# Association Between Serum Caffeine Concentrations, Intermittent Hypoxia and Apnea in Preterm Infants: A Prospective Observational Study

## TL;DR

This study found that lower caffeine levels in preterm infants are linked to more breathing problems, suggesting caffeine levels should be monitored to manage symptoms, but not necessarily based on gestational age alone.

## Contribution

The study provides new evidence that serum caffeine levels are associated with apnea and hypoxia in preterm infants, independent of gestational age.

## Key findings

- Serum caffeine concentrations did not differ significantly between preterm infants of different gestational ages.
- Lower caffeine levels were associated with increased apnea and hypoxia episodes, especially after the second week of life.
- A significant negative correlation was found between caffeine levels and hypoxia frequency in multiple weeks of life.

## Abstract

What are the main findings?
Serum caffeine concentrations did not differ significantly across gestational age groups (23–27 vs. 28–30 weeks) during the postnatal period.Lower serum caffeine levels were associated with an increased frequency of apnea of prematurity and intermittent hypoxia episodes, particularly after the second week of life.

Serum caffeine concentrations did not differ significantly across gestational age groups (23–27 vs. 28–30 weeks) during the postnatal period.

Lower serum caffeine levels were associated with an increased frequency of apnea of prematurity and intermittent hypoxia episodes, particularly after the second week of life.

What are the implications of the main finding?
Routine caffeine dose adjustment or serum monitoring based solely on gestational age may not be necessary in preterm infants ≤ 30 weeks’ gestation.Ensuring adequate serum caffeine concentrations may be important for reducing apnea and intermittent hypoxia, supporting individualized clinical assessment in symptomatic infants.

Routine caffeine dose adjustment or serum monitoring based solely on gestational age may not be necessary in preterm infants ≤ 30 weeks’ gestation.

Ensuring adequate serum caffeine concentrations may be important for reducing apnea and intermittent hypoxia, supporting individualized clinical assessment in symptomatic infants.

Background/Objectives: Caffeine citrate represents the standard pharmacological intervention for apnea of prematurity (AOP) and episodes of intermittent hypoxia (IH). Despite its widespread use, consensus regarding the necessity of routine serum monitoring, optimal dosing protocols, and precise clinical indications remains elusive. The primary objective of this investigation was to evaluate the longitudinal trajectory of serum caffeine concentrations in preterm infants and to analyze their correlation with the incidence of AOP and IH episodes. Furthermore, we sought to determine whether blood caffeine concentrations varied significantly across gestational ages throughout the postnatal period. Methods: This multicenter, prospective observational study enrolled preterm infants with a gestational age of ≤30 weeks. Participants were administered a standard loading dose of caffeine citrate within the first 24 h of life, followed by a standardized maintenance regimen. Serum caffeine levels were quantified on a weekly basis. The cohort was stratified into two distinct groups based on gestational age: Group 1 (23–27 weeks) and Group 2 (28–30 weeks). Results: The study yielded 588 serum caffeine measurements from a cohort of 104 preterm infants, characterized by a median gestational age of 28 weeks (range: 23–30 weeks) and a mean birth weight of 1034 ± 296 g. Statistical analysis revealed no significant disparities in serum caffeine concentrations across gestational age groups (p > 0.05). Notably, during the third week of life, infants with apneic episodes demonstrated significantly lower caffeine levels than those without apnea (p = 0.016). Furthermore, a significant negative correlation was identified between serum caffeine concentrations and the frequency of IH episodes during the third, fourth, and fifth weeks of life across multiple oxygen saturation thresholds. Conclusions: While serum caffeine concentrations in preterm infants did not vary significantly with gestational age, lower levels were associated with a higher incidence of AOP and IH episodes. These results suggest that while routine monitoring or dose adjustment based solely on gestational age may not be warranted, maintaining adequate serum levels is critical for symptom management. Future research should prioritize randomized controlled trials with expanded sample sizes, extended follow-up periods, and a rigorous analysis of adverse effects.