Obstetrical, perinatal and genetic outcomes associated with non-reportable prenatal cell free DNA screening results


Mary E. Norton, University of California, San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, CA. Electronic address: mary.norton@ucsf.edu.
Cora Macpherson, The Biostatistics Center, George Washington University, Washington, DC.
Zachary Demko, Natera Inc, San Carlos, CA.
Melissa Egbert, Natera Inc, San Carlos, CA.
Fergal Malone, Rotunda Hospital, Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology. Dublin, Ireland.
Ronald J. Wapner, Columbia Presbyterian Medical Center, Department of Obstetrics and Gynecology, New York, NY.
Ashley S. Roman, New York University Langone, Department of Obstetrics and Gynecology, New York, NY.
Asma Khalil, St George's Hospital, University of London, Department of Obstetrics and Gynecology, London, United Kingdom.
Revital Faro, St. Peter's University Hospital, Department of Obstetrics and Gynecology, New Brunswick, NJ.
Rajeevi Madankumar, Long Island Jewish Medical Center, Department of Obstetrics and Gynecology, Hyde Park, NY.
Noel Strong, Icahn School of Medicine at Mount Sinai, Department of Obstetrics and Gynecology, New York, NY.
Sina Haeri, Austin Maternal-Fetal Medicine, Austin, Tx.
Robert Silver, University of Utah, Department of Obstetrics and Gynecology, Salt Lake City, UT.
Nidhi Vohra, North Shore University Hospital, Department of Obstetrics and Gynecology, Manhasset, NY.
Jon Hyett, Royal Prince Alfred Hospital and Western Sydney University, Department of Obstetrics and Gynecology, Sydney, Australia.
Kimberly Martin, Natera Inc, San Carlos, CA.
Matthew Rabinowitz, Natera Inc, San Carlos, CA.
Bo Jacobsson, Sahlgrenska University Hospital, Department of Obstetrics and Gynecology, Gothenburg, Sweden; Sahlgrenska Academy, University of Gothenburg, Department of Obstetrics and Gynecology, Gothenburg, Sweden.
Pe'er Dar, Montefiore Medical Center, Albert Einstein College of Medicine, Department of Obstetrics and Gynecology and Women's Health, Bronx, NY.

Document Type

Journal Article

Publication Date



American journal of obstetrics and gynecology




adverse perinatal outcomes; cell free DNA screening; non-invasive prenatal screening; preeclampsia; preterm birth


BACKGROUND: The clinical implications of non-reportable cfDNA screening results are uncertain, but this may reflect poor placental implantation in some cases and be associated with adverse obstetrical and perinatal outcomes. OBJECTIVE: To assess the outcomes of pregnancies with non-reportable cell-free DNA (cfDNA) screening in a cohort of patients with complete genetic and obstetric outcomes. STUDY DESIGN: This was a prespecified secondary analysis of a multicenter prospective observational study of prenatal cfDNA screening for fetal aneuploidy and 22q11.2 deletion syndrome. Participants who underwent cfDNA screening from April 2015 through January 2019 were offered participation. Obstetric outcomes and neonatal genetic testing results were collected from 21 primary care and referral centers in the US, Europe, and Australia. The primary outcome was risk for adverse obstetrical and perinatal outcomes (aneuploidy, preterm birth (PTB) at <28, <34, and <37 weeks' gestation, preeclampsia, small for gestational age (SGA) or birthweight <10th percentile for gestational week, and a composite outcome that included PTB<37 weeks, preeclampsia, SGA, and stillbirth>20 weeks') after non-reportable cfDNA screening due to low fetal fraction or other causes. Multivariable analyses were performed, adjusting for variables known to be associated with obstetrical and perinatal outcomes, non-reportable results, or fetal fraction. RESULTS: In total, 25,199 pregnant individuals were screened, and 20,194 were enrolled. Genetic confirmation was missing in 1165 (5.8%), 1085 (5.4%) were lost to follow-up, and 93 (0.5%) withdrew; the final study cohort included 17,851 (88.4%) participants who had cfDNA, fetal or newborn genetic confirmatory testing, and obstetrical and perinatal outcomes collected. Results were non-reportable in 602 (3.4%). A sample was redrawn and testing again attempted in 427; in 112 (26.2%) results were again non-reportable. Non-reportable results were associated with higher BMI, chronic hypertension, later gestational age, lower fetal fraction, and Black race. Trisomy 13, 18, or 21 was confirmed in 1.6% with non-reportable tests vs. 0.7% with results (p=.013). PTB <28, 34, and 37 weeks, preeclampsia, and the composite outcome were higher after non-reportable results, and further increased with a second non-reportable test, while SGA was not increased. After adjustment for confounders, the aOR for aneuploidy was 2.2 (95% CI 1.1, 4.4) and 2.6 (95% CI 0.6, 10.8) and for the composite outcome was 1.5 (95% CI 1.2, 1.8) and 2.1 (95% CI 1.4, 3.2) after a first and second non-reportable test. In all, 94.9% of patients with non-reportable tests had a livebirth as compared to 98.8% with those with test results obtained (aOR for livebirth: 0.20 [95% CI 0.13-0.30]). CONCLUSIONS: Patients with non-reportable cfDNA results are at increased risk for a number of adverse outcomes, including aneuploidy as well as preeclampsia and preterm birth. They should be offered diagnostic genetic testing and clinicians should be aware of the increased risk of pregnancy complications.