Genetic–Immune Drivers of Pulmonary Arterial Hypertension Decompensation in Pregnancy and Postpartum: A Systematic Review and Translational Synthesis

Pulmonary arterial hypertension (PAH) remains one of the most catastrophic cardiovascular conditions encountered in pregnancy, yet the biological reasons pregnancy and the postpartum period so often precipitate sudden decompensation remain incompletely defined. Existing literature has largely framed risk in hemodynamic or clinical terms, while the deeper interaction between genetic susceptibility, immune dysregulation, and pregnancy-specific physiological stress has been addressed only in fragments. We undertook a systematic review, conducted in accordance with PRISMA 2020 guidance, to synthesize contemporary evidence on the genetic and immune drivers of PAH deterioration during pregnancy and the postpartum period, and to integrate these findings into a translational mechanistic framework.A comprehensive search of major biomedical databases identified 1,248 records, of which 37 studies met predefined inclusion criteria after duplicate removal, screening, and full-text eligibility assessment. Included studies spanned genetic association analyses, immune and inflammatory investigations, population-based outcome studies, and systematic reviews. Across this heterogeneous literature, a consistent signal emerged: pregnancy acts as a biological stress test that unmasks latent vulnerability conferred by pathogenic variants and polygenic modifiers affecting pulmonary vascular signaling, particularly within BMP-related pathways, while simultaneously reshaping immune responses within the pulmonary vascular niche. Immune activation, complement signaling, and cytokine-driven inflammation appear to amplify endothelial injury and maladaptive remodeling, with the postpartum immune rebound representing a critical inflection point for clinical collapse. Taken together, the evidence supports a model in which PAH decompensation in pregnancy is not solely a consequence of circulatory load, but the result of intersecting genetic and immune mechanisms activated in a narrow temporal window. This synthesis highlights opportunities for precision risk stratification, biomarker-guided surveillance, and immune-informed intervention, and underscores the need to rethink current approaches to pregnancy counseling and postpartum care in PAH.