Prolonged duration of persistent cell‐free fetal DNA from vanishing twin

Cell-free fetal DNA (cffDNA)-based non-invasive prenatal testing (NIPT) for aneuploidy provides a highly accurate screening test that may reduce the need for invasive testing1. It has also been utilized to determine fetal sex with greater than 98% accuracy2. Cumulatively, NIPT has an approximately 1% false-positive rate2, one-third of which has a biological explanation such as maternal copy number variant, maternal mosaicism, maternal malignancy, confined placental mosaicism, fetal mosaicism or a vanishing twin3. The rate of vanishing twin pregnancy detected by NIPT ranges from 0.42 to 0.6%4. Cotwin demise, however, contributes as much as 42.1% to confirmed false-positive NIPT results3,4. The duration of cffDNA persistence from a demised twin, which may interfere with NIPT accuracy, is currently unknown. To date, the longest documented interval following ultrasound identification of cotwin demise and its detection using NIPT is 8 weeks4. The following report is of a case of discordant sex identification using NIPT, 15 weeks after the identification of cotwin demise. A 31-year-old healthy nulliparous woman underwent in-vitro fertilization with double-embryo transfer. First-trimester ultrasound examinations from 6 + 1 weeks onwards demonstrated two gestational sacs: one containing a single live embryo and one that was anembryonic. First-trimester aneuploidy screening was negative. An ultrasound examination at 21 + 2 weeks identified an appropriately grown female fetus with a right-sided echogenic intracardiac focus and two-vessel cord. The couple pursued cffDNA testing at 21 + 3 weeks. Results indicated a male fetus with low aneuploidy risk. Due to discordance between the sex indicated using cffDNA testing and that indicated on ultrasound, the images were reviewed and the patient was referred for further genetic testing. Ultrasound at 23 + 2 weeks confirmed female genitalia and identified a likely fetal uterus. Repeat cffDNA testing at 28 + 6 weeks' gestation was consistent with a female fetus. Invasive investigations were declined. Following an uncomplicated vaginal delivery, a detailed physical exam confirmed normal female genitalia. The postnatal course was uncomplicated. This case describes misidentification of fetal sex due to a vanishing twin. The unique feature of this case is the 15 weeks separating the identification of cotwin demise and the discordant NIPT result. This is significantly longer than the previously documented interval of 8 weeks4. Gestational age at demise and persistence of fetal tissue may influence the fetal fraction of circulating DNA attributable to the demised twin and for how long it is detectable using conventional testing. Clinically, cffDNA testing is an adjunct to traditional aneuploidy screening. In this case, its persistence from the demised cotwin for at least 15 weeks indicates a risk of false positives throughout the primary period of aneuploidy screening, including after soft-marker identification on ultrasound. In cases of a known vanishing twin, it is important for practitioners to be aware of the potential for prolonged false-positive NIPT results secondary to the demised

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