Late-Onset Sepsis in Very Low Birth Weight Premature Infants: A 10-Year Review of a Brazilian Tertiary University Hospital—the Challenge Remains

Abstract

Objectives This study aimed to assess the incidence of late-onset sepsis (LOS), associated risk factors, and short-term prognosis in very low birth weight (VLBW) infants in a 10-year period.

Study Design A cohort study was conducted with 752 VLBW preterm infants—23 to 33 gestational weeks and 400 to 1,500 g birth weight—admitted to a neonatal intensive care unit from 2008 to 2017 and who survived over 72 hours. LOS was defined as clinical and laboratory signs of infection, whether or not confirmed by blood culture. VLBW infants were divided into groups and compared: no LOS versus proven LOS versus clinical LOS. Study variables included maternal, birth, and neonatal data, morbidities, procedures, etiological agents, and outcome—death, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage, and retinopathy of prematurity (ROP). Analysis of variance with multiple Tukey's or Wald's comparison with gamma distribution, and stepwise multiple logistic regression model, adjusted for year, and gestational age, were used for statistical analysis.

Results LOS incidence was 39% (proven LOS: 29%; clinical LOS: 10%). Septic VLBW infants showed higher mortality (proven LOS: 23.2%; clinical LOS: 41.9%) compared with no LOS (8.9%). Coagulase-negative staphylococci (56%), Gram-negative (26%), and fungi (8%) were the most frequent etiological agents. In comparing the groups, septic VLBW infants had lower gestational age and birth weight, presented more morbidities, and underwent more invasive procedures. The risk factors for proven and clinical LOS were days of mechanical ventilation and parenteral nutrition. LOS was associated with increased risk of death, BPD, and ROP.

Conclusion LOS showed high incidence and mortality, often caused by Gram-positive bacteria. Care interventions were the main risk factors associated. LOS had a major negative impact on short-term prognosis in VLBW infants. LOS reduction strategies are necessary and urgent.

Key Points

• LOS is associated with clinically significant neonatal morbidities and death in VLBW premature infants.

• There is association between LOS and duration of intensive care interventions.

• Quality improvement initiatives can be a pathway for LOS reduction.

Keywords

neonatal sepsis - premature infant - very low birth weight - prognosis - risk factor

Publication History

Received: 12 August 2022

Accepted: 03 April 2023

Article published online:
11 May 2023

• References

• 1 Stoll BJ, Hansen NI, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015; 314 (10) 1039-1051
• 2 Stoll BJ, Hansen N, Fanaroff AA. et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110 (2 Pt 1): 285-291
• 3 Glaser MA, Hughes LM, Jnah A, Newberry D. Neonatal sepsis: a review of pathophysiology and current management strategies. Adv Neonatal Care 2021; 21 (01) 49-60
• 4 de Souza Rugolo LM, Bentlin MR, Mussi-Pinhata M. et al; Brazilian Network on Neonatal Research. Late-onset sepsis in very low birth weight infants: a Brazilian Neonatal Research Network Study. J Trop Pediatr 2014; 60 (06) 415-421
• 5 Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol 2003; 27 (04) 293-301
• 6 Jiang S, Yang C, Yang C. et al; REIN-EPIQ Study Group. Epidemiology and microbiology of late-onset sepsis among preterm infants in China, 2015-2018: a cohort study. Int J Infect Dis 2020; 96: 1-9
• 7 Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13: 59
• 8 Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J Pediatr 2001; 138 (01) 92-100
• 9 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33 (01) 179-201
• 10 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92 (04) 529-534
• 11 Horbar JD, Carpenter JH, Badger GJ. et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012; 129 (06) 1019-1026
• 12 Su BH, Hsieh WS, Hsu CH, Chang JH, Lien R, Lin CH. Premature Baby Foundation of Taiwan (PBFT). Neonatal outcomes of extremely preterm infants from Taiwan: comparison with Canada, Japan, and the USA. Pediatr Neonatol 2015; 56 (01) 46-52
• 13 Mukhopadhyay S, Sengupta S, Puopolo KM. Challenges and opportunities for antibiotic stewardship among preterm infants. Arch Dis Child Fetal Neonatal Ed 2019; 104 (03) F327-F332
• 14 Sarkar S, Bhagat I, DeCristofaro JD, Wiswell TE, Spitzer AR. A study of the role of multiple site blood cultures in the evaluation of neonatal sepsis. J Perinatol 2006; 26 (01) 18-22
• 15 Mukhopadhyay S, Puopolo KM, Hansen NI. et al; NICHD Neonatal Research Network. Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions. Arch Dis Child Fetal Neonatal Ed 2021; 106 (05) 467-473
• 16 Köstlin-Gille N, Härtel C, Haug C. et al. Epidemiology of early and late onset neonatal sepsis in very low birthweight infants: data from the German Neonatal Network. Pediatr Infect Dis J 2021; 40 (03) 255-259
• 17 Bentlin MR, de Souza Rugolo LM. Late-onset sepsis: epidemiology, evaluation, and outcome. Neoreviews 2010; 11: e426-e35
• 18 Bedford Russell AR, Kumar R. Early onset neonatal sepsis: diagnostic dilemmas and practical management. Arch Dis Child Fetal Neonatal Ed 2015; 100 (04) F350-F354
• 19 Sola A, Mir R, Lemus L, Fariña D, Ortiz J, Golombek S. members of the 10th SIBEN Clinical Consensus. Suspected neonatal sepsis: Tenth Clinical Consensus of the Ibero-American Society of Neonatology (SIBEN). Neoreviews 2020; 21 (08) e505-e534
• 20 Celik IH, Hanna M, Canpolat FE. Mohan Pammi. Diagnosis of neonatal sepsis: the past, present and future. Pediatr Res 2022; 91 (02) 337-350
• 21 Berman L, Moss RL. Necrotizing enterocolitis: an update. Semin Fetal Neonatal Med 2011; 16 (03) 145-150
• 22 El Manouni El Hassani S, Berkhout DJC, Niemarkt HJ. et al. Risk factors for late-onset sepsis in preterm infants: a multicenter case-control study. Neonatology 2019; 116 (01) 42-51
• 23 Cailes B, Kortsalioudaki C, Buttery J. et al; neonIN network. Epidemiology of UK neonatal infections: the neonIN infection surveillance network. Arch Dis Child Fetal Neonatal Ed 2018; 103 (06) F547-F553
• 24 Gowda H, Norton R, White A, Kandasamy Y. Late-onset neonatal sepsis. A 10 year review from North Queensland, Australia. Pediatr Infect Dis J 2017; 36 (09) 883-888
• 25 Kung YH, Hsieh YF, Weng YH. et al. Risk factors of late-onset neonatal sepsis in Taiwan: a matched case-control study. J Microbiol Immunol Infect 2016; 49 (03) 430-435
• 26 Stoll BJ, Hansen NI, Adams-Chapman I. et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292 (19) 2357-2365
• 27 Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006; 19 (03) 290-297
• 28 Jiang S, Yang Z, Shan R. et al; Reduction of Infection in Neonatal Intensive Care Units using the Evidence-based Practice for Improving Quality Study Group. Neonatal outcomes following culture-negative late-onset sepsis among preterm infants. Pediatr Infect Dis J 2020; 39 (03) 232-238
• 29 Ting JY, Synnes A, Roberts A. et al; Canadian Neonatal Network Investigators. Association between antibiotic use and neonatal mortality and morbidities in very low-birth weight infants without culture-proven sepsis or necrotizing enterocolitis. JAMA Pediatr 2016; 170 (12) 1181-1187