Premature infants with congenital heart disease (CHD) face high perioperative mortality and neurological risk. We evaluated whether cardiopulmonary bypass timing independently influences mortality or neurologic injury in premature infants with CHD undergoing a cardiac surgery.

We conducted a 16-year (2008-2023) single-center retrospective cohort study of premature infants (<37 weeks of gestational age) who underwent cardiopulmonary bypass (CPB) for a cardiac surgery before 2 months of age. The primary outcome was in-hospital mortality. The secondary outcome was postoperative neurologic injury, defined as new or progressive intraventricular/parenchymal hemorrhage or an electroencephalography-confirmed seizure. Multivariable logistic regression was used to evaluate the association between age at CPB and outcomes.

Mortality was 23.6% among 284 premature infants (median gestation of 35 weeks) who underwent CPB before 2 months of age. Mortality was 75% for infants undergoing surgery within the first 48 hours of life, predominantly in lesions requiring immediate intervention (Ebstein anomaly and obstructed total anomalous pulmonary venous connection). Beyond this window, postnatal age at CPB was no longer associated with mortality. Cardiac lesion severity and operative weight were robust mortality predictors. Acute postoperative neurological injury occurred in 13.4% of infants with documented neurologic outcomes (n = 25/186) and was independently associated with the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category (adjusted odds ratio, 2.00; 95% CI, 1.32-3.02; P < .001), but not with CPB timing.

Among premature infants with CHD undergoing CPB, early mortality was concentrated within the first 48 hours of life and was driven primarily by lesions requiring immediate intervention. Once infants survived this period and surgery became a modifiable decision, chronological age at CPB was not associated with mortality or acute neurological injury. Operative weight and lesion complexity more accurately identified perioperative risk, supporting a shift from age-based timing strategies toward individualized, physiology-informed surgical planning.