Association between Hematocrit and Cranial MRI Abnormalities in Neonatal Hyperbilirubinemia

Association between Hematocrit and Cranial MRI Abnormalities in Neonatal Hyperbilirubinemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between Hematocrit and Cranial MRI Abnormalities in Neonatal Hyperbilirubinemia Hongjuan Wei, Liang Wang, Rufeng Ji, Yinyan Tang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6875215/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The association between hematocrit (HCT) and cranial MRI abnormalities continues to be a topic of controversy. At present, the available evidence regarding the relationship between HCT and cranial MRI abnormalities is inadequate. Objective: This study aims to elucidate the relationship between HCT and cranial MRI abnormalities in neonatal hyperbilirubinemia (NHB). Methods: We conducted a retrospective cross-sectional study of 410 neonates with hyperbilirubinemia. Neonatal blood parameters, maternal prenatal data, and cranial MRI findings were extracted from the electronic medical record system. Logistic regression and smooth curve fitting were used to analyze the associations. Results: After adjusting for confounding factors, multivariate logisticregression analysis showed that each 1% increase in HCT is associated with a 6% higher in the risk of cranialMRI abnormalities. Further exploratory subgroup analyses based on sex and mode of delivery revealed no significant interactions between these subgroups (all P for interaction > 0.05). Conclusions: Among NHB, higher HCT was significantly associated with higher risk of incident cranial MRI abnormalities. These findings suggest that HCT may serve as a potential risk factor for cranial MRI abnormalities and could be a relevant biomarker. Health sciences/Medical research Health sciences/Medical research/Paediatric research Hematocrit Magnetic resonance imaging Brain diseases Neonatal hyperbilirubinemia Figures Figure 1 Figure 2 Figure 3 Impact 1. In neonatal hyperbilirubinemia, higher hematocrit (HCT) levels are significantly associated with an increased risk of cranial MRl abnormalities, with each 1% rise in HCT corresponding to a 6% higher risk. 2. This study provides evidence supporting a dose-response relationship between HCT and cranial MRI abnormalities, helping to clarify existing controversies and suggesting its potential as a predictive biomarker for clinical use. 3. HCT can serve as a simple and practical biomarker to identify high-risk neonates, enabling optimized monitoring and intervention strategies to reduce potential neurodevelopmental sequelae. Introduction Neonatal cranial MRI abnormalities are a common and disabling condition worldwide. Emerging evidence suggests that neonates exhibiting such abnormalities face an elevated risk of long-term disabilities 1,2 . Therefore, a comprehensive understanding of cranial MRI abnormalities and their related factors may contribute to the prevention and control of such abnormalities, thus improving the prognosis and quality of life for neonates with cranial MRI abnormalities . HCT is an integral blood biomarker that provides insight into physiological and health status 3 . As a dynamic parameter that fluctuates in response to internal and external stimuli, the measurement of HCT serves as a sensitive gauge of the body's homeostatic control mechanisms 4,5 . Due to its responsiveness to changes in health conditions, HCT measurement plays a key role in diagnosing and managing various acute and chronic diseases 6,7 . Notably, preliminary studies suggest a potential association between HCT and cranial abnormalities, warranting further exploration 8,9 . Although cranial ultrasound screening is routinely employed in NHB, the relationship between HCT and cranial MRI abnormalities remains insufficiently characterized. Elucidating this association is essential for improving medical interventions and treatment strategies for neonates. Thus, the aim of this study is to investigate the potential correlation between neonatal HCT and cranial MRI abnormalities, with the intention of optimizing clinical management of neonatal health. MATERIALS AND METHODS Study population This study adhered to the STROBE guidelines for observational research. We conducted a retrospective cross-sectional analysis of 941 late-preterm and term neonates (≥35 weeks' gestation) with hyperbilirubinemia requiring NICU admission at Nanjing Lishui People’s Hospital (NJLSPH) from July 1, 2021 to December 31, 2024. Clinical data were abstracted from the institutional electronic medical records. Neonates with missing HCT or cranial MRI results were excluded . Ultimately, 410 patients were included in the final analysis (Figure 1). The study protocol received ethical approval from the NJLSPH Research Ethics Committee (Approval No. 2025KY0424-03). Due to the retrospective nature of the study and the use of fully anonymized data, the ethics committee waived the requirement for written informed consent. This study was registered at the Chinese Clinical Trial Registry Center (Registration Number: ChiCTR2500101885). Laboratory, MRI data collection and measures Data were retrospectively collected from NHB patients admitted to NJLSPH between July 1, 2021 and December 31, 2024. The database comprised demographic characteristics, laboratory parameters, and neuroimaging findings. Neonatal demographic characteristics included sex, birth weight, admission weight, age, blood type, and other relevant factors . Maternal demographic variables included gestational week, age, blood type, g ravidity , parity, and mode of delivery. Laboratory parameters consisted of hematologic indices (WBC, NEUT%, LYMPH%, RBC, HGB, HCT, MCV, MCH, RDW-CV, PLT), Inflammatory markers (hsCRP, PCT), and hepatic function (TBIL, ALT, AST, GGT, ALP, ALB, GLO). Clinical biochemical parameters (including TBIL, ALT, GGT, ALP, ALB, GLO) were quantified utilizing an automated clinical chemistry analyzer (AU5800; Beckman Coulter Trading Co. Ltd., China). Hematologic indices (hsCRP, WBC, RBC, HGB, HCT, MCV, MCH, RDW-CV) were assessed employing a hematology analyzer (BC-7500; Mindray Corporation, Shenzhen, China). Cranial magnetic resonance imaging (MRI) was performed on a 3.0T scanner, acquiring the following sequences: T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery (T2-FLAIR), T2-propeller (T2-Prop), diffusion-weighted imaging (DWI), apparent diffusion coefficient mapping (ADC), exponential apparent diffusion coefficient mapping (eADC), and susceptibility-weighted angiography (SWAN). During the neonatal hospitalization period, cranial MRI was performed in cases with serum bilirubin levels significantly elevated to or above 342 µmol/L 10 , abnormal cranial ultrasound screening results, or in the presence of high risk factors such as in utero cerebral developmental anomalies. MRI findings were categorized into two groups: normal and abnormal. MRI abnormalities included hemorrhagic lesions, ischemic lesions, choroid plexus cysts, venous malformation, neuroepithelial cysts, gray-white matter heterotopia, ventricular enlargement, hydrocephalus, etc. Abnormalities on cranial MRI do not include cephalohematomas that are detectable by visual inspection or palpation. (Table 1, Supplementary figure 1, Supplementaryfigure 2) Statistical analysis All statistical analyses were conducted using R Statistical Software (V4.2.2; R Foundation) and the Free Statistics analysis platform (Version 2.1, Beijing, China, http://www.clinicalscientists.cn/freestatistics). Statistical significance was defined as a two-sided P -value < 0.05. Histogram distributions, Q-Q plots, and the Kolmogorov-Smirnov test were employed to assess the normality of variable distributions. Normally distributed continuous variables were expressed as mean ± standard deviation (SD), while skewed continuous variables were represented as median with interquartile range (IQR). Categorical variables were presented as frequencies and percentages (%). Comparisons of continuous variables among groups were conducted using either the independent samples Student’s t-test or the Mann-Whitney U-test, depending on the distribution's normality. Categorical data were compared using the chi-square test or Fisher’s exact test as appropriate. We used logistic regression to investigate the associations between HCT with cranial MRI abnormalities in NHB. HCT was entered as a continuous variable (per 0.01 unit) and as a categorical variable (quartiles). We selected these confounders on the basis of clinical interest, previous scientific literature, significant covariates in the univariate analysis, or a ≥10% change in the effect estimate upon their inclusion in the model. We constructed three hierarchical regression models to sequentially account for potential confounding factors: Model I adjusted for basic neonatal characteristics (age, sex, birth weight, admission weight, and gestational week); Model II additionally incorporated maternal characteristics (maternal age, pre-pregnancy BMI, and delivery mode); Model III further included neonatal hematological parameters (WBC and PLT) to address residual confounding. Tests for trend were conducted with multivariate regression models by entering the median value of each quartile as a continuous variable in the models. We employed restricted cubic splines to model potential nonlinear associations between HCT and cranial MRI abnormalities in neonatal hyperbilirubinemia. HCT was parameterized as a continuous predictor with four prespecified knots at the 5th, 35th, 65th, and 95th percentiles according to standard recommendations 11 . Non-linearity was tested by including a quadratic term in the regression models. Subgroup analyses stratified by sex and delivery mode evaluated the association between HCT and cranial MRI abnormalities in NHB infants. Results Population characteristics A total of 410 NHB who underwent cranial MRI were included in the final analysis. Among these, 108 (26.3%) were diagnosed with cranial MRI abnormalities. As shown in Table 1, neonates with MRI abnormalities exhibited significantly higher HCT (50.9 ± 5.6% vs. 49.3 ± 6.0%, P = 0.019), and higher rates of vaginal delivery (88.9% vs. 60.6%, P < 0.001) compared to those without abnormalities. However, no statistically significant intergroup differences were observed in sex distribution, birth weight, gestational age, or most maternal characteristics (all P > 0.05). Association between HCT and cranial MRI abnormalities Multivariable logistic regression analysis demonstrated a significant positive association between HCT and the risk of cranial MRI abnormalities (Table 2). After adjusting for neonatal characteristics, maternal factors, and hematological parameters (Model Ⅲ), each 1% increase in HCT was associated with a 6% higher risk of abnormalities ( OR = 1.06, 95% CI : 1.01-1.12, P = 0.015). When HCT was analyzed by quartiles, neonates in the highest quartile (Q4: 53.8-65.6%) had a 2.4-fold increased risk of abnormalities compared to those in the lowest quartile (Q1: 33.2-45.8%) ( OR = 2.39, 95% CI : 1.07-5.35, P = 0.034). A significant positive trend was observed across quartiles ( P for trend = 0.026). The restricted cubic spline analysis confirmed a linear dose-response relationship ( P for nonlinearity = 0.908), with the risk of abnormalities increasing steadily with higher HCT (Figure 2). Stratified analyses by sex and delivery mode revealed consistent associations, and no significant interactions were detected ( P for interaction > 0.05). The effect size was slightly more pronounced in male neonates ( OR = 1.08, 95% CI : 1.01-1.16) and those delivered by cesarean section ( OR = 1.18, 95% CI : 1.00-1.39) (Table 3, Figure 3). Discussion Summary of key findings Our study demonstrates a significant linear association between HCT and cranial MRI abnormalities in NHB. The analysis of 410 cases revealed that each 1% increase in HCT was associated with a 6% higher risk of abnormalities (adjusted OR = 1.06, 95% CI : 1.01 - 1.12), with neonates in the highest HCT quartile showing a 2.4-fold increased risk compared to those in the lowest quartile. These findings remained consistent across multiple adjusted models and were confirmed by restricted cubic spline analysis ( P for nonlinearity = 0.908). Notably, the robustness of this association was further underscored by stratified analyses, which revealed consistent effects across sex and delivery mode, with no significant interactions ( P > 0.05). Comparison with existing literature Our findings concur with recent studies that underscore the role of hematological factors in neonatal neurological injury while offering significant new insights. A 2022 study by Rosen et al. 12 