Victor Vaca-Merino; Raúl Sánchez & Fabiola Zambrano

Neutrophil extracellular trap (NET) formation, or NETosis, has emerged as a pivotal factor in the maternal-fetal immune dialogue. During pregnancy, neutrophils infiltrate the decidua and placenta, where their activation must be finely balanced between defending against pathogens and preserving fetal tolerance. Excessive NETosis is increasingly implicated in pregnancy complications by injuring trophoblasts, inciting placental inflammation, and disrupting maternal vascular homeostasis. This review synthesizes clinical, molecular, and immunological evidence on key themes: the dual role of NETosis at the maternal-fetal interface, NETosis-driven placental pathology in preeclampsia and related disorders, metabolic modulation of NETosis in gestational diabetes with downstream trophoblast apoptosis, NETosis as a mediator between maternal inflammatory conditions (autoimmune disease, periodontal disease) and adverse pregnancy outcomes, and the dynamic changes in neutrophil phenotype from early gestation to the pro-NETotic state of the puerperium. We highlight how NET components (DNA, histones, proteases) provoke endothelial damage, complement activation, and thrombo-inflammation in the placenta, while also questioning how evolution may have harnessed NETs for reproductive success. Throughout, we pose unresolved questions, for example, could targeting NETosis or its upstream drivers (like IL-8, ROS, or HMGB1) ameliorate disorders such as preeclampsia without compromising host defense? By integrating insights from recent studies, including those on preeclampsia, gestational diabetes, systemic lupus erythematosus, periodontal disease, and postpartum immunity, this review aims to present a humanized yet authoritative perspective. Understanding NETosis in pregnancy may unlock novel biomarkers and therapies to promote healthier pregnancies and outcomes for both mother and child.

KEY WORDS: Neutrophil extracellular traps (NETs); Pregnancy; Trophoblasts; Placenta.

VACA-MERINO, V.; SÁNCHEZ, R. & ZAMBRANO, F. How NETosis shapes the conversation between mother and fetus: impacts on trophoblasts, the placenta, and healthy pregnancy. Int. J. Morphol., 44(4):1406-1416, 2026.