Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis B Alshaikh1,2, K Yusuf2 and R Sauve1,2 OBJECTIVE: To study the impact of neonatal sepsis on the long-term neurodevelopmental outcome in very low birth weight (VLBW) infants. STUDY DESIGN: Systematic review and meta-analysis of observational studies comparing neurodevelopmental outcomes in VLBW infants exposed to culture-proven sepsis in the neonatal period with similar infants without sepsis. RESULT: Seventeen studies involving 15 331 infants were included in the meta-analysis. Sepsis in VLBW infants was associated with an increased risk of one or more long-term neurodevelopmental impairments (odds ratio (OR) 2.09; 95% confidence interval (CI) 1.65 to 2.65) including cerebral palsy (CP; OR 2.09; 95% CI 1.78 to 2.45). Heterogeneity (I 2 ¼ 36.9%; P ¼ 0.06) between the studies was significant and related to variations in patient characteristics, causative pathogens and follow-up methods. Sensitivity analyses based on study design, follow-up rate and year of birth were not significantly different from the overall analysis. CONCLUSION: The meta-analysis suggests that sepsis in VLBW infants is associated with a worse neurodevelopmental outcome including higher incidence of CP. Journal of Perinatology (2013) 33, 558–564; doi:10.1038/jp.2012.167; published online 17 January 2013 Keywords: sepsis; long-term neurodevelopmental outcome; cerebral palsy; premature infants INTRODUCTION Sepsis is a clinical syndrome characterized by systemic signs of infection accompanied by bacteremia.1 The sepsis rate in premature infants has significantly risen in the last three decades because of increased survival of very low birth weight (VLBW) infants,2 prolonged stay in neonatal intensive care units3 and frequent exposure to protracted instrumentation, such as intravascular lines and endotracheal tubes. Neonatal literature indicates that 11 to 46% of VLBW infants experience a cultureproven infection during hospitalization, and this incidence is inversely proportional to gestational age and birth weight.3,4 The relationship between infection and neurodevelopmental outcome of surviving VLBW infants has been correlated to cerebral white matter injury, particularly periventricular leukomalacia.5–7 The white matter injury resulting from sepsis is a multifactorial process involving the production of pro-inflammatory cytokines, increased blood–brain barrier permeability and hypoxic ischemic events resulting from hypotension and impaired autoregulation of cerebral blood flow.5,8,9 Systematic review on association between intrauterine infection and poor neurodevelopmental outcome has shown increased risk of cerebral palsy (CP) and periventricular leukomalacia in preterm infants.10 However, studies on relationships between neonatal infection and poor neurodevelopmental outcome have conflicting results. Advances in immunology and microbiology have opened the door for researchers to produce drugs containing immunogloblins and anti-cytokines to prevent sepsis or to protect infected infants from brain injury.11–13 The objective of our review was to systematically evaluate the current data reporting associations between neonatal sepsis and neurodevelopmental outcome in preterm infants. This is critically important in determining the impact of neonatal sepsis on long-term prognosis, and for guiding development of therapeutic interventions. METHODS Search strategy Both manual and electronic search strategies were used to identify relevant studies that evaluated the association between neonatal sepsis and neurodevelopmental outcome. Our search was done initially in January 2012 and updated in June 2012 including: MEDLINE, PUBMED, EMBASE, and CINAHL (Cumulative Index to Nursing and Allied Health). In addition, we searched the reference list of retrieved articles and abstracts of two major pediatric international annual meetings (American Pediatric Society and the European Society for Pediatric Research) in the last 2 years. Searches were limited to observational trials in human newborn infants but no language restrictions were applied. All studies including neonates were considered for this review. Authors were contacted for additional or missing information, first by sending two emails and if no reply we tried to contact the author by phone. A combination of text words and exploded medical subject headings were used to maximize the volume of retrieved literature. Searches were performed using the following search themes that created using the Boolean search term ‘or’ then combined by the Boolean operator ‘and’ in varying combination: (1) Sepsis: sepsis or infection or pathogen. (2) Neurodevelopmental outcome: mental retardation or CP or blindness or deafness or