demonstrated that twin anemia polycythemia sequence (TAPS) was associated with fetal brain lesions, particularly in polycythemic twins, suggesting thathigherHCT may contribute to neurological injury. Additionally, Spruijt et al. 13 reported cerebellar hemorrhage in both fetal and neonatal cases of twin-twin transfusion syndrome, further supporting the association between hematological disturbances and brain injury. Consistent with these findings, a study by Tang et al. 14 investigated the clinical and imaging characteristics of neonatal polycythemia and brain damage. They found that 45.7% of neonates with polycythemia had brain injuries, with severity correlating with the duration of polycythemia, cerebral oxygen saturation, and abnormal cerebral hemodynamics. This highlights the significant impact of HCT on neonatal brain health and supports our focus on hematological factors in neonatal neurological outcomes. However, our study extends these findings in several key aspects: First, by demonstrating a linear relationship across the entire HCT spectrum rather than just at extreme values; second, through the use of more sensitive and objective MRI-based outcomes; and third, by focusing specifically on the hyperbilirubinemia population, where the interaction between HCT and bilirubin may be particularly relevant. In contrast to our findings, a 2023 study by Gire et al. 15 reported no significant association between early Hb levels and neurodevelopmental outcomes at two years of age in very preterm infants. This discrepancy may arise from differences in study design and population. Gire et al. specifically examined very preterm infants with a mean gestational age of 28.7 weeks, using Hb levels as the primary hematological parameter, whereas our study evaluated HCT in NHB. Moreover, their study assessed neurodevelopmental outcomes at two years of age using the Ages and Stages Questionnaire (ASQ), while we utilized cranial MRI as a more immediate and objective measure of brain injury. Furthermore, Gire et al.’s study did not specifically focus on the hyperbilirubinemia infants, which may have influenced the observed associations. Similarly, the systematic review by Kalteren et al. 16 highlighted inconsistent correlations between HCT and cerebral oxygenation in preterm infants, with some studies reporting no association. This difference may reflect the complex interplay among anemia, transfusion practices, and gestational age-specific cerebrovascular responses. Importantly, neither of these studies specifically examined the hyperbilirubinemia population, where the combined effects of HCT and bilirubin toxicity might exacerbate neurological risks. Notably, our subgroup analysis of all admitted neonates (Supplementarytable 1) demonstrated that those undergoing MRI exhibited significantly higher bilirubin levels (328.3 vs 283.9 μmol/L, P < 0.001) and longer hospital stays (102.9 vs 83.5 hours, P < 0.001), suggesting that these factors may interact with HCT to influence neurological outcomes. Dose-response relationship between HCT and cranial abnormalities In our study, cranial MRI abnormalities were predominantly hemorrhagic lesions (70.4%), followed by ischemic lesions (13.9%), other abnormalities (12.0%), and combined hemorrhagic and ischemic lesions (3.7%) (Supplementaryfigures 2). The dose-response relationship between HCT and cranial MRI abnormalities was rigorously evaluated through both continuous and quartile-based analyses (Tables 2 and 3). When analyzed as a continuous variable, each 1% increase in HCT was associated with a 6% higher risk of MRI abnormalities in the fully adjusted model ( OR : 1.06, 95% CI : 1.01-1.12, P = 0.015). More importantly, the quartile analysis revealed a clear biological gradient, with neonates in the higher HCT quartiles (Q3 and Q4) demonstrating significantly increased risks compared to the reference group (Q1), with adjusted OR s of 2.37 (95% CI : 1.08-5.20) and 2.39 (95% CI : 1.07-5.35) respectively. The statistically significant trend test ( P for trend = 0.026) across fully adjusted models further supports this dose-dependent pattern. Notably, this relationship persisted across progressively adjusted models, with the effect size increasing from Model I to Model III, suggesting that the observed association is independent of potential confounding factors including demographic characteristics, maternal factors, and hematologic parameters. The consistency of this trend across different analytical approaches (continuous vs. categorical) and increasing strength of association with more comprehensive adjustment strengthens the biological plausibility of our findings. Subgroup analyses (Table 3) revealed that this dose-response relationship was particularly evident in male neonates (adjusted OR : 1.08, P = 0.025), but was not statistically significant in females. The underlying mechanisms for this differential susceptibility remain unclear. Future studies with larger sample sizes should specifically examine these biological pathways to elucidate the basis for this sex-dependent response. The absence of significant interaction by delivery mode ( P = 0.678) indicates that the observed association between HCT and cranial MRI abnormalities is robust across different delivery modes. Biological mechanisms The association between elevated HCT and cranial MRI abnormalities in NHB likely involves multiple pathways. Elevated HCT increases blood viscosity, impairing cerebral microcirculation and reducing oxygen delivery 17 , as demonstrated by pseudo-continuous arterial spin labeling (pCASL) MRI studies showing an inverse correlation between HCT and cerebral blood flow 18 . This hemodynamic compromise may exacerbate bilirubin-induced neurotoxicity, particularly in neonates with immature cerebral autoregulation 19 . Additionally, high HCT promotes a pro-inflammatory state characterized by elevated cytokines (e.g., IL-6, IL-8) 20 , which may further impair blood-brain barrier function and increase oxidative stress. Bilirubin, in high concentrations, generates reactive oxygen species, further damaging vulnerable neonatal neurons 21,22 . Together, these effects (reduced perfusion, inflammation, and oxidative injury) likely contribute to the observed MRI abnormalities in NHB with elevated HCT. Study strengths and limitations This study has several notable strengths, including