Immune imbalance and inflammatory pathways in hypertensive disorders of pregnancy: Consequences for embryonic and fetal development

Hypertensive disorders of pregnancy (HDP), including preeclampsia, remain a major cause of maternal and perinatal morbidity and mortality worldwide, affecting 5-10% of pregnancies. This review synthesizes evidence positioning immune dysregulation as a continuous developmental determinant linking peri-implantation maladaptation to placental dysfunction, systemic endothelial injury, and long-term fetal programming. Successful pregnancy requires tightly coordinated maternal-fetal immune tolerance, mediated by decidual natural killer cells, regulatory T cells (Tregs), M2-polarized macrophages, tolerogenic dendritic cells, and cytokine/checkpoint networks (IL-10, TGF-β, LIF, PD-1/PD-L1). Failure of this staged adaptation reduced Treg frequency and function, Th1/Th17 dominance, cytotoxic NK-cell skewing, pro-inflammatory macrophage polarization, inflammasome (NLRP3) activation, complement dysregulation, and AT1-receptor autoantibodies impairs spiral-artery remodeling and trophoblast invasion. The resulting placental hypoxia, oxidative stress, and anti-angiogenic imbalance (elevated sFlt-1/PlGF) drive the maternal syndrome while releasing pathogenic extracellular vesicles that disseminate inflammatory signals. These processes may contribute to fetal growth restriction and long-term neurodevelopmental and cardiometabolic vulnerability. Epidemiological studies have reported associations between maternal HDP, particularly preeclampsia, and subsequent neurodevelopmental outcomes including autism-spectrum disorder; however, these associations are observational, effect sizes are modest, and residual confounding by prematurity, fetal growth restriction, maternal metabolic and psychiatric conditions, socioeconomic factors, and familial susceptibility remains possible. Accordingly, current evidence does not establish that preeclampsia directly causes autism-spectrum disorder. Therapeutic opportunities include low-dose aspirin, agents targeting angiogenic or inflammasome pathways, and experimental exosome-based approaches, with future precision strategies matching interventions to immune endotypes. Bridging traditionally separate domains of immunology, placentology, and developmental programming, this synthesis highlights the maternal-placental-fetal immune axis as a unified continuum and identifies opportunities for earlier prevention and endotype-guided therapy to reduce the intergenerational burden of HDP.