Cell-free DNA is a relatively new technology for screening of fetal chromosomal abnormalities, with an unprecedented accuracy in the detection of trisomy 21. This test is also known as non-invasive prenatal testing (NIPT). In 1997, Lo et al. first described the presence and measurability of cell-free DNA in maternal blood and subsequently reported that levels of cell-free fetal DNA (cffDNA) were increased in pregnant women carrying fetuses with trisomy 21. There has been recent clinical introduction of cffDNA testing to screen for common fetal chromosomal abnormalities, with studies reporting its use in an Australian setting . Given the high detection rate for trisomy 21, cffDNA testing has become increasingly popular and is recommended for both high-risk and general obstetric populations. Cell-free ‘fetal’ DNA originates from the placenta, and increased amounts are shown to correlate with larger placental mass. The proportion of placental DNA in the total cell-free DNA is known as fetal fraction, and higher fetal fraction values have been associated with higher test accuracy. In recent years, our group has shown that fetal fraction levels are associated with first trimester biomarkers of pre-eclampsia at 11-14 weeks of gestational age. Low fetal fraction is associated with higher mean arterial pressure, higher uterine artery resistance on Doppler ultrasound, with lower placental growth factor levels and with higher predicted probability of developing pre-eclampsia and fetal growth restriction (Rolnik DL et al. Association between fetal fraction on cell-free DNA testing and first-trimester markers for pre-eclampsia. Ultrasound Obstet Gynecol. 2018;52(6):722-7). Previous studies from our group have also demonstrated that fetal fraction is decreased in IVF pregnancies and in women with increased body mass index, and these are important risk factors for the development of pre-eclampsia (Rolnik DL et al. Influence of Body Mass Index on Fetal Fraction Increase With Gestation and Cell-Free DNA Test Failure. Obstet Gynecol. 2018;132(2):436-43; and Lee TJ et al. Cell-free fetal DNA testing in singleton IVF conceptions. Hum Reprod. 2018;33(4):572-8.). Pre-eclampsia and fetal growth restriction account for half a million perinatal deaths every year, and 76,000 mothers die from pre-eclampsia complication annually. Women at high risk for pre-eclampsia benefit from prophylaxis with aspirin initiated before 14 weeks (Rolnik DL et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017;377(7):613-22.). Whether fetal fraction indeed correlates with actual adverse pregnancy outcomes is uncertain. In this study, we aim to merge pregnancy outcomes collected by state-wide data linkage with a large dataset of women undergoing cell-free DNA testing to investigate the possible association of fetal fraction with birthweight and pregnancy complications, and its added value in screening for pre-eclampsia and fetal growth restriction when integrated in a multi marker predictive algorithm.
Cell-free DNA test, NIPT, fetal fraction, early pregnancy screening, pre-eclampsia, fetal growth restriction.
School of Clinical Sciences at Monash Health / Hudson Institute of Medical Research » Obstetrics and Gynaceology
Monash Medical Centre Clayton