a well characterized sample of NHB with standardized cranial MRI assessments, comprehensive adjustment for potential confounders (including maternal, neonatal, and hematological factors), and demonstration of a clear dose-response relationship between HCT and cranial MRI abnormalities. However, the study has several limitations. First, due to its cross-sectional design, we cannot establish temporal relationships or definitively prove causality between HCT and neurological injury. Second, the single center design may limit generalizability to other populations. Third, while we adjusted for multiple potential confounders, residual confounding from unmeasured factors cannot be excluded. These limitations warrant careful consideration when interpreting the findings. Conclusion This study found that high levels of HCT were significantly associated with a higher risk of incident cranial MRI abnormalities among NHB. These findings suggest that HCT measurement could direct current risk stratification protocols for neurological complications in this vulnerable population. The results highlight the potential clinical utility of incorporating hematologic parameters into neuroimaging decision making algorithms for NHB. Further multicenter studies are warranted to validate these findings and investigate their implications for clinical management strategies. Abbreviations NJLSPH, Nanjing Lishui People’s Hospital; ChiCTR, Chinese Clinical Trial Registry Center; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; NICU, Neonatal Intensive Care Unit; ASQ, Ages and stages questionnaire; MRI, Magnetic resonance imaging; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; T2-FLAIR, T2-fluid-attenuated inversion recovery imaging; T2-Prop, T2-propeller imaging; DWI, Diffusion weighted imaging; ADC, Apparent diffusion coefficient mapping; eADC, Exponential apparent diffusion coefficient mapping; SWAN, Susceptibility weighted angiography; pCASL, Pseudo-continuous arterial spin labeling; hsCRP, High-sensitivity C-reactive protein; RBC, Red blood cell; HGB, Hemoglobin; HCT, Hematocrit; MCV, Mean corpuscular volume; MCH, Mean corpuscular hemoglobin; RDW-CV, Red cell distribution width coefficient of variation; WBC, White blood cell; NEUT, Neutrophil; LYMPH, Lymphocyte; MONO, Monocyte; PLT, Platelet; PCT, Plateletcrit; MPV, Mean platelet volume; PDW, Platelet distribution width; P-LCR, Platelet large cell ratio; EO, Eosinophil; TBIL, Total bilirubin; DBIL, Direct bilirubin; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; GGT, Gamma-glutamyl transferase; ALP, Alkaline phosphatase; ALB, Albumin; GLO, Globulin; A/G, Albumin/Globulin ratio; TP, Total protein; GLU, Glucose; CK, Creatine kinase; CK-MB, Creatine kinase MB; LDH, Lactate dehydrogenase; K + , Potassium; Na + , Sodium; Cl - , Chloride; Ca 2+ , Calcium; CO 2 CP, Carbon dioxide combining power; NHB, Neonatal hyperbilirubinemia; IL-6, Interleukin-6; IL-8, Interleukin-8; BMI, Body mass index; IVF, In vitro fertilization; HDP, Hypertensive disorders in pregnancy; GDM, Gestational diabetes mellitus; ICP, Intrahepatic cholestasis of pregnancy; TAPS , Twin anemia polycythemia sequence; Declarations AUTHOR CONTRIBUTIONS This study was conceived and designed by all authors. Hongjuan Wei (Principal Investigator) provided overall scientific oversight. Liang Wang drafted the initial manuscript under the direct supervision of the corresponding author, Hongjuan Wei. Rufeng Ji and Yinyan Tang performed the literature search, data extraction, and analysis. All authors critically reviewed, revised, and approved the final manuscript for submission. COMPETING INTERESTS The authors declare no competing interests. ACKNOWLEDGEMENTS We gratefully acknowledge Dr. Jie Liu from the Department of Vascular and Endovascular Surgery, Chinese PLA General Hospital, for providing statistical support for this study. We also thank Dr. Qilin Yang from the Department of Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, for his consultation on study design and critical review of the manuscript. PATIENT CONSENT STATEMENT The Ethics Committee granted a waiver of written informed consent owing to the retrospective nature of the research and complete anonymization of all data. FUNDING No funding. References Lewis, J. D. et al. Automated Neuroprognostication Via Machine Learning in Neonates with Hypoxic-Ischemic Encephalopathy. Ann Neurol 97 , 791-802 (2025). Lew, C. O. et al. Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE). Radiol Artif Intell 6 , e240076 (2024). Wang, X., Wang, S., Chen, M., Lv, Y., Chen, X. & Yang, C. The value of hematocrit for predicting bronchopulmonary dysplasia in very low birth weight preterm infants. Medicine (Baltimore) 102 , e35056 (2023). Scholkmann, F., Ostojic, D., Isler, H., Bassler, D., Wolf, M. & Karen, T. Reference Ranges for Hemoglobin and Hematocrit Levels in Neonates as a Function of Gestational Age (22⁻42 Weeks) and Postnatal Age (0⁻29 Days): Mathematical Modeling. Children (Basel) 6 , 38 (2019). Zucchini, L. et al. Characterization of a Novel Approach for Neonatal Hematocrit Screening Based on Penetration Velocity in Lateral Flow Test Strip. Sensors (Basel) 23 , 2813 (2023). Ho, T. T. et al. Red blood cell transfusions increase fecal calprotectin levels in premature infants. J Perinatol 35 , 837-841 (2015). Goel, R., Cushing, M. M. & Tobian, A. A. Pediatric Patient Blood Management Programs: Not Just Transfusing Little Adults. Transfus Med Rev 30 , 235-241 (2016). de la Vega Muns, G., Quencer, R., Ezuddin, N. S. & Saigal, G. Utility of Hounsfield unit and hematocrit values in the diagnosis of acute venous sinus thrombosis in unenhanced brain CTs in the pediatric population. Pediatr Radiol 49 , 234-239 (2019). Peng, K., Adegboro, A. A., Li, Y., Liu, H., Xiong, B. & Li, X. The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study. Sci Rep 14 , 11694 (2024). Subspecialty Group of Neonatology, t. S. o. P., Chinese Medical, A., Editorial Board, C. J. o. P. & . [Guidelines on the clinical management of neonatal hyperbilirubinemia (2025)]. Zhonghua Er Ke Za Zhi 63 , 338-350 (2025). Harrell, F. E. Jr . Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis . New York: Springer, 2015, p.20-24. Rosen, H. et al. Fetal and neonatal brain injury in twins complicated by twin anemia polycythemia sequence. Prenat Diagn 42 , 978-984 (2022). Spruijt, M. S. et al. Fetal and neonatal neuroimaging in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 63 , 746-757 (2024). Tang, Z. Z., Zhou, C. L., Wang, H. M., Hou, X. L., Liu, Y. F. & Jiang, Y. [Relationship between neonatal polycythemia and brain damage]. Zhonghua Er Ke Za Zhi 44 , 845-849 (2006). Gire, C. et al. Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children. Children (Basel) 10 , 209 (2023). Kalteren, W. S., Verhagen, E. A., Mintzer, J. P., Bos, A. F. & Kooi, E. Anemia and Red Blood Cell Transfusions, Cerebral Oxygenation, Brain Injury and Development, and Neurodevelopmental Outcome in Preterm Infants: A Systematic Review. Front Pediatr 9 , 644462 (2021). Kameneva, M. V., Watach, M. J. & Borovetz, H. S. Rheologic dissimilarities in female and male blood: potential link to development of cardiovascular diseases. Adv Exp Med Biol 530 , 689-696 (2003). Ibaraki, M., Nakamura, K., Matsubara, K., Shinohara, Y. & Kinoshita, T. Effect of hematocrit on cerebral blood flow measured by pseudo-continuous arterial spin labeling MRI: A comparative study with (15)O-water positron emission tomography. Magn Reson Imaging 84 , 58-68 (2021). Watchko, J. F. & Tiribelli, C. Bilirubin-induced neurologic damage--mechanisms and management approaches. N Engl J Med 369 , 2021-2030 (2013). Jain, A. et al. Aberrant expression of cytokines in polycythemia vera correlate with the risk of thrombosis. Blood Cells Mol Dis 89 , 102565 (2021). Liu, C. et al. Alleviation of Microglia Mediating Hippocampal Neuron Impairments and Depression-Related Behaviors by Urolithin B via the SIRT1-FOXO1 Pathway. CNS Neurosci Ther 31 , e70379 (2025). Lee, Z. M., Chang, L. S., Kuo, K. C., Lin, M. C. & Yu, H. R. Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants. Children (Basel) 10 , 926 (2023). Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.doc Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6875215","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":485368363,"identity":"f4454938-2fed-4282-a9f9-0b96a3c861d8","order_by":0,"name":"Hongjuan Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYDCCA1BagoGHweCDgY0dMVoYG2BaDGcUpCWTpoWZ58MhCA8f4DueY/7wZ9thOckZuQeKbQwOMDOwHz66AZ8WyTNvDBsk2w4bS0vkJRjnGNzhY+BJS7uBT4vBjRzDBsO2w4nzpHMMgFqeMTNI8JgR1pLYdrgerMXC4DBjA1FaDrYdTpAGaWEgRovkmWeFMxvOpRvOnP/GwLDHIC2ZjZBf+I4nb/j4o8xaXuLMGTODH39s7PjZDx/Dq4WBIcOAgZGtGcRiMwCT+JWDQPoDBoY/dSAW8wPCqkfBKBgFo2AkAgDDmVD8IwxmzAAAAABJRU5ErkJggg==","orcid":"","institution":"Nanjing Lishui People’s Hospital, Southeast University","correspondingAuthor":true,"prefix":"","firstName":"Hongjuan","middleName":"","lastName":"Wei","suffix":""},{"id":485368364,"identity":"5133ab31-f8b8-458d-a5ef-036605f51ede","order_by":1,"name":"Liang Wang","email":"","orcid":"","institution":"Nanjing Lishui People’s Hospital, Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Wang","suffix":""},{"id":485368365,"identity":"7c30822d-e277-4d0c-927d-18a1f514fef3","order_by":2,"name":"Rufeng Ji","email":"","orcid":"","institution":"Nanjing Lishui People’s Hospital, Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Rufeng","middleName":"","lastName":"Ji","suffix":""},{"id":485368366,"identity":"ec9ab254-9ea4-4193-8f09-303de99fabaa","order_by":3,"name":"Yinyan Tang","email":"","orcid":"","institution":"Nanjing Lishui People’s Hospital, Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Yinyan","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2025-06-11 23:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6875215/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6875215/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87030969,"identity":"5ce6d6d2-515b-457b-be55-c5bb42b87801","added_by":"auto","created_at":"2025-07-18 12:47:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":126522,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart for the study population.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.Flowchartforthestudypopulation..png","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/73fe86059aeca29622e0c867.png"},{"id":87030975,"identity":"30115f31-57c9-4a37-9852-aa0ca7fc5391","added_by":"auto","created_at":"2025-07-18 12:47:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":227156,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLinear dose-response relationship between HCT and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e of cranial MRI abnormalities. \u003c/strong\u003eThe \u003cstrong\u003epink \u003c/strong\u003esolid line indicates multivariate adjusted OR and the \u003cstrong\u003epink \u003c/strong\u003edashed lines indicate the 95% \u003cem\u003eCI\u003c/em\u003e derived from restricted cubic spline regression. The blue histogram represents the frequency distribution of HCT values across the study population. Knots are located at the 5th, 35th, 65th, and 95th percentiles for each of the HCT. The horizontal dotted lines represent the \u003cem\u003eOR\u003c/em\u003e of 1.0 (reference point). The reference point was set at the median level of HCT (49.8 %). The logistic regression was adjusted for age, sex, birth weight, admission weight, week of gestation, maternal age, \u003cstrong\u003epre-pregnancy\u003c/strong\u003e BMI, delivery mode, WBC , and PLT.\u003c/p\u003e","description":"","filename":"Figure2LineardoseresponserelationshipbetweenHCTandORofcranialMRIabnormalities..png","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/9e60c5e9504862f19976cbec.png"},{"id":87032273,"identity":"79e356de-f73d-4aff-bd59-82524593f82e","added_by":"auto","created_at":"2025-07-18 12:55:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":275076,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of subgroup analyses for the association between HCT and cranial MRI abnormalities in NHB. The purple diamond represents the \u003cem\u003eOR\u003c/em\u003e and 95% \u003cem\u003eCI\u003c/em\u003efor each 1% increase in HCT (continuous variable) on the risk of cranial MRI abnormalities.The green dots with blue lines display the stratified \u003cem\u003eOR\u003c/em\u003eand 95% \u003cem\u003eCI\u003c/em\u003e for each subgroup (sex and delivery mode). Subgroup stratification includes sex (male vs. female) and delivery mode (vaginal delivery vs. cesarean section). Results are derived from Model III, adjusted for age, sex, birth weight, admission weight, week of gestation, maternal age, pre-pregnancy BMI, delivery mode, WBC, and PLT. \u003cem\u003eP for interaction\u003c/em\u003e values are provided for subgroup comparisons.