Unsaturated fatty acids as immunometabolic modulators in high-risk pregnancies: mechanisms, clinical evidence, and translational perspectives.

High-risk pregnancies (HRPs) are characterized by the convergence of metabolic dysfunction, chronic low-grade inflammation, and placental maladaptation, leading to increased maternal and perinatal morbidity and mortality. Emerging evidence indicates that these conditions are driven by a tightly integrated immunometabolic axis, in which metabolic stress activates innate immune pathways, amplifying systemic and placental inflammation. Unsaturated fatty acids (UFAs), including monounsaturated and polyunsaturated fatty acids (PUFAs), have gained attention as key modulators of this axis. Omega-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), influence membrane composition, lipid mediator synthesis, and intracellular signaling pathways involved in inflammation and metabolism. At the cellular level, these fatty acids attenuate pro-inflammatory signaling through nuclear factor kappa B (NF-κB), modulate inflammasome activation, improve mitochondrial function, and promote the production of specialized pro-resolving mediators (SPMs), thereby facilitating the resolution of inflammation. Clinical evidence from observational studies, randomized controlled trials, and meta-analyses supports the role for omega-3 supplementation in reducing the risk of preterm birth, particularly among women with low baseline DHA status. However, findings for other outcomes, including preeclampsia and gestational diabetes, remain heterogeneous, likely reflecting variability in study design, baseline nutritional status, dosage, and timing of intervention. Although several studies support a beneficial role of omega-3 supplementation, the overall clinical evidence remains heterogeneous. While reductions in preterm birth are consistently observed, findings for other outcomes, such as preeclampsia and gestational diabetes, are inconsistent across randomized controlled trials. Differences in study design, baseline nutritional status, timing, dosage, and adherence likely contribute to these discrepancies. Importantly, several well-conducted trials have reported null effects, highlighting the need for cautious interpretation and more targeted approaches. This review synthesizes current evidence on the immunometabolic mechanisms underlying HRPs and highlights UFAs as biologically plausible and clinically relevant modulators. It focuses on the importance of precision nutrition approaches that incorporate baseline nutritional assessment and biomarker-guided stratification which may ultimately improve maternal and fetal outcomes in high-risk populations.