Natural history and evaluation of abnormal or nonreportable NIPT results and its association with maternal neoplasia

National Human Genome Research Institute

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Abstract

In the twelve years since it became clinically available, noninvasive screening for fetal aneuploidy by sequencing cell-free (cf) DNA fragments that circulate in maternal blood has disrupted established global paradigms for prenatal care. In general, these tests work by mapping sequenced DNA fragments and determining if there are excess or reduced copy numbers compared to a reference genome. Commercial laboratories in the United States each have their own proprietary analytic algorithms. Around 1% of the time, a non-reportable test result is generated that is due to either technical issues (such as insufficient DNA or low fetal fraction in the sample) or biological issues (such as a twin demise or confined placental or maternal mosaicism). The acronym for this study is the IDENTIFY Study: Incidental DEtection of maternal Neoplasia Participants undergo an initial evaluation at the Clinical Center to diagnose possible neoplasia. All collected clinical, laboratory and imaging information is discussed in monthly multidisciplinary team meetings. If neoplasia is discovered, results are shared with participants and referring physicians and guide subsequent clinical management. Participants will be followed for up to five years post-partum to collect all available medical information. Dr. Bianchi and Amy Turriff, CGC, performed over 35 outreach activities to increase national and international awareness among obstetric care providers of the potential of NIPT to detect maternal malignancy and to establish relationships for referrals. These included multiple Ob/Gyn Grand Rounds hospital presentations, case presentations to commercial laboratories providing NIPT results, lecturing to the state of Californias Perinatal Testing Program, and participating in multiple Continuing Medical Education conferences. To educate medical oncologists we wrote a peer-reviewed commentary on the potential to detect maternal malignancy via NIPT that was published in the Journal of Clinical Oncology (IF=32) in August 2022. As a result of this outreach, participant enrollment in our IRB-approved protocol has increased significantly since enrollment began in December 2019. To date we have enrolled 98 participants. They have come from all over the US and four have come from Canada. Of these, six are Black (6.1%), four are Asian or Pacific Islander (4.1%), one is of multiple races (1.0%), 12 are White, Hispanic (12.2%), and 75 are White, non-Hispanic (76.5%). Our interim results show that 52% of participants have a clinically silent malignancy. While lymphoma is the most common diagnosis, we have also detected extremely rare tumors such as adrenocortical carcinoma (incidence=1 in 1,000,000). Other biological explanations for the unusual noninvasive prenatal testing results include confined placental mosaicism, benign uterine leiomyomas, and clonal abnormal hematopoiesis. What has been missing, to date, is the voice of the pregnant person after receiving incidental prenatal screening results. Amy Turriff and Skye Miner, PhD (Dept of Bioethics, NIHCC) designed and completed a study that examined the personal impact of receiving noninvasive prenatal screening results that suggest maternal malignancy. In this study, we sought to explore patient perspectives by interviewing 49 individuals who received non-reportable or discordant NIPT results and enrolled in the IDENTIFY study. They were interviewed before and after receiving the outcome of their clinical evaluations for cancer. Interviews were independently coded by two researchers and analyzed thematically. After analysis of the qualitative data, three themes were identified: 1) limited pre-test awareness of maternal incidental findings caused considerable confusion for the participants, whose initial concerns focused on their babies; 2) the care providers communication influenced how participants perceived their risk of cancer and their need to be evaluated; and 3) the participants perceived value in receiving maternal incidental findings from NIPT despite any stress it caused them during their pregnancies. Participants viewed the ability to detect occult malignancies as an added benefit of NIPT and felt strongly that this information should be disclosed. Admittedly, the study group may be biased because they chose to come to the NIH to be evaluated for cancer. We did not capture the experiences of people who declined to participate in the IDENTIFY study or those who were not referred to us. This study demonstrated that obstetric providers need to 1) be aware that maternal incidental findings can be found following cfDNA sequencing; 2) inform pregnant people of the potential to receive these results during pre-test counseling, and 3) provide accurate and objective information during post-test counseling. This information is crucial considering the high incidence of malignancy we are detecting in IDENTIFY study participants.