The review, led by neonatologist Yunus E. Dogan of the University of Florida together with colleagues spanning neonatology, cardiac surgery, and radiology, integrated eleven prospective and retrospective cohort studies published between 2016 and 2025. Its central numbers are sobering. Preoperative brain injury, detected on magnetic resonance imaging performed before any surgical intervention, is found in between 12 and 54 percent of neonates with congenital heart disease. That enormous range reflects differences in lesion definitions, imaging protocols, and cardiac diagnoses across studies, but even the most conservative estimates mean that at least one in eight babies arrives at the cardiac operating table with a brain that has already been injured. After surgery, the burden persists, with new lesions appearing on postoperative scans in a substantial fraction of survivors.

The patterns of injury are distinctive and diagnostically revealing. Before surgery, the most common findings are white matter injury, arterial ischemic stroke, and cerebral hemorrhage. White matter injury, sometimes described as periventricular leukomalacia-like damage, strikes the fatty sheathed fibers that connect distant brain regions and are still being actively myelinated in the third trimester. After surgery, the imaging signature shifts: white matter injury remains dominant, but clinicians also see focal infarctions that are often thromboembolic in origin, tiny microhemorrhages scattered through the parenchyma, and cerebral venous thrombosis. This temporal fingerprint, captured by serial MRI, allows researchers to distinguish lesions that were present at birth from those acquired in the operating room or intensive care unit, and it has fundamentally changed the framing of the problem from a surgical complication to a continuum of vulnerability that begins in utero.

Why is the fetal brain so fragile when the heart is malformed? The answer lies in the peculiar plumbing of fetal circulation and the metabolic demands of the rapidly growing brain. In a normal fetus, the placenta delivers oxygenated blood, and the brain enjoys a privileged, high-flow supply. In fetuses with critical heart defects, however, the anatomy reroutes this flow. In conditions such as hypoplastic left heart syndrome or transposition of the great arteries, oxygen-rich and oxygen-poor blood mix abnormally, and the cerebral circulation may be perfused at lower pressure, lower oxygen content, or both. Advanced fetal MRI studies have measured this directly, showing reduced fetal cerebral oxygen consumption associated with smaller brain size, delayed cortical development correlated with reduced oxygen delivery, and altered hemodynamic responses when mothers are given supplemental oxygen. The result is a brain that reaches birth with globally reduced volumes, microstructural abnormalities in structures like the corpus callosum, and in some cases aberrant functional connectivity detectable before any operation.

The maternal-fetal environment adds another layer of risk. The review highlights evidence linking placental dysfunction and preeclampsia to preoperative focal white matter injury in neonates with complex heart disease, an emerging field some researchers call neuroplacentology. Three-dimensional volumetric MRI of the placenta in fetuses with complex congenital heart disease has revealed measurable differences compared with controls, and placental pathology correlates with neuroimaging abnormalities after birth. In other words, the same compromised maternal-fetal conditions that stress the heart may simultaneously starve the developing brain of oxygen and nutrients. Perinatal and neonatal characteristics compound this vulnerability: male sex, prematurity, and low birth weight all emerge as risk factors, echoing patterns seen in preterm brain injury more broadly. Notably, the immature oligodendrocytes that build myelin in the third trimester are exquisitely sensitive to hypoxia-ischemia and inflammation, which helps explain why white matter bears the brunt of the damage in this population.

Cerebral autoregulation, the brain’s ability to maintain steady blood flow despite swings in blood pressure, appears to be impaired in many of these newborns even before surgery. Studies of preoperative infants with congenital heart disease have documented blunted autoregulatory capacity, and novel noninvasive measures of cerebrovascular stability are being tested against invasive monitoring to bring this physiology to the bedside. The clinical implication is profound: a blood pressure that is perfectly adequate for one baby’s brain may be dangerously low for another’s, and the transition from fetal to neonatal circulation, with its shifting shunts and falling pulmonary resistance, is a period of particular hazard. Preoperative procedures such as balloon atrial septostomy have been scrutinized as potential stroke triggers, though large studies suggest that oxygenation and time to surgery are more important determinants of injury than the procedure itself.

