Non-Invasive Prenatal Testing in Donor-Oocyte Pregnancies: Biological Determinants, Algorithmic Limitations and Clinical Implications.

Abstract

Non-invasive prenatal testing (NIPT) based on circulating cell-free DNA (cfDNA) has transformed prenatal screening for common aneuploidies, but its interpretation is less straightforward in pregnancies conceived with donor oocytes. In this setting, fetal chromosomal risk is largely donor-driven, whereas cfDNA interpretability is shaped mainly by the recipient and the placenta. Donor-oocyte pregnancies are enriched for advanced maternal age, obesity, hypertensive and immunologic complications, low-molecular-weight heparin exposure, multiple gestation, vanishing twin, and placental dysfunction - all factors that can destabilize the cfDNA signal. Fetal fraction should therefore be read not only as a technical quality metric but also as a biological marker of placental performance. Analytical platform behavior also matters; counting-based and single-nucleotide polymorphism-based approaches may behave differently in biologically complex samples, particularly for sex chromosome findings and in the setting of maternal confounding. In donor-oocyte pregnancies, a no-call result may be clinically informative rather than neutral. Pre-test counseling, explicit communication with the laboratory, availability of fetal-fraction reporting, and integration with first-trimester ultrasound are essential. Donor-oocyte pregnancy should be regarded as a biologically distinct model for cfDNA screening, one that exposes the limits of generic NIPT algorithms and argues for more tailored interpretation.