Efficient management of assisted reproductive technology (ART) cycles in patients with severe extragenital pathology (EGP) requires a shift from standard localizedtherapeutic protocols to complex systems biology frameworks. Chronic conditions such as diabetes, liver diseases, metabolic syndromes, and Polyendocrine Metabolic Ovarian Syndrome (PMOS) severely alter the microenvironment of the developing oocyte, leading to accumulated oxidative stress and compromised mitochondrial competence. Methodology: The S.I.G.M.A. Protocol provides a comprehensive, 5-stage architectural framework designed to transition the maternal organism from a state of metabolic "survival" to a state of reproductive "creation." The core components include: Systemic Stabilization (metabolic flux correction), Interdisciplinary Board coordination via strict Decision Gates, Genetic & Teratogenic Audit utilizing FDA safety standards, Mitochondrial & Molecular Sync (Mitochondrial Rescue and ATP enhancement), and an Adaptive Implantation Roadmap based on a freeze-all segmented cycle approach.Conclusion: Implementing this methodology eliminates information gaps between medical specialists, protects embryo epigenetics, and ensures synchrony between embryo development and endometrial receptivity, ultimately reducing early pregnancy losses in high-risk group To establish a systemic standard of care for complex reproductive cases, reducing early reproductive losses.