Empiric Antibiotic Therapy and Neurodevelopment Outcome of Very Low Birth Weight Infants

Abstract

Objective

To determine the effects of empiric antibiotic therapy within the first 72 hours after birth, in cases of suspected early-onset sepsis without positive blood cultures, on the neurodevelopment of VLBW infants.

Methods

Cohort study conducted from January 2014 to December 2021, included neonates from 24 to 32 weeks' gestation. They were categorized based on receiving early antibiotics. Outcomes measured included neonatal morbidities and scores on the Bayley Scales of Infant Development, Third Edition (BSID-III), at 12 to 36 months corrected age.

Results

Of 261 VLBW infants 52.9% (n = 138) received empiric antibiotics within the first 72 hours, while 47.1% (n = 123) did not. Multivariate analysis revealed no association between early antibiotics and neurodevelopmental delay. Severe intraventricular hemorrhage independently correlated with delays, while late-onset sepsis and bronchopulmonary dysplasia contributed to specific motor and cognitive delays. Propensity score matching (PSM) was conducted using various models that included gestational age, late-onset sepsis, severe intraventricular hemorrhage, bronchopulmonary dysplasia, and clinical chorioamnionitis. However, antibiotic use was not independently associated with an increased risk of developmental delay in the applied models.

Conclusion

Although the use of antibiotics did not emerge as an independent factor contributing to developmental delay, VLBW infants who received antibiotics had more morbidities during their NICU stay.

Keywords

very low birth weight newborn - prematurity - neurodevelopment - empiric antibiotic - neonatal sepsis - early-onset sepsis

