The cannabinoidergic system acquired a reputation as the most abundant G-protein coupled receptor in the CNS that acts as retrograde modulator of neurotransmitter release. Recently, endocannabinoids (ECBs) have been highlighted as Neurodevelopmental signaling cues that exert a regulatory role in brain development. The interruption in ECB system elements (including receptors and enzymes of synthesis and degradation) in the developing brain is in relation with postnatal CNS pathophysiology. The rapid rates of ECB synthesis/degradation reveal the existence of a dynamically regulated ECB tone during the active neurogenesis.

Objectives The aim of this study protocol is to systematically review the literature to examine the effects of developmental care on preterm infants’ Neurodevelopment in the neonatal intensive care unit (NICU). Materials & Methods Studies will be retrieved through searching the following databases: Web of Science, PubMed, EMBASE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), and Scopus. Randomized controlled trials will be included with randomization at either individual or cluster level. The primary outcome will be to evaluate the effect of developmental care on the mental and motor development of NICU neonates. The secondary outcome will be neonatal weight gain and length of stay during NICU hospitalization. The assessment tool for the development should be the Bayley Scales of Infant and Toddler Development, in any of the first, second and third editions. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) will be employed to identify relevant articles and report the screening process. The agreement between two experts in developmental neonatology will be reached in selecting all studies. Afterward, data will be extracted and compared by two reviewers. Any discrepancies in the extracted data will be discussed to reach a consensus. The extracted data will be imported to Review Manager 5. 3 by one reviewer. Finally, the risk of bias for all selected studies will be independently evaluated by two reviewers using the Cochrane Collaboration’ s tool. A meta-analysis will be performed to assess the possible quantitative impact of developmental interventions on the desired primary and secondary objectives. A random effect will be used if the I-square statistics is equal or more than 75%; otherwise, a fixed effect will be applied. Publication bias will be assessed using Egger’ s test and illustration with the funnel plot. The Standardized Mean Difference (SMD) with 95% confidence interval will be estimated through Metan command in STATA 14. The method provided in the Cochrane handbook will be used in this statistical analysis. The significance level will be 0. 05.