Temporal persistence of residual fetal cell‐free DNA from a deceased cotwin after selective fetal reduction in dichorionic diamniotic twin pregnancies

Abstract

Objectives: To determine the temporal persistence of the residual cell-free DNA (cfDNA) of the deceased cotwin in maternal circulation after selective fetal reduction and evaluate its long persistence in noninvasive prenatal testing (NIPT).Methods: Dichorionic diamniotic twins (N ¼ 5) undergoing selective fetal reduction because of a trisomy were recruited. After informed consent, maternal blood was collected immediately before reduction and periodically after reduction until birth.The plasma cfDNA of each sample was sequenced and analyzed for fetal aneuploidy and fetal fractions.Results: In all pregnancies, the fetal fraction of the cfDNA of the deceased fetus increased to peak at 7-9 weeks after fetal reduction, and subsequently decreased gradually to almost undetectable during the late third trimester. The NIPT T-scores persistently reflected the detection of fetal trisomy up to 16 (median 9.5) weeks after fetal reduction. Conclusions:Residual cfDNA from the deceased cotwin after selective reduction at 14-17 gestational weeks led to the persistent generation of false-positive NIPT results for up to 16 weeks postdemise. Thus, providing NIPT for pregnancies with a cotwin demise in early second trimester is prone to misleading results and not recommended. Key PointsWhat's already known about this topic? � The estimated prevalence of a cotwin's fetal demise in all twin pregnancies is 6.2%, although the prevalence might be underestimated. The deceased fetus releases residual cell-free DNA (cfDNA) to the maternal circulation, leading to false-positive findings of fetal aneuploidy on noninvasive prenatal testing (NIPT). However, the evidence is still needed to determine the implications of longitudinal residual cfDNA for NIPT use.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cell‐free DNA testing of maternal blood in screening for trisomies in twin pregnancy: updated cohort study at 10–14 weeks and meta‐analysis

“…If cfDNA testing is adopted as a first-line method of screening for trisomy in twin pregnancy, it is still imperative that women should be offered an 11-14-week scan for, first, accurate dating of pregnancy from the crown-rump length of the largest twin, second, diagnosis of chorionicity, which is the main determinant of a wide range of adverse outcomes 34 , third, measurement of fetal nuchal translucency thickness and assessment of intertwin discordance in crown-rump length, which have a strong influence on adverse pregnancy outcome 35,36 , fourth, diagnosis of a vanishing twin, because this would preclude the use of cfDNA testing for at least 16 weeks after the estimated time of fetal demise 37,38 , fifth, early diagnosis of major fetal abnormalities 39 , sixth, to determine the presence of major defects, such as holoprosencephaly or exomphalos, in which case an invasive test with microarray rather than cfDNA testing would be the appropriate pregnancy management 40 , seventh, early screening for preterm pre-eclampsia, which is 8-9-times more common in twins than in singleton pregnancies 41,42 , and, eighth, measurement of cervical length, because, if this is short, prophylactic use of vaginal progesterone could substantially reduce the risk of preterm birth 43 .…”

Performance of cell‐free DNA testing for common fetal trisomies in triplet pregnancies

“…This situation raises the question of when cfDNA testing should be performed after reduction. CfDNA from trisomic embryos has been shown to persist up to 16 weeks after selective termination of pregnancy in the 1st trimester 25 . However, Kleinfinger et al shows that the delay between the sample and the date of the end of the pregnancy in vanishing twin does not seem to play a role in the test's performance 26 .…”

“…CfDNA from trisomic embryos has been shown to persist up to 16 weeks after selective termination of pregnancy in the 1st trimester. 25 However, Kleinfinger et al shows that the delay between the sample and the date of the end of the pregnancy in vanishing twin does not seem to play a role in the test's performance. 26 The reliability of the results in the twin mode, whether there are two or 3 fetuses (i.e.…”

Application of non-invasive prenatal testing to 91,280 spontaneous pregnancies and 3477 pregnancies conceived by in vitro fertilization

“…Since foetal cfDNA is derived mainly from the trophoblast cells of the placental villi and because the continuous turnover of cytotrophoblasts induces apoptosis to release cfDNA into the maternal blood and does not fully represent the foetus, differences in genetic information between placental and foetal tissue may influence NIPT [ 7 – 9 ]. Yang et al [ 30 ] and Mi et al [ 31 ] reported that the development of ART led to a significant increase in the number of lost twin pregnancies, that residual foetal cfDNA in deceased twins could persist for 16 weeks and that residual foetal cfDNA may affect NIPT outcomes. Tatjana et al [ 32 ] reported that maternal malignancy can also affect NIPT.…”