Then comes the operation, and with it a new set of insults. Cardiopulmonary bypass, the heart-lung machine that sustains circulation during repair, exposes the brain to nonphysiological flow, embolic debris, inflammatory activation, and ischemia-reperfusion injury when the heart is restarted. Neonatal blood is uniquely challenging in this setting: standard heparin doses achieve less consistent thrombin inhibition in newborns than in older patients, and the coagulation system swings between thrombosis and bleeding with little margin for error. Anticoagulation strategy, surgical timing, hemodynamic instability, and the use of extracorporeal membrane oxygenation all emerge in the review as procedural risk factors for postoperative brain injury. Focal infarctions after surgery are frequently thromboembolic, and cerebral sinovenous thrombosis has been documented in infants undergoing cardiac surgery, sometimes producing thalamic hemorrhage and requiring difficult anticoagulation decisions in a fragile patient.

There is, however, genuine cause for optimism embedded in the data. The review notes that advances in blood pressure management, tailored perfusion strategies, and optimized surgical timing have already reduced postoperative injury rates, and recent multicenter work has documented a declining incidence of postoperative neonatal brain injury over time. Studies comparing cohorts with different practice approaches show that institutional choices matter, and European collaborative data have begun to map which perioperative factors predict long-term neurodevelopmental outcomes better than conventional imaging alone. The stakes of these improvements are high: perioperative brain injury on neonatal MRI is associated with worse school-age neurodevelopment, reduced white matter volume predicts language difficulties, and hippocampal volume reductions in adolescents with congenital heart disease track with intellectual function. Survivors face elevated rates of motor delay, cognitive and executive function deficits, and abnormalities in brain regions regulating anxiety and mood.

The path forward, as the authors frame it, is precision neuroprotection across the entire continuum of care. Antenatal interventions, including maternal hyperoxia strategies being tested with blood oxygenation level dependent fetal MRI, could potentially bolster the fetal brain before birth. Individualized hemodynamic management targets, guided by continuous cerebral autoregulation monitoring rather than population-wide blood pressure thresholds, could protect the brain during bypass and in the intensive care unit. Multimodal neuromonitoring, incorporating continuous electroencephalography and amplitude-integrated EEG, which has been shown to predict preoperative MRI findings, could catch injury in real time. Risk-stratified anticoagulation could balance clot and bleeding risks, and neuroprotective drugs such as allopurinol are already in phase III randomized trials for babies requiring bypass surgery. Finally, long-term neurodevelopmental surveillance programs would ensure that early injuries, however subtle, are met with early intervention.

For the roughly one percent of newborns whose hearts form differently, the message of this synthesis is both a warning and a promise. The brain injury that shadows congenital heart disease is not an inevitable consequence of a defective heart, nor simply the price of a heroic operation. It is a mechanistically traceable process, visible on MRI from fetal life onward, driven by hypoxemia, impaired autoregulation, inflammation, and thrombosis, and shaped by the placenta, the delivery room, the bypass circuit, and the intensive care unit. Each of those checkpoints is now a target. If the trajectory of declining postoperative injury continues, and if antenatal and precision perioperative strategies mature from promising trials into standard care, the generation of children born with heart defects may one day keep their hearts repaired without paying a hidden neurological price.

Subject of Research: Brain injury mechanisms, MRI patterns, and perioperative risk factors in neonates with congenital heart disease

Article Title: Brain injury in congenital heart disease: pathophysiology, MRI patterns, and perioperative risk factors

Article References: Dogan, Y. E., Vargas-Boggiano, D. A., Bleiweis, M., Philip, J., Narasimhulu, S. S., Tuna, I., & Weiss, M. D. (2026). Brain injury in congenital heart disease: pathophysiology, MRI patterns, and perioperative risk factors. Pediatric Research. https://doi.org/10.1038/s41390-026-05454-x

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05454-x

Keywords: congenital heart disease, brain injury, white matter injury, neonatal stroke, MRI, cardiopulmonary bypass, cerebral autoregulation, placental dysfunction, neuroprotection, neurodevelopmental outcomes, fetal circulation, thromboembolism