Implications of Failure to Achieve a Result from Prenatal Maternal Serum Cell-Free DNA Testing: A Historical Cohort Study

N. Chan, M. E. Smet, R. Sandow, F. Da Silva Costa, A. McLennan

Research output: Contribution to journalEditorialOtherpeer-review

2 Citations (Scopus)


Noninvasive prenatal testing (NIPT) involves the analysis of cell-free DNA fragments in maternal serum. During pregnancy, cell-free DNA consists of both maternal fragments, primarily from hematopoietic cells, and fetal fragments, released from trophoblasts during apoptosis. Although laboratories use different technologies, in general, these DNA fragments are all sequenced, and their chromosomal origins identified using the maternal genome as a reference, and processed by counting algorithms to identify chromosomal imbalances. Overall, it is reported that approximately 2% to 3% of NIPT tests return an inconclusive result. As the use of NIPT has become more widespread, it has been reported that NIPT failure may have clinical significance. The researchers performed a historical cohort study that included pregnant women who undertook NIPT at a private multisite prenatal screening service in Sydney, Australia, between June 2013 and March 2016, and failed to obtain a result. The maternal characteristics, other antenatal investigations and pregnancy outcomes for these women were comparedwith women in the same practice who obtained a result, and to the general Australian obstetric population. Antenatal investigations included pregnancy-associated plasma protein A (PAPP-A), free β-human chorionic gonadotrophin (β-hCG), placental growth factor (PlGF), uterine artery pulsatility index (PI), and mean arterial pressure (MAP). Pregnancy outcomes included chromosomal abnormality, preeclampsia, gestational diabetes, small-for-gestational age (SGA), and preterm delivery. Outcome data included pregnancy complications, delivery mode, and neonatal characteristics, and were self-reported by the study participants via telephone interview conducted after the conclusion of the pregnancy. Definitions in this population were as follows: preterm delivery was delivery before 37 weeks of gestation; SGA is birth weight less than 10th percentile adjusted for gestational age; preeclampsia is hypertension and coexistence of at least one of proteinuria, uteroplacental dysfunction, maternal organ dysfunction (renal insufficiency, liver involvement, or neurological complications); gestational diabetes mellitus is any of fasting plasma glucose level of 5.1 to 6.9 mmol/L, 1-hour post 75-g oral glucose load greater than 10 mmol/L, or 2-hour post 75-g oral glucose load of 8.5 to 11 mmol/L. A total of 12,033 women underwent NIPT at Sydney Ultrasound For Women during the study period, with 6375 (53%) undertaking Harmony tests and 5658 (47%) undertaking GeneSyte tests. The study found 131 participants who received an inconclusive result (1.1%), of whom 119 (90.8%) were conducted by Harmony and 12 (9.2%) by GeneSyte. The Harmony inconclusive test result rate of 1.9%(119/6375) was significantly higher than that for GeneSyte (0.2%, 12/5658; P < 0.0001). Low fetal fractionwas reported as the cause of NIPT failure in 59women (45%), and technical assay failure or logistical issues were responsible in 59 women (45%). In 13 women (10%), the reason for failure was not reported. Of the 131 women who failed to obtain a result, 75 underwent a subsequent sample collection for NIPTeither with GeneSyte,Harmony, Verifi, or Panorama, whereas the remainder pursued alternative screening pathways. Of the 75 who underwent a repeat NIPT, 13 (17.3% of all repeat samples; 28.3% of repeat Harmony samples) again received an inconclusive result. Women with failed NIPT results had lower levels of PAPP-A (0.75 vs 1.14 MoM, P < 0.0001), and free b-hCG (0.71 vs 1.01 MoM, P < 0.0001) as well as increased uterine artery pulsatility index (1.79 vs 1.65MoM, P = 0.02). These women also had significantly higher rates of chromosomal aneuploidy (6.5% vs 0.2%, P < 0.0001), preeclampsia (11% vs 1.5%, P < 0.0001), and gestational diabetes (23% vs 7.5%, P < 0.0001) compared with the general obstetric population. Rates of preterm delivery and SGAwere not significantly increased. This study demonstrated that women who failed to receive a result from NIPTwere at increased risk for adverse pregnancy outcomes, including chromosome abnormalities and pregnancy complications such as preeclampsia and gestational diabetes. Moreover, the failure rate of NIPT indicates that there is still an important role for combined first-trimester ultrasound and biochemical screening and for conventional invasive prenatal testing (chorionic villus sampling, amniocentesis), which rarely fails to report a result and also tests for a larger number of chromosomal and genetic abnormalities. A potential future study in this cohort of women may investigate the placenta-maternal immunological interface through exosome testing to provide additional insight into abnormal placental function.

Original languageEnglish
Pages (from-to)611-613
Number of pages3
JournalObstetrical and Gynecological Survey
Issue number11
Publication statusPublished - Nov 2018

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