In a groundbreaking systematic review published in Pediatric Research, a team of researchers led by van Oldenmark et al. sheds new light on two elusive yet critical neurological conditions affecting preterm infants: perinatal arterial ischemic stroke (PAIS) and neonatal cerebral sinovenous thrombosis (CSVT). These cerebrovascular events, which disrupt blood flow to delicate neonatal brain tissue, have long been recognized contributors to significant morbidity, including cerebral palsy, but their manifestations and outcomes in preterm infants remain inadequately characterized. This comprehensive synthesis, spanning studies published from 2004 to 2025, illuminates the intricate epidemiology, distinct risk factors, clinical presentations, neuroimaging patterns, and sobering neurodevelopmental consequences of PAIS and CSVT specifically in infants born before 37 weeks of gestation.
Preterm infants, distinguished by their physiologic immaturity and vulnerability, present a unique challenge in neonatal neurology. The review pooled data from 14 studies encompassing 132 cases of PAIS and 57 cases of CSVT, revealing that the incidence of both conditions escalates inversely with gestational age. This finding underscores the heightened susceptibility of extremely premature neonates to cerebrovascular insults—a vulnerability likely rooted in fragile cerebral vasculature, disturbances in coagulation pathways, and systemic morbidities common in this population. The increased occurrence of these strokes in the earliest gestational ages demands urgent attention to refine diagnostic vigilance and preventive strategies targeted at the highest-risk preterm infants.
Diverging somewhat from term neonates, preterm infants with PAIS exhibited distinct risk factor profiles, with the review highlighting the notable association of twin-to-twin transfusion syndrome, which complicates monochorionic twin pregnancies by disrupting synchronized blood supply and inducing ischemic injury. Additionally, fetal heart rate abnormalities emerged as a significant precursor, often reflecting intrauterine distress that may precipitate cerebral hypoperfusion. Neonatal hypoglycemia—a metabolic imbalance notorious for exacerbating neuronal injury—also featured prominently among the risk factors predisposing preterm infants to arterial ischemic events. Together, these findings elucidate a multifactorial risk landscape that intertwines obstetric, fetal, and neonatal vulnerabilities specifically tailored to preterm physiology.
A prominent insight from the review concerns the neuroanatomical patterns of injury. Perforator artery strokes dominated PAIS cases in preterm infants. These small, penetrating arteries supply critical deep brain structures and their occlusion portends devastating neurological sequelae. In parallel, CSVT in this population showed a strong predilection for the transverse sinus, a major venous drainage pathway in the brain. Thrombosis in this sinus can precipitate venous congestion, hemorrhagic transformation, and global cerebral dysfunction. These anatomic patterns, identifiable via advanced neuroimaging techniques such as MRI and MR venography, provide crucial diagnostic clues, enabling differentiation of these pathologies from other causes of neonatal encephalopathy.
Neuroimaging, a cornerstone in the early diagnosis of neonatal stroke, often exhibits subtleties in preterm infants due to their ongoing cerebral maturation and the frequent coexistence of other brain injuries such as intraventricular hemorrhage and periventricular leukomalacia. The review emphasizes the enhanced sensitivity of diffusion-weighted imaging (DWI) sequences in detecting early ischemic injury in this fragile group, facilitating more timely diagnosis compared to conventional imaging. However, challenges remain, particularly given the difficulty in performing MRI scans in critically ill preterm neonates and the variability in imaging protocols across centers. This underscores a pressing need for standardized neuroimaging guidelines to optimize stroke detection and monitoring in this demographic.
While some risk factors for PAIS and CSVT in preterm infants overlap with those in term neonates, the review draws attention to a constellation of prematurity-related complications uniquely amplifying vulnerability. Prolonged mechanical ventilation, often necessary for respiratory support in preterm infants, raises the risk of systemic inflammation and fluctuating cerebral perfusion, thereby setting the stage for ischemic injury. Additionally, postoperative states—especially following procedures such as patent ductus arteriosus ligation or necrotizing enterocolitis surgeries—introduce hemodynamic instability and prothrombotic conditions that were prevalent in the reviewed cases. These associations highlight the intricate interplay between medical interventions, systemic instability, and brain injury in preterm neonates.
