Effects of sildenafil treatment on placental immune cell subsets in early-onset fetal growth restriction

Introduction: Early onset fetal growth restriction is a common pregnancy complication with significant risk of perinatal mortality and morbidity. The most common etiology is placental insufficiency, reflected by several placental lesions that appear with fetal growth restriction. Placental immune cells are involved in almost all aspects of the development of the placenta and immune cell imbalances have been related to common pregnancy complications. The STRIDER trial investigated the therapeutic potential of sildenafil. No clinical improvements were observed, however, since sildenafil can have immunological effects, we aimed to investigate if sildenafil alters local placental immune cells. Methods: Placental samples from 146 patients were included from the STRIDER trial and stained with IHC for leukocytes (CD45), macrophages (CD68 and CD206), T cells (CD3 and CD8), regulatory T cells (FOXP3) and NK cells (CD56). Immune cells were quantified in the decidua basalis and villi at term using a trained detection classifier. In addition, maternal plasma cytokines were measured at inclusion. Results: In the sildenafil group, numbers of CD3+ T cells, CD68+ and CD206+ macrophages and CD56+ NK cell were greater in the decidua basalis compared to the control group. Correlating maternal plasma cytokines to placental immune cell subsets showed predominantly negative correlations in the placebo group, whereas most cytokines correlated positively to placental immune cells in the sildenafil group. Discussion: Our data demonstrates the immunomodulatory effects of sildenafil in pregnancies complicated by early onset fetal growth restriction and offers valuable insights on the use of immunomodulatory drugs in pregnancy.