**Background:** With advances in perinatal medicine, neonatal mortality has declined, but NICU admissions rose from 6.4% in 2007 to 7.2% in 2018. Prolonged NICU length of stay (LOS-NICU) exposes newborns to hospital environments (noise, light, infections), increasing complications and potentially causing developmental retardation, cognitive impairment, and neurodevelopmental disorders. It also prevents parent-newborn bonding, increases hospitalization costs, and strains healthcare resources. This systematic review aimed to identify risk factors influencing LOS-NICU to inform interventions.
**Methods:** A systematic search of PubMed, Web of Science, Embase, and Cochrane Library was conducted for English-language studies published from January 1994 to October 2022. The review followed PRISMA guidelines and was registered with PROSPERO (CRD42022370357). Inclusion criteria: newborns/preterm/LBW infants admitted to NICU; LOS-NICU as primary outcome; prospective or retrospective cohort studies; multivariate analysis with >2 covariates. Exclusion criteria: wrong population (e.g., general pediatrics), wrong outcomes (death, costs, readmission), specific disease areas (e.g., congenital heart disease), conference proceedings, reviews, letters, editorials, single-factor analyses, clinical trials, and non-English publications. Two reviewers independently extracted data; a third senior reviewer resolved disagreements. Quality was assessed using a modified QUIPS tool (5 domains, max score 75): high quality (≥60), moderate (45–59), low (<45).
**Key Results:** Of 4,713 initially identified articles, 23 studies met inclusion criteria (4 prospective, 19 retrospective; 14 multicenter, 9 single-center). Sample sizes ranged from 191 to 760,037 newborns. Five studies were high quality, 18 moderate quality, none low quality. The studies reported 58 statistically significant risk factors across six categories: (1) inherent factors (73.9% of studies), (2) antenatal treatment and maternal factors (34.7%), (3) diseases and adverse conditions of the newborn (78.3%), (4) treatment of the newborn (21.7%), (5) clinical scores and laboratory indicators (43.5%), and (6) organizational factors (34.7%). The most consistently identified risk factors were: birth weight (14/23 studies, 60.9%), gestational age (10/23, 43.5%), sepsis (7/23, 30.4%), NEC (5/23, 21.7%), BPD (5/23, 21.7%), and ROP (4/23, 17.2%). Other notable factors included small for gestational age (6 studies), mode of delivery (5 studies), congenital anomalies (4 studies), sex (4 studies), neonatal AKI (3 studies), and various clinical scores (SNAPPE/SNAPPE-II, CRIB, TRIPS, Apgar, MAIN, Hassan scale). A meta-analysis was not feasible due to significant heterogeneity in study design, population, outcome definitions, and statistical methods.
**Clinical Implications:** Birth weight and gestational age are the most important inherent risk factors, but predictions based solely on these are inaccurate; combining them with disease severity scores improves accuracy. Sepsis, NEC, BPD, and ROP are critical disease-related factors that prolong treatment and LOS. A Polish study found median LOS-NICU was twice as long for infected vs. uninfected newborns. Neonatal AKI (overall incidence 29.9%) independently increased LOS and mortality (4× higher mortality). Mode of delivery showed conflicting results across studies. The Hassan scale was noted to distinguish long-stay from short-stay newborns better than other composite scores. Organizational factors (e.g., children's hospitals vs. perinatal centers) also influenced LOS. The review highlights the need for future well-designed prospective studies that include sociodemographic factors (family income, parental health) and consider machine learning approaches to improve prediction accuracy.