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The effects of caffeine use in NICU on the neurodevelopmental outcome of premature infants: A

prospective review

Lauren Phung1, Rawad Obeid, MD2

1Oakland University William Beaumont School of Medicine, 2Dept. Of Pediatric Neurology, Corewell Health East

  • Prematurity remains a major cause of neonatal morbidity as the developing brain is vulnerable to intermittent hypoxia and inflammation.
  • Caffeine citrate (CC) is a cornerstone therapy in the NICU for apnea of prematurity, with neuroprotective effects through antioxidation and anti inflammation.1,2

Figure 1: Molecular mechanisms of Caffeine

(Created with BioRender.com)

  • Early administration within 48 hours after birth appears to mitigate neurodevelopmental impairments in preclinical and clinical studies, though additional prospective studies of the long-term neuroprotective effects of CC are needed.3
  • High daily average dose caffeine was associated with better motor, language, and cognitive performance than low-dose caffeine in multivariable analyses adjusted for gestational age and respiratory disease.4

Introduction

Aims and Objectives

  • Evaluate the consistency the protocol of CC administration at NICU Corewell Health East NICU between the years of 2020 and 2024.
  • Evaluate the cumulative dose of CC given in NICU on the neurodevelopmental outcomes of preterm infants measured at follow-up visits.
  • The cumulative dose of caffeine is calculated as the sum of the initiation dose and the product of the maintenance dose and the number of days on maintenance.
  • Alberta Infant Motor Score (AIMS), Peabody scores, and Bayley III scores are also collected at follow-up visits. Rating for the referenced scores is determined as follows:
  • AIMS score < 10th percentile is abnormal
  • Peabody Grasp and Visual: ∆ Peabody score in months and corrected age in months is within 2 STDs (1 STD = 1 month), neurodevelopment is marked as consistent.
  • Bayley III score < 85 is abnormal

Methods

Results

  • The following variables were collected: demographics, birth weight, neonatal comorbidities, Apgar scores, evidence of caffeine administration, and duration of mechanical ventilation.

References

  1. Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther. 2017;23(4):272-290. doi:10.1111/cns.12684
  2. Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SR. Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J. 2008;414(3):441-452. doi:10.1042/BJ20080489
  3. Helwich E, Rutkowska M, Bokiniec R, Gulczyńska E, Hożejowski R. Intraventricular hemorrhage in premature infants with Respiratory Distress Syndrome treated with surfactant: incidence and risk factors in the prospective cohort study. Dev Period Med. 2017;21(4):328-335.

doi:10.34763/devperiodmed.20172104.328335

  1. Ostrem BEL, Odell E, Grelli KN, et al. Cumulative caffeine exposure predicts neurodevelopmental outcomes in premature infants. Pediatr Res. Published online September 20, 2025. doi:10.1038/s41390-025-04387-1
  • Clinical comorbidities including PVL, SGA, PDA, BPD, and NEC, as well as low birth weight and low Apgar score are most significantly associated with a higher likelihood of reduced AIMS scores at short-term follow-up, consistent with current literature.
  • Higher cumulative doses of caffeine citrate were not significantly associated with improvements in short- or long-term neurodevelopmental scores. This lack of significance may stem from unmeasured confounding factors or the extreme ranges of cumulative caffeine dosing observed within the current sample.
  • Subsequent studies will evaluate the impact of average daily caffeine dosage using an expanded sample size and multivariate adjustments to minimize multicollinearity among clinical characteristics.

Discussion

  • Within the Corewell Health system, approximately 99.9% of preterm infants born at <32 weeks’ gestational age receive caffeine citrate within the first 24 hours of life.

Table 1: Univariate analysis of the effects of clinical characteristics of the cohort and cumulative dose of caffeine on the neurodevelopmental outcomes of

<32 GAS weeks preterm infants.

(*p-value < 0.05; OR of impairment for categorical variables; OR of no impairment for continuous variable; Firth's correction with the logistic regression

models was used to account for the smaller sample size of the Bayley III scores)

Abbreviations

CC: Caffeine citrate

SGA: Small gestational age

PVL: periventricular leukomalacia BPD: Bronchopulmonary dysplasia NEC: necrotizing enterocolitis

DART: Dexamethasone: A Randomized Trial

OR: Odd ratio

NICU: Neonatal intensive care unit