Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta‐analysis

Abstract

Objectives To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy and to define the performance of the test by combining our results with those identified in a systematic review of the literature. MethodsThe data for the prospective study were derived from screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation. Two populations were included; first, self-referred women to the Fetal Medicine Centre in London or Brugmann University Hospital in Brussels and, second, women selected for the cfDNA test after routine first-trimester combined testing at one of two National Health Service hospitals in England. This dataset was used to determine the performance of screening for the three trisomies. Search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancy. A meta-analysis was then performed using our data and those in the studies identified by the literature search. ResultsIn our dataset of 997 twin pregnancies with a cfDNA result and known outcome, the test classified correctly 16 (94.1%) of the 17 cases of trisomy 21, nine (90.0%) of the 10 cases of trisomy 18, one (50.0%) of the two cases of trisomy 13 and 962 (99.4%) of the 968 cases without any of the three trisomies. The literature search identified seven relevant studies, excluding our previous papers because their data are included in the current study. In the combined populations of our study and the seven studies identified by the literature search, there were 56 trisomy-21 and 3718 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 98.2% (95% CI, 83.2-99.8%) and 0.05% (95% CI, 0.01-0.26%), respectively. In the combined total of 18 cases of trisomy 18 and 3143 nontrisomy-18 pregnancies, the pooled weighted DR and FPR were 88.9% (95% CI, 64.8-97.2%) and 0.03% (95% CI, 0.00-0.33%), respectively. For trisomy 13, there were only three affected cases and two (66.7%) of these were detected by the cfDNA test at a FPR of 0.19% (5/2569). ConclusionsThe performance of cfDNA testing for trisomy 21 in twin pregnancy is similar to that reported in singleton pregnancy and is superior to that of the first-trimester combined test or second-trimester biochemical testing. The number of cases of trisomies 18 and 13 is too small for accurate assessment of the predictive performance of the cfDNA test.Conclusiones La bondad del desempeño de la prueba de cfDNA para la trisomía 21 en el embarazo de gemelos es similar a la reportada en embarazos con fetoúnico y es superior a la de la prueba combinada del primer trimestre o a la de la prueba bioquímica del segundo trimestre. El número de casos de trisomías 18 y 13 es demasiado...

Clinical performance of non‐invasive prenatal testing for trisomies 21, 18 and 13 in twin pregnancies: A cohort study and a systematic meta‐analysis

“…Xu et al reported that the sensitivity and specificity were 0.9896 and 0.9997 for detection of trisomy 21, 1.00 and 0.9997 for trisomy 18, and 1.00 and 0.9997 for trisomy 13, respectively, in a multicenter follow‐up study of 31 515 singleton pregnancies in southeastern China 39 . All of the above data suggest that the performance of NIPT for trisomy 21 in twin pregnancies was similar to that in singleton pregnancies, as also reported by Nicolaides et al 38 Nicolaides et al mainly compared the pooled weighted detection rate (DR) and false‐positive rate, whereas we mainly analyzed the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and AUC. What is more, we conducted a subgroup analysis to enrich our content.…”

“…Thus 32 studies remained to be assessed for eligibility by reading of the full text. Eventually, 21 relevant studies met all the inclusion criteria and were included in this meta‐analysis 9,19‐38 . A flow chart summarizing the selected eligible studies in systematic review is shown in Figure 1.…”

“…In terms of flow and timing, four studies together with our study were assessed as unclear risk as they had a small population lost to follow up and adverse pregnant outcomes or the NIPT test failed to provide results in some cases 21,32,36,37 . Eight studies were rated as high‐risk because the population of lost to follow up and adverse pregnant outcomes was large 25‐28,30,33,35,38 . The remaining studies were assessed as low‐risk.…”

First‐trimester screening for trisomies in pregnancies with vanishing twin

“…In vanishing-twin pregnancies with a CRL measurement of the dead embryo, the mean log 10 MoM was assumed to depend linearly on time since demise; this linear relationship was assumed to continue until the mean log 10 MoM equaled that in vanishing-twin pregnancies with an empty sac. Beyond this, the mean was taken to be constant at this value for all vanishing twins.…”

Validation of fetal DNA fraction estimation and its application in noninvasive prenatal testing for aneuploidy detection in multiple pregnancies

“…The sensitivity is reduced by 9% for trisomy 21 (T21), 28% for trisomy 18 (T18), and 22% for trisomy 13 (T13) in twin pregnancies compared with those in singleton pregnancies . Very recently, a study showed that the performance of NIPT for T21 in twin pregnancy is similar to that reported in singleton pregnancy, with the sensitivity of 98.2% (95% CI, 83.2%‐99.8%) . Due to the lack of sufficient validation data of the test specificity and sensitivity, NIPT is recommended with caution for twin pregnancies and is not recommended for higher‐order multiple pregnancies .…”