Fetal fraction-based risk algorithm for non-invasive prenatal testing: screening for trisomies 13 and 18 and triploidy in women with low cell-free fetal DNA

Abstract

Objective: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF).

Methods: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively.

Results: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%).

Conclusions: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: NIPT; fetal fraction; guidelines; maternal weight; pregnancy loss; prenatal screening; triploidy; trisomy.

Figure 1

Flowchart showing how fetal fraction (FF)‐based risk (FFBR) algorithm determines FFBR risk score for each patient. Prior risk is based on gestational age and maternal age.

Figure 2

Distribution of fetal fraction‐based risk (FFBR) scores in cases for which single‐nucleotide polymorphism‐based non‐invasive prenatal testing did not return a result, in entire cohort (n = 1148) (a), and in cases with FFBR score ≥ 25% (n = 78) (b). Unaffected pregnancies (), and cases with trisomy 18 () and triploidy () are shown. Pregnancy losses include only those of unknown karyotype ().

Figure 3

Relationship between maternal weight and fetal fraction (FF) (at 11 weeks' gestation) at FF‐based risk (FFBR) score of 1%, according to maternal age: 20 years (); 30 years (); 35 years () and 40 years (). Region under each line corresponds to a high FFBR score for that maternal age; thus, at this gestational age, a 20‐year‐old woman weighing 200 lb (90.7 kg) would receive a high FFBR score if her FF were less than ∼2.0%, whereas a 40‐year‐old woman at the same weight would receive a high FFBR score if her FF were less than ∼4.5%. Likewise, a 20‐year‐old woman with a FF of 3% would receive a high FFBR score if her weight were less than approximately 150 lb (68.0 kg), whereas at the same FF, a 40‐year‐old woman would receive a low FFBR score only when her weight was over ∼260 lb (117.9 kg).