Low fetal fraction in cell‐free DNA testing is associated with adverse pregnancy outcome: Analysis of a subcohort of the TRIDENT‐2 study

Abstract

Objectives To assess the association between low fetal fraction (FF) in prenatal cell‐free DNA (cfDNA) testing and adverse pregnancy outcomes. Methods We conducted a retrospective cohort study of participants of the TRIDENT‐2 study (Dutch nationwide government‐supported study offering cfDNA screening for fetal aneuploidies) who received a failed test result due to low FF (<4%) between April 2017 until February 2018. Outcome measures included pregnancy‐induced hypertension (PIH), pre‐eclampsia (PE), small for gestational age neonates (SGA), spontaneous preterm birth (sPTB), gestational diabetes mellitus (GDM), chromosomal aberrations, and congenital structural anomalies. Results Test failure due to low FF occurred in 295 women (1.12% of tests performed). Information regarding pregnancy outcomes was available for 96.3% of these women. The incidence of PIH, PE, SGA, sPTB, and GDM was 11.2%, 4.1%, 7.3%, 5.1%, and 14.8%, respectively. The prevalence of chromosomal aberrations and congenital structural anomalies was 1.4% and 4.1%, respectively. Incidences of PIH, PE ≥ 34 weeks of gestation, GDM, and prevalence of aneuploidy and congenital structural anomalies were higher in women with low FF compared to the general Dutch obstetric population. Conclusion Low FF is associated with adverse pregnancy outcomes. The value of FF in the prediction of these outcomes needs to be further established.

Lower fetal fraction in clinical cell‐free DNA screening results is associated with increased risk of hypertensive disorders of pregnancy

“…Our results support that the possible use of FFs on clinical cfDNA screening reports for the prediction of adverse pregnancy outcomes deserves further investigation in larger prospective studies. [21][22][23][24] Fetal cells enter maternal circulation through trophoblast apoptosis, and thus it is not surprising that pathologies affecting the placenta would impact the FF. 36 The pathophysiology of HPD, specifically preeclampsia, is thought to be due to abnormal trophoblast invasion of uterine vessels during placentation.…”

“…Several studies have shown that there is an increase in both fetal and total cfDNA in women with preeclampsia and other hypertensive disorders of pregnancy (HPD), but the FF remains low due to the greater percentage of maternal cfDNA in the plasma. [21][22][23][24] Moreover, it has recently been shown that there is a positive correlation between FF and placental proteins such as beta-hCG, PAPP-A, and PlGF, all of which are biomarkers of placental function. 25 In a case-control study that included euploid, trisomy 21, and trisomy 18 pregnancies, Ashoor et al found that FF correlated with levels of maternal PAPP-A and beta-hCG, which are known placenta-derived serum biomarkers used to screen for aneuploidy.…”

“…28,29 This was the basis for a number of studies investigating the potential of FF as a biomarker for obstetric complications that may be associated with or caused by abnormal placentation, such as HPD and fetal growth restriction (FGR). 20,22,23,26,29,30 Becking et al showed that among women who had a failed cfDNA test result due to low FF in the TRIDENT-2 study, there was a higher incidence of pregnancy-induced hypertension and preeclampsia when compared to the general Dutch population, 22 but conclude that further research is needed to evaluate the predictive value of FF in detecting HPD. Bender et al also showed that women screened during the first and second trimester who were later diagnosed with HPD had lower fetal fractions, but they found that this was no longer significant after adjusting for confounding variables.…”

“…FF is also affected by fetoplacental factors given that cffDNA arises from the placenta. Several studies have shown that there is an increase in both fetal and total cfDNA in women with preeclampsia and other hypertensive disorders of pregnancy (HPD), but the FF remains low due to the greater percentage of maternal cfDNA in the plasma 21–24 . Moreover, it has recently been shown that there is a positive correlation between FF and placental proteins such as beta‐hCG, PAPP‐A, and PlGF, all of which are biomarkers of placental function 25 .…”

“…Thus, it has been postulated that women with an increased risk for placental disorders will more likely have lower FFs 28,29 . This was the basis for a number of studies investigating the potential of FF as a biomarker for obstetric complications that may be associated with or caused by abnormal placentation, such as HPD and fetal growth restriction (FGR) 20,22,23,26,29,30 . Becking et al.…”