Perhaps most distressingly, the neurodevelopmental outcomes emerging from PAIS and CSVT in preterm infants reflect substantial morbidity and mortality. The synthesis reveals alarmingly high rates of neurologic impairment, encompassing motor deficits consistent with cerebral palsy, cognitive delays, and epilepsy. Mortality rates were notably pronounced in CSVT cases, consistent with the severity of venous outflow obstruction and secondary complications such as extensive hemorrhagic infarctions. These grim outcomes accentuate the critical need for early recognition and effective interventions to mitigate long-term disability in this highly vulnerable group.
The comprehensive nature of this review also exposes significant knowledge gaps, particularly the paucity of large-scale, controlled studies focusing exclusively on the preterm population. Existing literature is fragmented, often limited by small sample sizes and heterogeneity in study design, which complicates the formulation of evidence-based guidelines. The authors advocate for multicenter collaborations and prospective cohort studies that can better elucidate causal pathways, refine prognostic markers, and evaluate therapeutic modalities tailored to the preterm brain’s unique physiology and injury mechanisms.
Prevention emerges as a pivotal theme, yet it remains largely aspirational at present. Given the intricate web of obstetric and neonatal risk factors, a multifaceted preventative approach is warranted. Optimizing maternal-fetal monitoring to detect conditions such as twin-to-twin transfusion syndrome, maintaining meticulous hemodynamic stability postnatally, and managing metabolic derangements like hypoglycemia are strategies highlighted in the review. However, translating these strategies into practice demands concerted efforts, including heightened clinical awareness and resource allocation.
Early diagnosis, integral to improving outcomes, faces hurdles due to the often subtle or nonspecific clinical presentation of stroke in preterm neonates. Seizures, apnea, and hypotonia may be attributed to a spectrum of neonatal conditions, delaying suspicion for cerebrovascular injury. The review underscores the potential of integrating neuroimaging protocols with close clinical monitoring to enhance early detection. Moreover, advances in cerebral near-infrared spectroscopy and biomarkers hold promise for non-invasive, bedside assessment to flag evolving cerebral ischemia before irreversible injury occurs.
Therapeutic options for PAIS and CSVT in preterm infants remain limited and are fraught with uncertainties regarding safety and efficacy. Anticoagulation, a mainstay in CSVT treatment in older children and adults, is challenging in preterm neonates due to bleeding risks and immature hemostatic systems. The review calls for carefully designed clinical trials to evaluate anticoagulation regimens, thrombolysis, and neuroprotective agents, emphasizing that therapeutic advances must balance efficacy with the delicate vulnerability of the developing brain.
This systematic review by van Oldenmark and colleagues thus represents a critical milestone in neonatal neurology research, emphasizing that preterm infants afflicted by PAIS and CSVT comprise a unique subset with distinct epidemiologic profiles, risks, and outcomes. Recognition of these nuances carries profound implications for clinical care pathways, research priorities, and health policy. As neonatal intensive care advances and survival of the smallest preemies improves, the imperative to mitigate devastating neurological sequelae has never been greater.
In sum, this landmark synthesis compels the neonatal and pediatric neurology communities to galvanize efforts toward comprehensive, multidisciplinary approaches encompassing prevention, refined diagnostics, and innovative therapies. Only through sustained scientific inquiry and translational advances can we hope to improve the fragile neurological futures of preterm infants confronted by these insidious cerebrovascular insults.
Subject of Research:
Perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous thrombosis (CSVT) in preterm neonates
Article Title:
Perinatal arterial ischemic stroke (PAIS) and neonatal cerebral sinovenous thrombosis (CSVT) in the preterm neonate: a systematic review
Article References:
van Oldenmark, B.O., van Steenis, A., van der Aa, N.E. et al. Perinatal arterial ischemic stroke (PAIS) and neonatal cerebral sinovenous thrombosis (CSVT) in the preterm neonate: a systematic review. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04800-3
Image Credits: AI Generated
DOI: 12 February 2026
