Effect of Multimodal Interventions on Pain, Stress, and Neurodevelopmental Outcomes in Neonates With Malignant and Benign Tumors: Protocol for a Systematic Review.

Background: Both benign and malignant tumors in neonates frequently necessitate invasive diagnostic and therapeutic procedures, exposing infants to significant pain and stress during critical periods of brain development. Procedural stress can disrupt the hypothalamic-pituitary-adrenal axis, affect synaptic pruning, and alter myelination, potentially leading to long-term cognitive and neurodevelopmental impairments. While standard medical care remains the cornerstone of management, there is growing interest in multimodal interventions-including integrative therapies, physiotherapy, and non-pharmacological approaches such as massage, music therapy, kangaroo care, and sensory stimulation-to mitigate discomfort and support neurodevelopmental outcomes. Objective: This study aimed to systematically evaluate how well multimodal therapies reduce stress and suffering while enhancing neurodevelopmental outcomes in infants with both benign and malignant tumors. Methods: The PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) standards will be followed in the conduct of this systematic review. Studies that use multimodal therapies (eg, physiotherapy, massage, music therapy, kangaroo care, or other non-pharmacologic techniques) for newborns with proven malignant or benign tumors will be considered. A thorough literature search will be conducted using databases such as the PubMed, Embase, and CINAHL, Cochrane, and CancerLi. Cohort studies, case-control studies, quasi-experimental studies, and randomized controlled trials will all be considered. Measures of pain (such as validated neonatal pain scales), stress (such as cortisol levels and behavioral markers), and neurodevelopment (such as the Bayley Scales of Infant Development) will be the main objectives. Results: The anticipated timeline for completing this systematic review is June 2025 to December 2027. Two independent reviewers will conduct each stage of the review process in a blinded manner to minimize bias. Conclusions: This systematic review aims to provide evidence-based insights into the role of multimodal interventions in enhancing standard care for neonates undergoing tumor-related procedures. Conclusions regarding clinical impact will be conditional on the quality and consistency of the evidence, as assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). The findings are expected to guide future research, inform cautious clinical recommendations, and support the development of integrative strategies to optimize neurodevelopmental outcomes in this vulnerable population.