Cell free DNA screening for fetal aneuploidy in Ireland: An observational study of outcomes following insufficient fetal fraction

Abstract

Objectives: To determine maternal factors associated with low fetal fraction (FF). To determine the proportion of women who receive a result from repeat non-invasive prenatal testing (NIPT) testing. To identify any significant associations between pregnancy interventions or outcomes and low FF.

Study design: Retrospective observational study of 4465 women undergoing antenatal screening by targeted cell free DNA (cfDNA) testing at an Irish tertiary maternity hospital between January 2017 and December 2022. Patients who failed to obtain a result after the first NIPT were analyzed in two cohorts; those who received a result on a repeat sample and those who failed to ever achieve a result despite a second, third or fourth cfDNA test.

Results: Risk of insufficient FF significantly increased with elevated maternal BMI (OR 1.07; 95% CI 1.01-1.13, p = 0.03) and in-vitro fertilization (IVF) (OR 3.4; 95% CI 1.19-9.4, p = 0.02). Women with no result were more likely to have diagnostic invasive testing (p < 0.01), but had no increased risk of aneuploidy. Repeated failed NIPT attempts due to low FF were significantly associated with the subsequent development of hypertensive diseases of pregnancy (p = 0.03). Greater than 70% of patients who were unsuccessful in a first or second attempt at NIPT due to low FF yielded a result following a second or third sample.

Conclusions: High BMI and IVF conceptions are greater contributors to low FF than fetal aneuploidy. Repeating NIPT yields a result in greater than 70% of cases. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Fetal fraction (FF) in prenatal cfDNA testing is influenced by maternal and pregnancy factors including body mass index (BMI) and IVF. Low FF has been associated with adverse pregnancy outcomes including fetal aneuploidy and hypertensive diseases of pregnancy. WHAT DOES THIS STUDY ADD?: In a large Irish population, increasing maternal BMI and in-vitro fertilization are the most significant contributors to repeated test failures due to low FF. Greater than 70% of patients with test failure due to low FF will receive a result on 2nd and 3rd NIPT attempts. Patients with no result from NIPT were more likely to undergo diagnostic invasive testing but the risk of aneuploidy was not significantly increased.

Keywords: Aneuploidy; Low fetal fraction; NIPT.