Here, by studying clinical samples, in vitro cell models (HTR‐8/SVneo cell line and primary human EVTs), ex vivo first‐trimester villous explants and an in vivo abortion mouse model, we found that disruption of a GDF15–Jagged‐1 (JAG1) axis increased the risk of URPL by impairing EVT invasion and migration. Here, GDF15 is linked to abortion.