Protocol for a prospective observational cohort study to assess clinical applications of expanded noninvasive prenatal testing (NIPT) in pregnancies with placental dysfunction.

introductionExpanded non-invasive prenatal testing (NIPT) utilizing cell-free DNA (cfDNA) in maternal blood enables the detection of common trisomies as well as rare autosomal trisomies and large deletions and duplications within the genome of the placenta and, therefore, the fetus. Given that cfDNA predominantly originates from trophoblastic cells, expanded NIPT also holds the potential to reveal confined placental mosaicism (CPM). CPM has been associated with placental dysfunction, which can result in reduced levels of the circulating placental biomarkers routinely tested as part of first-trimester aneuploidy screening and in early-onset fetal growth restriction (eoFGR). This study aims to explore whether expanded NIPT adds clinical value compared with targeted NIPT in pregnancies exhibiting placental dysfunction, which is proxied herein by first-trimester pregnancy-associated plasma protein A (PAPP-A) or the beta-subunit of human chorionic gonadotropin (β-hCG) values <0.3 multiples of the median (MoM) or the diagnosis of eoFGR. MATERIALS AND

methodsThis is a prospective, multicenter, observational cohort study conducted at six Spanish sites from 2021 to 2026. Inclusion criteria are singleton pregnancies with PAPP-A or β-hCG values <0.3 MoM in the first-trimester or eoFGR defined as FGR diagnosed before 32 + 0 weeks of gestation in the absence of congenital anomalies according to Delphi criteria. Expanded NIPT is performed in all enrolled patients, and pregnancy and perinatal outcomes are evaluated. PROTOCOL VERSION: 6.0, 27th January 2026.