Establishment of pregnancy through successful embryo implantation and placentation requires crosstalk between multiple maternal cell types and invading fetal trophoblast cells. Defects in this process have been associated with multiple adverse perinatal outcomes including hypertensive disorders of pregnancy, placenta accreta, and recurrent miscarriage. While immune cells were originally thought to only play a role in maternal tolerance of the semi-allogenic fetus, an active role in pregnancy establishment is becoming increasingly apparent. Uterine natural killer (uNK) cells are of specific interest due to their cyclic increase in number during the window of implantation. As a distinct entity from their peripheral blood counterparts, understanding the biology and function of uNK cells will provide the framework for understanding their role in early pregnancy establishment and adverse pregnancy outcomes.

This review discusses unique uNK cell characteristics and presents clinical implications resulting from their dysfunction. We also systematically present existing knowledge about uNK cell function in three processes critical for successful human embryo implantation and placentation: stromal cell decidualization, spiral artery remodeling, and extravillous trophoblast invasion. We also review features of uNK cells that could help guide future investigations.

With such intimate involvement in pregnancy, it is plausible that abnormalities in NK cell number and function could play a critical role in abnormal implantation and placentation resulting in adverse perinatal outcomes. It is therefore imperative to dissect the unique physiological role of uNK cells in pregnancy and use this knowledge to inform clinical practice by determining how uNK cell dysfunction could lead to reproductive failure.