Interventional strategies for fetal growth restriction: a systematic review and horizon scan of placental bioengineering, maternal vasotherapy, and intrauterine nutrient gene delivery

Abstract

Fetal growth restriction (FGR) remains one of the most complex and unresolved conditions in perinatology, contributing significantly to perinatal morbidity and long-term cardiometabolic complications despite extensive research. Although substantial progress has been made in fetal surveillance and risk stratification, no universally accepted treatment has yet consistently restored in utero fetal growth. This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, critically evaluated current and emerging therapeutic strategies while exploring the translational prospects of future interventions. Comprehensive searches across multiple scientific databases and clinical registries through March 2025 identified 268 records. Following duplicate removal, screening, and quality assessment using the Risk of Bias in Systematic Reviews framework, 33 studies fulfilled the eligibility criteria, of which 20 were selected as core studies for detailed mechanistic and translational analysis. Among the reviewed interventions, maternal vasoactive therapies, including nitric oxide donors, phosphodiesterase inhibitors, and dietary nitrate supplementation, were the most extensively studied. These therapies generally improved uteroplacental blood flow, although their effects on fetal growth outcomes were inconsistent. Emerging experimental approaches, such as placental gene therapy, mesenchymal stem cell–mediated placental repair, nanoparticle-assisted drug delivery, and modulation of ferroptosis pathways, showed promising biological effects in preclinical investigations by directly targeting the underlying mechanisms of placental dysfunction rather than its secondary manifestations. Simultaneously, advances in nutrigenomics, metabolomic profiling, and artificial intelligence–assisted diagnostics are driving the transition toward precision-based management by facilitating earlier recognition of distinct FGR phenotypes and enabling individualized timing of therapy. Overall, the current body of evidence suggests that the management of FGR is gradually evolving from a predominantly surveillance-oriented approach to one increasingly focused on targeted biological intervention and placental restoration. Nevertheless, considerable heterogeneity in study methodologies, limited sample sizes, and the preliminary nature of several emerging technologies continue to restrict definitive clinical conclusions. This review highlights the critical need for integrated translational research frameworks, ethically robust clinical trials, and globally adaptable implementation strategies to fully harness the therapeutic potential developing across the maternal–placental–fetal interface.