Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants

Abstract

Objective: To examine the effect of early initiation of caffeine therapy on neonatal outcomes and characterize the use of caffeine therapy in very low birth weight (VLBW) infants.

Study design: We analyzed a cohort of 62 056 VLBW infants discharged between 1997 and 2010 who received caffeine therapy. We compared outcomes in infants receiving early caffeine therapy (initial dose before 3 days of life) and those receiving late caffeine therapy (initial dose at or after 3 days of life) through propensity scoring using baseline and early clinical variables. The primary outcome was the association between the timing of caffeine initiation and the incidence of bronchopulmonary dysplasia (BPD) or death.

Results: We propensity score-matched 29 070 VLBW infants at a 1:1. Of infants receiving early caffeine therapy, 3681 (27.6%) died or developed BPD, compared with 4591 infants (34.0%) receiving late caffeine therapy (OR, 0.74; 99% CI, 0.69-0.80). Infants receiving early caffeine had a lower incidence of BPD (23.1% vs 30.7%; OR, 0.68; 95% CI, 0.63-0.73) and a higher incidence of death (4.5% vs 3.7%; OR, 1.23; 95% CI, 1.05-1.43). Infants receiving early caffeine therapy had less treatment of patent ductus arteriosus (OR, 0.60; 95% CI, 0.55-0.65) and a shorter duration of mechanical ventilation (mean difference, 6 days; P < .001).

Conclusion: Early caffeine initiation is associated with a decreased incidence of BPD. Randomized trials are needed to determine the efficacy and safety of early caffeine prophylaxis in VLBW infants.

Figure 1

After propensity matching, 29,070 patients (53%) meeting inclusion criteria were eligible for analysis of the primary and secondary outcomes. *Patients receiving multiple methylxanthines included in the evaluation of trends in methylxanthine use over time. **Select comparisons of full cohort meeting inclusion and exclusion criteria, including unmatched patients, were performed. Abbreviations: DOL, day of life;

Figure 2

(online). Histogram demonstrates distribution in the number of infants receiving caffeine therapy by postnatal age at initiation. Data presented for a total of 51,623 unmatched infants <1500 g at birth who received caffeine therapy. Infants with caffeine initiation beyond 28 days since birth, comprising 5.6% of patients, not depicted (N=3084).

Figure 3

(online). The mean and median postnatal age at caffeine initiation in very-low-birth-weight infants demonstrates a trend towards early caffeine therapy over time. R² = 0.89 for negative correlation between birth year and mean age at caffeine initiation. Whisker bars indicate 95% confidence intervals for mean values and interquartile range for median values.

Figure 4

(online). The percent of very-low-birth-weight (VLBW) infants receiving methylxanthine therapy as a fraction of overall methylxanthine use (top panel) and number of VLBW infants receiving methylxanthines (bottom panel) are displayed. Exclusive use of caffeine increased from 26% in 1997 to 96% in 2010. Treatment with methylxanthines other than caffeine, including multiple methylxanthines, predominated prior to 2001, and infrequent after 2007 (<5%).

Figure 5

(online). Graph denotes the percent of very-low-birth-weight (VLBW) and extremely-low-birth-weight (ELBW) infants exposed to caffeine during hospitalization. Whisker bars indicate 95% confidence intervals.