Publication History

Received: 11 July 2024

Accepted: 17 March 2025

Accepted Manuscript online:
19 March 2025

Article published online:
27 March 2025

• References

• 1 Flannery DD, Edwards EM, Puopolo KM, Horbar JD. Early-onset sepsis among very preterm infants. Pediatrics 2021; 148 (04) e2021052456
• 2 Stoll BJ, Puopolo KM, Hansen NI. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early-onset neonatal sepsis 2015 to 2017, the rise of Escherichia coli, and the need for novel prevention strategies. JAMA Pediatr 2020; 174 (07) e200593
• 3 Silva ACB, Anchieta LM, Lopes MFP, Romanelli RMC. Inadequate use of antibiotics and increase in neonatal sepsis caused by resistant bacteria related to health care assistance: a systematic review. Braz J Infect Dis 2018; 22 (04) 328-337
• 4 Stocker M, Klingenberg C, Navér L. et al. Less is more: antibiotics at the beginning of life. Nat Commun 2023; 14 (01) 2423
• 5 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
• 6 Sola A. Mismanagement of antibiotics in neonatal medicine. Glob J Pediatr Neonatal Care 2020; 2 (02)
• 7 Ting JY, Synnes A, Roberts A. et al; Canadian Neonatal Network and Canadian Neonatal Follow-Up Network. Association of antibiotic utilization and neurodevelopmental outcomes among extremely low gestational age neonates without proven sepsis or necrotizing enterocolitis. Am J Perinatol 2018; 35 (10) 972-978
• 8 Mukhopadhyay S, Puopolo KM, Hansen NI. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Impact of early-onset sepsis and antibiotic use on death or survival with neurodevelopmental impairment at 2 years of age among extremely preterm infants. J Pediatr 2020; 221: 39-46.e5
• 9 Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011; 159 (05) 720-725
• 10 Torres D, Muñoz T, Bancalari A, Manríquez C. Tratamiento antibiótico empírico inicial prolongado y riesgo de morbimortalidad en recién nacidos de muy bajo peso al nacer. Rev Chil Pediatr 2018; 89 (05) 600-605
• 11 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
• 12 Albers CA, Grieve AJ. Bayley scales of infant and toddler development. J Psychoeduc Assess 2007; 25 (02) 180-190
• 13 Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used?. Pediatr Res 2014; 75 (05) 670-674
• 14 Procianoy RS, Silveira RC. The challenges of neonatal sepsis management. J Pediatr (Rio J) 2020; 96 (Suppl. 01) 80-86
• 15 Rees P, Callan C, Chadda KR. et al. Preterm brain injury and neurodevelopmental outcomes: a meta-analysis. Pediatrics 2022; 150 (06) e2022057442
• 16 Ehrenkranz RA, Walsh MC, Vohr BR. et al; National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116 (06) 1353-1360
• 17 Schlapbach LJ, Aebischer M, Adams M. et al; Swiss Neonatal Network and Follow-Up Group. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 2011; 128 (02) e348-e357
• 18 Jung E, Lee BS. Late-onset sepsis as a risk factor for bronchopulmonary dysplasia in extremely low birth weight infants: a nationwide cohort study. Sci Rep 2019; 9 (01) 15448
• 19 Kuban KC, O'Shea TM, Allred EN. et al; ELGAN Study Investigators. Systemic inflammation and cerebral palsy risk in extremely preterm infants. J Child Neurol 2014; 29 (12) 1692-1698
• 20 Letouzey M, Lorthe E, Marchand-Martin L. et al; EPIPAGE-2 Infectious Diseases Working Group. Early antibiotic exposure and adverse outcomes in very preterm infants at low risk of early-onset sepsis: the EPIPAGE-2 cohort study. J Pediatr 2022; 243: 91-98.e4
• 21 Underwood MA, Sohn K. The microbiota of the extremely preterm infant. Clin Perinatol 2017; 44 (02) 407-427
• 22 Wan X, Eguchi A, Sakamoto A. et al. Impact of broad-spectrum antibiotics on the gut-microbiota-spleen-brain axis. Brain Behav Immun Health 2022; 27: 100573
• 23 Needham BD, Funabashi M, Adame MD. et al. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature 2022; 602 (7898): 647-653
• 24 Ye Y, Tong HYK, Chong WH. et al. A systematic review and meta-analysis of the effects of long-term antibiotic use on cognitive outcomes. Sci Rep 2024; 14 (01) 4026
• 25 Hou S, Yu Y, Wu Y. et al. Association between antibiotic overexposure and adverse outcomes in very-low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis: a multicenter prospective study. Indian J Pediatr 2022; 89 (08) 785-792
• 26 Deianova N, de Boer NK, Aoulad Ahajan H. et al. Duration of neonatal antibiotic exposure in preterm infants in association with health and developmental outcomes in early childhood. Antibiotics (Basel) 2023; 12 (06) 967
• 27 Panceri C, Valentini NC, Silveira RC, Smith BA, Procianoy RS. Neonatal adverse outcomes, neonatal birth risks, and socioeconomic status: combined influence on preterm infants' cognitive, language, and motor development in Brazil. J Child Neurol 2020; 35 (14) 989-998
• 28 Liang LD, Kotadia N, English L. et al. Predictors of mortality in neonates and infants hospitalized with sepsis or serious infections in developing countries: a systematic review. Front Pediatr 2018; 6: 277
• 29 Li SJ, Tsao PN, Tu YK. et al. Cognitive and motor development in preterm children from 6 to 36 months of age: trajectories, risk factors and predictability. Early Hum Dev 2022; 172: 105634
• 30 Murray E, Fernandes M, Newton CRJ. et al. Evaluation of the INTERGROWTH-21st neurodevelopment assessment (INTER-NDA) in 2 year-old children. PLoS One 2018; 13 (02) e0193406
• 31 Camerota M, McGowan EC, Aschner J. et al; program collaborators for Environmental influences on Child Health Outcomes. Neurodevelopmental and behavioral outcomes of very preterm infants: latent profile analysis in the environmental influences on child health outcomes (ECHO) program. Pediatr Res 2024; 95 (01) 377-385
• 32 Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46 (03) 399-424
• 33 Spencer HJJ, Dantuluri KL, Thurm C. et al. Variation in antibiotic use among neonatal intensive care units in the United States. Infect Control Hosp Epidemiol 2022; 43 (12) 1945-1947
• 34 Villar J, Restrepo-Méndez MC, McGready R. et al. Association between preterm-birth phenotypes and differential morbidity, growth, and neurodevelopment at age 2 years: results from the INTERBIO-21st newborn study. JAMA Pediatr 2021; 175 (05) 483-493