

Management

• Detailed medical and family history
• Comprehensive physical exam including
  • Breast | Head & Neck | Pelvic including cervical cancer screening | Rectal
  • Follow-up any positive findings
• Labs
  • CBC with differential | Complete metabolic profile | Urinalysis | Fecal occult blood testing
• Imaging
  • Consider patient’s desire for information, costs, personal and family history
  • Tests that may be ordered
    • CXR and/or breast imaging
    • Upper and lower GI endoscopy
    • Whole body diffusion weighted MRI

KEY POINTS:

• NIPS reports may return results suggesting increased maternal risk for malignancy
• Prenatal NIPS screening tests are not designed or validated to detect malignancies
• Positive predictive values for malignancy span a range with highest risks seen for multiple aneuploidies
• Currently, there are no standardized professional guidelines for next steps following a NIPS result suggesting possible maternal malignancy
• Suggested work up for malignancy includes consideration of patient’s desire for information, costs, personal and family history
• Referral to an oncology specialist may also be considered

Learn More – Primary Sources:

Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening (Rink et al. Obstetrics and Gynecology, 2022)

NIH IDENTIFY Study: To enroll patients with NIPS results suspicious for maternal malignancy

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Genetic Services Locator-NSGC 

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