Background/Purpose: Fetal growth restriction (FGR) significantly contributes to adverse pregnancy outcomes (APOs) in women with rheumatologic diseases. Understanding the immunopathologic mechanisms underlying FGR is critical for risk stratification and management. The objective of this study is to systematically review the immunologic/vascular mechanisms underlying FGR in systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis (RA), systemic sclerosis (SSc), ANCA-associated vasculitis (AAV), and seronegative spondyloarthropathies (SpA), and to characterize mechanistic pathways linking autoimmunity to FGR.

Methods: We conducted a systematic search of PubMed and Google Scholar for studies published between 1995 and 2024 that evaluated placental pathology, immune dysregulation, and pregnancy outcomes in women with rheumatologic diseases. Eligible studies included prospective cohorts, retrospective analyses, and placental histopathology investigations. Findings were synthesized narratively due to the heterogeneity of mechanisms.

Results: In SLE and APS, abnormal complement activation, impaired angiogenic signaling, and trophoblast dysfunction contribute to placental insufficiency and FGR. Elevated levels of complement activation products (Bb, sC5b-9) throughout gestation were associated with APOs. In APS, anti-phospholipid antibodies induce trophoblast apoptosis, impair spiral artery remodeling, promote thrombosis, and placental infarction. In RA, cytokine dysregulation, including elevated IL-6 and TNF-α levels and decreased IL-10, were linked to decidual vasculopathy and reduced pro-angiogenic signaling, contributing to low birth weight and preterm birth. In AAV, injury to the syncytiotrophoblasts and endothelial cells of the spiral veins can lead to chorangiosis and focal placental infarction associated with FGR and pre-eclampsia. In SSc, extensive decidual vasculopathy, stromal fibrosis, and hypoperfusion of chorionic villi led to high rates of FGR, preterm birth, and stillbirth. In SpA, elevated rates of preterm birth and cesarean delivery were observed, with limited but suggestive evidence of inflammatory placental lesions. Across diseases, impaired trophoblast function, vascular remodeling, and angiogenic imbalance emerged as overlapping mechanisms of placental insufficiency.

Conclusion: Autoimmune rheumatic diseases contribute to fetal growth restriction through diverse pathways involving immune-mediated placental injury and vascular dysfunction. Early identification of at-risk pregnancies and targeted therapeutic interventions addressing these mechanisms may improve neonatal outcomes. Further research is warranted to delineate disease-specific versus shared pathways to guide precision management strategies.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mechanisms-of-fetal-growth-restriction-in-rheumatologic-autoimmune-diseases-insights-into-placental-pathology-and-immune-dysregulation/