Neurodevelopmental Outcomes After Suspected or Proven Sepsis: Secondary Analysis of INIS Trial Database

Rationale Neonatal sepsis is an important determinant of adverse neurodevelopmental outcome [Adams-Chapman 2006, Stoll 2004]. A recent meta-analysis estimated that neonatal sepsis more than doubled the risk of adverse neurodevelopmental outcome in very-low-birth-weight (VLBW) infants (OR 2.09 [95%CI 1.65-2.65]), including cerebral palsy (OR 2.09 [95%CI 1.78-2.45]).[Alshaikh 2013] When a baby with signs suggestive of sepsis, it is common practice to commence intravenous antibiotic treatment as soon as possible after cultures from blood and relevant additional sites have been obtained. However, cultures remain negative in an important subgroup of babies treated for sepsis, despite convincing clinical and/or laboratory signs of sepsis being present. Although there is some evidence to suggest that long-term outcomes following neonatal sepsis may differ according to whether or not the diagnosis was confirmed by culture,[Stoll 2004, Schlapbach 2011] to the best of the investigators' knowledge a direct comparison between these groups has never been made. Greater understanding of the impact of culture-positivity on long-term outcomes in the setting of clinical neonatal sepsis is essential to better inform parents about the future prospects of their child and to guide patient follow-up.

Objective Investigate differences in neurodevelopmental outcome at two years after neonatal sepsis according to whether or not the diagnosis was confirmed by culture.

Research questions Primary Are neurodevelopmental outcomes at two years different between babies with suspected versus culture-proven sepsis? Secondary Are neurodevelopmental outcomes at two years different between babies with suspected versus culture-proven sepsis when considered according to the underlying pathogen?

Design Secondary cohort analysis of all babies included in the International Neonatal Immunotherapy Study (INIS) randomized controlled trial (RCT).[INIS Study Collaborative Group 2008]

Study population The study population consists of all babies included in the INIS trial. The INIS trial was an RCT of intravenous immunoglobulin (two infusions of 500 mg/kg body weight polyvalent IgG) versus placebo in the treatment of suspected or proven neonatal sepsis.[INIS Study Collaborative Group 2008] 3493 infants were included from 113 hospitals in nine countries.[INIS Collaborative Group 2011] There was no difference between the treatment groups in the primary outcome of death or major disability at the age of two years (RR 1.00 [95%CI 0.92-1.08]), or in any of the secondary outcomes. Neither was an effect of immunoglobulin demonstrated in any of the pre-specified subgroup analyses. As the intervention under study did not have an impact on any of the outcomes, secondary observational analyses within the dataset are feasible.