Necrotising enterocolitis (NEC) is a severe intestinal disease affecting very preterm infants. This multicentre retrospective cohort study examined whether postnatal exposure to caffeine citrate is associated with the incidence of NEC (≥stage IIA) and surgical NEC in very preterm infants (VPIs) born before 32 weeks' gestation.
The investigation was a retrospective cohort analysis conducted across Level III neonatal intensive care units participating in the Chinese Neonatal Network. The design and setting were described as multicentre and aimed to capture routine clinical practice across participating NICUs.
The study population comprised neonates with gestational age under 32 weeks. A total of 45,624 VPIs met inclusion criteria and were included in the analysis. No additional participant selection details were provided in the source summary.
Exposure was defined as receipt of at least one dose of caffeine citrate after birth. Among the cohort, 36,514 VPIs received caffeine citrate and 9,110 VPIs did not receive caffeine. The summary reports an analysis of timing of administration, distinguishing early administration (within 72 hours after birth) from later or no exposure.
Primary outcomes were the incidence of NEC (≥stage IIA) and the incidence of surgical NEC. Secondary outcomes listed in the source included severe neonatal morbidities—severe intraventricular haemorrhage, severe retinopathy of prematurity, late-onset sepsis, bronchopulmonary dysplasia—as well as death, duration of parenteral nutrition, and length of NICU stay. The source summary reports results for the primary outcomes and key subgroup findings; detailed secondary outcome results were not reported in the provided abstract.
The analysis reported adjusted odds ratios (aORs) and adjusted absolute risks (aARs) with 95% confidence intervals to compare NEC outcomes between caffeine-exposed and unexposed infants. The source provides these adjusted measures for the main comparisons, for early administration versus none, and for prespecified subgroup analyses.
Overall, among the 36,514 VPIs who received at least one dose of caffeine citrate, 2,315 (6.3%) developed NEC (≥stage IIA) and 849 (2.3%) experienced surgical NEC. Among the 9,110 VPIs without caffeine exposure, 544 (6.0%) developed NEC (≥stage IIA) and 263 (2.9%) experienced surgical NEC.
Adjusted analyses indicated no statistically significant association between caffeine citrate exposure and the incidence of NEC (≥stage IIA): aOR 1.01 (95% CI 0.83 to 1.24) and adjusted absolute risk -0.15 (95% CI -1.21 to 0.92).
When timing of initiation was considered, early administration of caffeine citrate (within 72 hours after birth) was associated with a lower incidence of surgical NEC. The adjusted odds ratio for surgical NEC with early caffeine was 0.76 (95% CI 0.64 to 0.89), and the adjusted absolute risk was -0.92 (95% CI -1.55 to -0.29), indicating a statistically significant reduction in surgical NEC associated with early dosing.
The study performed subgroup analyses that identified potentially differential associations:
Among VPIs receiving invasive ventilation at admission, caffeine citrate administration was associated with a reduced incidence of NEC (≥stage IIA): aOR 0.80 (95% CI 0.67 to 0.94); adjusted absolute risk -2.04 (95% CI -3.82 to -0.25).
Among VPIs who received vasopressors before NEC occurred, caffeine citrate administration was associated with a larger reduction in NEC (≥stage IIA): aOR 0.64 (95% CI 0.52 to 0.78); adjusted absolute risk -5.17 (95% CI -7.94 to -2.39).
These subgroup findings suggest the association between caffeine citrate and reduced NEC risk may be more pronounced in higher-risk infants requiring respiratory or circulatory support.
In this large multicentre cohort of 45,624 VPIs, exposure to caffeine citrate overall was not associated with a change in incidence of NEC (≥stage IIA). However, early administration within 72 hours of birth was associated with a lower incidence of surgical NEC, and caffeine exposure was linked to reduced NEC (≥stage IIA) in prespecified high-risk subgroups (those requiring invasive ventilation at admission and those who received vasopressors before NEC).
These findings suggest timing of caffeine initiation and baseline illness severity may influence observed associations with NEC outcomes. The results may inform clinical consideration of early caffeine use in selected high-risk VPIs, while recognizing the need to interpret observational results in the context of potential confounding.
The source summary did not report details such as caffeine dosing regimens, cumulative exposure, exact timing beyond the 72-hour threshold, specific adjustment covariates, or detailed secondary outcome results. The summary also did not report potential confounders or methods used to address indication bias; these details were not included in the provided text.