To examine the association between caffeine citrate administration and necrotising enterocolitis (NEC) in very preterm infants (VPIs).

A multicentre retrospective cohort study.

Level III neonatal intensive care units participating in the Chinese Neonatal Network.

The participants comprised neonates with a gestational age of under 32 weeks.

Exposure to caffeine citrate administration after birth.

Primary outcome measures were the incidence of NEC (≥stage IIA) and surgical NEC. Secondary outcome measures included severe neonatal morbidities, including severe intraventricular haemorrhages, severe retinopathy of prematurity, late-onset sepsis, bronchopulmonary dysplasia, death, duration of parenteral nutrition and length of neonatal intensive care unit stay.

A total of 45 624 VPIs were included. Among 36 514 who received at least one dose of caffeine citrate, 2315 (6.3%) developed NEC (≥stage IIA) and 849 (2.3%) experienced surgical NEC. Among 9110 VPIs without caffeine exposure, 544 (6.0%) developed NEC (≥stage IIA) and 263 (2.9%) experienced surgical NEC. Caffeine citrate exposure did not affect the incidence of NEC (≥stage IIA) between groups (adjusted OR (aOR), 1.01; 95% CI 0.83 to 1.24; adjusted absolute risk (aAR), –0.15; 95% CI –1.21 to 0.92); however, its early administration (within 72 hours after birth) was associated with a lower incidence of surgical NEC (aOR, 0.76; 95% CI 0.64 to 0.89; aAR, –0.92; 95% CI –1.55 to –0.29). In subgroup analysis, caffeine citrate administration was associated with a reduction in the incidence of NEC (≥stage IIA) among VPIs receiving invasive ventilation at admission (aOR, 0.8; 95% CI 0.67 to 0.94; aAR, –2.04; 95% CI –3.82 to –0.25) and vasopressors before NEC occurred (aOR, 0.64; 95% CI 0.52 to 0.78; aAR, –5.17; 95% CI –7.94 to –2.39).

While the incidence of NEC (≥stage IIA) in VPIs has not been affected by caffeine citrate, early administration (within 72 hours after birth) was associated with a reduced incidence of surgical NEC. Furthermore, among VPIs who received invasive ventilation at admission and vasopressors, the administration of caffeine citrate was potentially correlated with a decreased occurrence of NEC (≥stage IIA).