Jaundice is a common condition in newborn infants, affecting more than 80% of them (1). High bilirubin levels can lead to acute bilirubin encephalopathy and kernicterus, which are serious neurological complications. Therefore, careful monitoring of the cranial status in patients with neonatal hyperbilirubinemia is essential to prevent and manage these potential complications (2). CUS is an easily accessible and well-accepted first-line imaging modality that is widely used to screen preterm and high-risk infants for brain injury during the neonatal period (3). Various studies have sought to identify prognostic factors associated with CUAs. Preterm, intracranial infection, hypoxia and other factors have been shown to have independent predictive value (4). One potential predictive clinical variable is RDW-CV. RDW-CV is a vital blood parameter that serves as a key indicator of physiological health and plays a crucial role in assessing overall well-being and bodily function. Recently RDW-CV has been found to have prognostic value in subarachnoid hemorrhage and other intracranial diseases (5). In these studies, it was shown that increased value of RDW was an independent prognostic factor for poor outcome in these patients. We hypothesize that the incorporation of RDW will improve prediction of overall CUAs in neonatal hyperbilirubinemia. Although CUS screening is routinely performed for neonatal hyperbilirubinemia, the relationship between RDW-CV and CUAs in neonates remains unclear. Understanding the relationship between these factors is essential for improving medical interventions and treatment of neonates. Therefore, this study aimed to explore the potential correlation between neonatal RDW-CV and CUAs, with the goal of enhancing the care and management of neonatal health.

This retrospective cross-sectional study, conducted in NJLSPH, included cases of neonatal hyperbilirubinemia at ≥35 weeks. This study found a significant association between RDW-CV and CUAs in neonatal hyperbilirubinemia (Table 2).

RDW is a hematologic parameter routinely measured in clinical blood tests, and it reflects the volume heterogeneity of peripheral red blood cells (RBCs) (6). Compared with observing RBCs on a blood smear with the naked eye, it can more objectively reflect the degree of the unequal size of red blood cells (7). Variations in RDW are attributed to multiple factors, including nutritional deficiency (vitamin B12), bone marrow suppression, hemolysis, and splenic sequestration (8). RDW is associated with various diseases (9, 10), such as cardiovascular disease, diabetes, and kidney disease. As a clinical biomarker, RDW plays an increasing role in predicting outcomes in hematologic malignancies, as well as lung, breast, and gastrointestinal cancer (11–13).

Limited research has been conducted on the relationship between RDW-CV and the nervous system, particularly in neonates. Chugh et al. examined the correlation between RDW-CV and functional outcomes in subarachnoid hemorrhage in a cohort of 40 patients. Their findings indicated that higher RDW-CV levels were linked to unfavorable outcomes, suggesting that RDW may serve as a valuable prognostic indicator in patients (5). Increased RDW is associated with hematoma expansion in patients with intracerebral hemorrhage (14, 15). Another study found that non-survivors of intracerebral hemorrhage had higher RDW levels during the first week than survivors (16). In this study, we investigated the correlation between RDW-CV and CUAs in patients with neonatal hyperbilirubinemia with a gestational age of ≥35 weeks. Our findings showed that the risk of CUAs tended to increase with increasing RDW-CV levels, consistent with the literature. We controlled for potential confounders in our multivariable analysis, as detailed in Sub-Table 1, to isolate RDW-CV's effect on CUAs risk. Sensitivity analysis confirmed the robustness of RDW-CV's association with CUAs, independent of common confounders. Other noteworthy findings emerged from this study. First, subventricular cysts accounted for the largest number of CUAs. Second, the incidence of left-hemisphere abnormalities was significantly higher than that of the right and bilateral hemispheres (Figure 3). The exact reason for this is not clear, and further investigation is warranted to validate our findings and elucidate the underlying mechanisms.

However, Kelly et al. (17) reported that although RDW is a prognostic factor for survival in many inflammatory, prothrombotic, and neoplastic diseases, preoperative RDW was not associated with overall survival in patients with glioblastoma (GBM). These differences in findings may be related to differences in population heterogeneity, sample size, and diversity of unknown factors that could contribute to body development. The above studies suggest that although ultrasound screening is abnormal, further follow-up is needed to determine any complications.

Regarding potential mechanisms and clinical implications, emerging studies have suggested a link between RDW and inflammation. RDW has been shown to increase in inflammatory states (18, 19). Some studies have shown that specific inflammatory cytokines, including IL-6, ESR, and CRP, are positively correlated with RDW. A possible underlying mechanism is that pro-inflammatory cytokines suppress maturing RBCs, allowing newer and larger reticulocytes to enter the bloodstream, leading to increased RDW (20, 21).

Inflammation plays a vital role in neurological development. Many studies show the presence of an association between biomarkers of oxidative stress and brain damage in newborns (22, 23). Klein et al. (24) reported that systemic inflammation causes chronic activation of microglia and maldevelopment of the cerebellum in mice. Yanni et al. (25) noted that placental inflammation followed by postnatal systemic inflammation predisposes individuals to indicators of white matter damage on CUS, cerebral palsy, low developmental indices, and microcephaly. Therefore, inflammation may be a significant factor connecting RDW and traumatic brain injury. Further research is required to clarify the potential association between RDW and CUAs.

This study has several strengths. It investigated the correlation between RDW-CV and CUAs, an area that has not received substantial attention from clinicians. This analysis has the potential to enhance clinicians’ evaluation of neurological abnormalities in children with neonatal hyperbilirubinemia. Nonetheless, the present study has some limitations that warrant consideration. First, it is important to acknowledge that an observational study differs from a randomized controlled trial (RCT); thus, the findings obtained may diverge from the anticipated results of an RCT owing to inherent limitations in the study design. Therefore, our findings should be interpreted in the context of this distinction. Despite these limitations, the data obtained in our study offer valuable insights into the association between RDW-CV and CUAs, contributing additional evidence to this field of research.

This study revealed a proportional relationship between a higher RDW-CV and an increased risk of CUAs in neonatal hyperbilirubinemia. These results demonstrate the importance of RDW-CV in neonatal hyperbilirubinemia. This study showed that RDW-CV may serve as a risk factor and predictor of CUAs. Further research is required to confirm this hypothesis.