\u003c/p\u003e","description":"","filename":"Figure3.ForestplotofsubgroupanalysesfortheassociationbetweenHCTandcranialMRIabnormalitiesinNHB..png","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/1793ad23caffe9739eb34bc6.png"},{"id":90814929,"identity":"e2710c10-9962-4cc2-814d-7d571e877fb7","added_by":"auto","created_at":"2025-09-08 12:53:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1387801,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/f585671e-5652-4b0f-80fb-169e03764e6c.pdf"},{"id":87030981,"identity":"eb1d590a-2b4c-469b-b943-9c214a56f5d5","added_by":"auto","created_at":"2025-07-18 12:47:15","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45218136,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.doc","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/5f98cb095d90b0799cea0beb.doc"},{"id":87030971,"identity":"7583420c-a7ef-43cf-8279-9b8454354e89","added_by":"auto","created_at":"2025-07-18 12:47:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":42823,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6875215/v1/3a4d8d78dffa7c5de2319794.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAssociation between Hematocrit and Cranial MRI Abnormalities in Neonatal Hyperbilirubinemia\u003c/p\u003e","fulltext":[{"header":"Impact","content":"\u003cp\u003e1.\u0026nbsp;In neonatal hyperbilirubinemia, higher hematocrit (HCT) levels are significantly associated with an increased risk of cranial MRl abnormalities, with each 1% rise in HCT corresponding to a 6% higher risk.\u003c/p\u003e\n\u003cp\u003e2. This study provides evidence supporting a dose-response relationship between HCT and cranial MRI abnormalities, helping to clarify existing controversies and suggesting its potential as a predictive biomarker for clinical use.\u003c/p\u003e\n\u003cp\u003e3. HCT can serve as a simple and practical biomarker to identify high-risk neonates, enabling optimized monitoring and intervention strategies to reduce potential neurodevelopmental sequelae.\u003c/p\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eNeonatal cranial MRI abnormalities are a common and disabling condition worldwide.\u0026nbsp;\u003cstrong\u003eEmerging evidence suggests that neonates exhibiting such abnormalities face an elevated risk of long-term disabilities\u003c/strong\u003e\u003csup\u003e1,2\u003c/sup\u003e. Therefore, a comprehensive understanding of cranial MRI abnormalities and\u0026nbsp;\u003cstrong\u003etheir\u003c/strong\u003e related factors may contribute to the prevention and control of such abnormalities,\u0026nbsp;\u003cstrong\u003ethus improving the prognosis and quality of life for neonates with cranial MRI abnormalities\u003c/strong\u003e. HCT is an integral blood biomarker that provides insight into\u0026nbsp;\u003cstrong\u003ephysiological and health status\u003c/strong\u003e\u003csup\u003e3\u003c/sup\u003e. As a dynamic parameter that fluctuates in response to internal and external stimuli, the measurement of HCT serves as a sensitive gauge of the body\u0026apos;s homeostatic control mechanisms\u003csup\u003e4,5\u003c/sup\u003e. Due to its responsiveness to changes in health conditions, HCT measurement plays a key role in diagnosing and managing various acute and chronic diseases\u003csup\u003e6,7\u003c/sup\u003e.\u0026nbsp;Notably, preliminary studies suggest a potential association between HCT and cranial abnormalities, warranting further exploration\u003csup\u003e8,9\u003c/sup\u003e.\u0026nbsp;Although cranial ultrasound screening is routinely employed in NHB, the relationship between HCT and cranial MRI abnormalities remains insufficiently characterized.\u0026nbsp;\u003cem\u003eElucidating this association\u003c/em\u003e is essential for improving medical interventions and treatment strategies for neonates.\u0026nbsp;Thus, the aim of this study is to investigate the potential correlation between neonatal HCT and cranial MRI abnormalities, with the intention of\u0026nbsp;\u003cstrong\u003eoptimizing clinical management\u003c/strong\u003e of neonatal health.\u003c/p\u003e\n"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the STROBE guidelines for observational research. We conducted a retrospective cross-sectional analysis of 941 late-preterm and term neonates (\u0026ge;35 weeks\u0026apos; gestation) with hyperbilirubinemia requiring NICU admission at Nanjing Lishui People\u0026rsquo;s Hospital (NJLSPH) from July 1, 2021 to December 31, 2024. Clinical data were abstracted from the institutional electronic medical records. \u003cstrong\u003eNeonates with missing HCT or cranial MRI results were excluded\u003c/strong\u003e. Ultimately, 410 patients were included in the final analysis (Figure 1). The study protocol received ethical approval from the NJLSPH Research Ethics Committee (Approval No. 2025KY0424-03). Due to the retrospective nature of the study and the use of fully anonymized data, the ethics committee waived the requirement for written informed consent. This study was registered at the Chinese Clinical Trial Registry Center (Registration Number: ChiCTR2500101885).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory, MRI data collection and measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were retrospectively collected from NHB patients admitted to NJLSPH between July 1, 2021 and December 31, 2024. The database comprised demographic characteristics, laboratory parameters, and neuroimaging findings. Neonatal demographic characteristics included sex, birth weight, admission weight, age, blood type, \u003cstrong\u003eand other relevant factors\u003c/strong\u003e. \u003cstrong\u003eMaternal demographic variables\u003c/strong\u003e included gestational week, age, blood type, g\u003cstrong\u003eravidity\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e parity, and mode of delivery. Laboratory parameters consisted of hematologic indices (WBC, NEUT%, LYMPH%, RBC, HGB, HCT, MCV, MCH, RDW-CV, PLT), Inflammatory markers (hsCRP, PCT), and hepatic function (TBIL, ALT, AST, GGT, ALP, ALB, GLO). Clinical biochemical parameters (including TBIL, ALT, GGT, ALP, ALB, GLO) were quantified utilizing an automated clinical chemistry analyzer (AU5800; Beckman Coulter Trading Co. Ltd., China). Hematologic indices (hsCRP, WBC, RBC, HGB, HCT, MCV, MCH, RDW-CV) were assessed employing a hematology analyzer (BC-7500; Mindray Corporation, Shenzhen, China). Cranial magnetic resonance imaging (MRI) was performed on a 3.0T scanner, acquiring the following sequences: T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery (T2-FLAIR), T2-propeller (T2-Prop), diffusion-weighted imaging (DWI), apparent diffusion coefficient mapping (ADC), exponential apparent diffusion coefficient mapping (eADC), and susceptibility-weighted angiography (SWAN). During the neonatal hospitalization period, cranial MRI was performed in cases with serum bilirubin levels significantly elevated to or above 342 \u0026micro;mol/L\u003csup\u003e10\u003c/sup\u003e, abnormal cranial ultrasound screening results, or in the presence of high risk factors such as in utero cerebral developmental anomalies. MRI findings were categorized into two groups: normal and abnormal. MRI abnormalities included hemorrhagic lesions, ischemic lesions, choroid plexus cysts, venous malformation, neuroepithelial cysts, gray-white matter heterotopia, ventricular enlargement, hydrocephalus, etc. Abnormalities on cranial MRI do not include cephalohematomas that are detectable by visual inspection or palpation. (Table 1, Supplementary figure 1, Supplementaryfigure 2)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were conducted using R Statistical Software (V4.2.2; R Foundation) and the Free Statistics analysis platform (Version 2.1, Beijing, China, http://www.clinicalscientists.cn/freestatistics). Statistical significance was defined as a two-sided \u003cem\u003eP\u003c/em\u003e-value \u0026lt; 0.05. Histogram distributions, Q-Q plots, and the Kolmogorov-Smirnov test were employed to assess the normality of variable distributions. Normally distributed continuous variables were expressed as mean \u0026plusmn; standard deviation (SD), while skewed continuous variables were represented as median with interquartile range (IQR). Categorical variables were presented as frequencies and percentages (%). Comparisons of continuous variables among groups were conducted using either the independent samples Student\u0026rsquo;s t-test or the Mann-Whitney U-test, depending on the distribution\u0026apos;s normality. Categorical data were compared using the chi-square test or Fisher\u0026rsquo;s exact test as appropriate. We used logistic regression to investigate the associations between HCT with cranial MRI abnormalities in NHB. HCT was entered as a continuous variable (per 0.01 unit) and as a categorical variable (quartiles). We selected these confounders on the basis of clinical interest, previous scientific literature, significant covariates in the univariate analysis, or a \u0026ge;10% change in the effect estimate upon their inclusion in the model. We constructed three hierarchical regression models to sequentially account for potential confounding factors: Model I adjusted for basic neonatal characteristics (age, sex, birth weight, admission weight, and gestational week); Model II additionally incorporated maternal characteristics (maternal age, pre-pregnancy BMI, and delivery mode); Model III further included neonatal hematological parameters (WBC and PLT) to address residual confounding. Tests for trend were conducted with multivariate regression models by entering the median value of each quartile as a continuous variable in the models. We employed restricted cubic splines to model potential nonlinear associations between HCT and cranial MRI abnormalities in neonatal hyperbilirubinemia. HCT was parameterized as a continuous predictor with four prespecified knots at the 5th, 35th, 65th, and 95th percentiles according to standard recommendations\u003csup\u003e11\u003c/sup\u003e. Non-linearity was tested by including a quadratic term in the regression models. Subgroup analyses stratified by sex and delivery mode evaluated the association between HCT and cranial MRI abnormalities in NHB infants.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePopulation characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 410 NHB who underwent cranial MRI were included in the final analysis. Among these, 108 (26.3%) were diagnosed with cranial MRI abnormalities. As shown in Table 1, neonates with MRI abnormalities exhibited significantly higher HCT (50.9 \u0026plusmn; 5.6% vs. 49.3 \u0026plusmn; 6.0%, \u003cem\u003eP\u003c/em\u003e = 0.019), and higher rates of vaginal delivery (88.9% vs. 60.6%, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) compared to those without abnormalities. \u003cstrong\u003eHowever, no statistically significant intergroup differences were observed in sex distribution, birth weight, gestational age, or most maternal characteristics (all\u0026nbsp;\u003c/strong\u003e\u003cem\u003eP\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;\u0026gt; 0.05).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation between HCT and cranial MRI abnormalities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression analysis demonstrated a significant positive association between HCT and the risk of cranial MRI abnormalities (Table 2). After adjusting for neonatal characteristics, maternal factors, and hematological parameters (Model\u0026nbsp;Ⅲ), each 1% increase in HCT was associated with a 6% higher risk of abnormalities (\u003cem\u003eOR\u003c/em\u003e = 1.06, 95% \u003cem\u003eCI\u003c/em\u003e: 1.01-1.12, \u003cem\u003eP\u003c/em\u003e = 0.015). When HCT was analyzed by quartiles, neonates in the highest quartile (Q4: 53.8-65.6%) had a 2.4-fold increased risk of abnormalities compared to those in the lowest quartile (Q1: 33.2-45.8%) (\u003cem\u003eOR\u003c/em\u003e = 2.39, 95% \u003cem\u003eCI\u003c/em\u003e: 1.07-5.35, \u003cem\u003eP\u003c/em\u003e = 0.034). A significant positive trend was observed across quartiles (\u003cem\u003eP\u003c/em\u003e for trend = 0.026). The restricted cubic spline analysis confirmed a linear dose-response relationship (\u003cem\u003eP\u003c/em\u003e for nonlinearity = 0.908), with the risk of abnormalities increasing steadily with higher HCT (Figure 2). Stratified analyses by sex and delivery mode revealed consistent associations, and no significant interactions were detected (\u003cem\u003eP\u003c/em\u003e for interaction \u0026gt; 0.05). The effect size was slightly more pronounced in male neonates (\u003cem\u003eOR\u003c/em\u003e = 1.08, 95% \u003cem\u003eCI\u003c/em\u003e: 1.01-1.16) and those delivered by cesarean section (\u003cem\u003eOR\u003c/em\u003e = 1.18, 95% \u003cem\u003eCI\u003c/em\u003e: 1.00-1.39) (Table 3, Figure 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSummary of key findings\u003c/p\u003e\n\u003cp\u003eOur study demonstrates a significant linear association between HCT and cranial MRI abnormalities in NHB. The analysis of 410 cases revealed that each 1% increase in HCT was associated with a 6% higher risk of abnormalities (adjusted \u003cem\u003eOR\u0026nbsp;\u003c/em\u003e= 1.06, 95% \u003cem\u003eCI\u003c/em\u003e: 1.01 - 1.12), with neonates in the highest HCT quartile showing a 2.4-fold increased risk compared to those in the lowest quartile. These findings remained consistent across multiple adjusted models and were confirmed by restricted cubic spline analysis (\u003cem\u003eP\u003c/em\u003e for nonlinearity = 0.908). Notably, the robustness of this association was further underscored by stratified analyses, which revealed consistent effects across sex and delivery mode, with no significant interactions (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003eComparison with existing\u0026nbsp;literature\u003c/p\u003e\n\u003cp\u003eOur findings concur with recent studies that underscore the role of hematological factors in neonatal neurological injury while offering significant new insights. A 2022 study by Rosen et al.\u003csup\u003e12\u003c/sup\u003e demonstrated that twin anemia polycythemia sequence (TAPS) was associated with fetal brain lesions, particularly in polycythemic twins, suggesting thathigherHCT may contribute to neurological injury. Additionally, Spruijt et al.\u003csup\u003e13\u003c/sup\u003e reported cerebellar hemorrhage in both fetal and neonatal cases of twin-twin transfusion syndrome, further supporting the association between hematological disturbances and brain injury. Consistent with these findings, a study by Tang et al.\u003csup\u003e14\u003c/sup\u003einvestigated the clinical and imaging characteristics of neonatal polycythemia and brain damage. They found that 45.7% of neonates with polycythemia had brain injuries, with severity correlating with the duration of polycythemia, cerebral oxygen saturation, and abnormal cerebral hemodynamics. This highlights the significant impact of HCT on neonatal brain health and supports our focus on hematological factors in neonatal neurological outcomes. However, our study extends these findings in several key aspects: First, by demonstrating a linear relationship across the entire HCT spectrum rather than just at extreme values; second, through the use of more sensitive and objective MRI-based outcomes; and third, by focusing specifically on the hyperbilirubinemia population, where the interaction between HCT and bilirubin may be particularly relevant.\u003c/p\u003e\n\u003cp\u003eIn contrast to our findings, a 2023 study by Gire et al.\u003csup\u003e15\u003c/sup\u003e reported no significant association between early Hb levels and neurodevelopmental outcomes at two years of age in very preterm infants. This discrepancy may arise from differences in study design and population. Gire et al. specifically examined very preterm infants with a mean gestational age of 28.7 weeks, using Hb levels as the primary hematological parameter, whereas our study evaluated HCT in NHB. Moreover, their study assessed neurodevelopmental outcomes at two years of age using the Ages and Stages Questionnaire (ASQ), while we utilized cranial MRI as a more immediate and objective measure of brain injury. Furthermore, Gire et al.\u0026rsquo;s study did not specifically focus on the hyperbilirubinemia infants, which may have influenced the observed associations. Similarly, the systematic review by Kalteren et al.\u003csup\u003e16\u003c/sup\u003e highlighted inconsistent correlations between HCT and cerebral oxygenation in preterm infants, with some studies reporting no association. This difference may reflect the complex interplay among anemia, transfusion practices, and gestational age-specific cerebrovascular responses. Importantly, neither of these studies specifically examined the hyperbilirubinemia population, where the combined effects of HCT and bilirubin toxicity might exacerbate neurological risks. Notably, our subgroup analysis of all admitted neonates (Supplementarytable 1) demonstrated that those undergoing MRI exhibited significantly higher bilirubin levels (328.3 vs 283.9 \u0026mu;mol/L, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) and longer hospital stays (102.9 vs 83.5 hours, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), suggesting that these factors may interact with HCT to influence neurological outcomes.\u003c/p\u003e\n\u003cp\u003eDose-response\u0026nbsp;relationship\u0026nbsp;between HCT and\u0026nbsp;cranial\u0026nbsp;abnormalities\u003c/p\u003e\n\u003cp\u003eIn our study, cranial MRI abnormalities were predominantly hemorrhagic lesions (70.4%), followed by ischemic lesions (13.9%), other abnormalities (12.0%), and combined hemorrhagic and ischemic lesions (3.7%) (Supplementaryfigures 2). The dose-response relationship between HCT and cranial MRI abnormalities was rigorously evaluated through both continuous and quartile-based analyses (Tables 2 and 3). When analyzed as a continuous variable, each 1% increase in HCT was associated with a 6% higher risk of MRI abnormalities in the fully adjusted model (\u003cem\u003eOR\u003c/em\u003e: 1.06, 95% \u003cem\u003eCI\u003c/em\u003e: 1.01-1.12, \u003cem\u003eP\u003c/em\u003e = 0.015). More importantly, the quartile analysis revealed a clear biological gradient, with neonates in the higher HCT quartiles (Q3 and Q4) demonstrating significantly increased risks compared to the reference group (Q1), with adjusted \u003cem\u003eOR\u003c/em\u003e\u003cem\u003es\u003c/em\u003e of 2.37 (95% \u003cem\u003eCI\u003c/em\u003e: 1.08-5.20) and 2.39 (95% \u003cem\u003eCI\u003c/em\u003e: 1.07-5.35) respectively. The statistically significant trend test (\u003cem\u003eP\u003c/em\u003e for trend = 0.026) across fully adjusted models further supports this dose-dependent pattern. Notably, this relationship persisted across progressively adjusted models, with the effect size increasing from Model I to Model III, suggesting that the observed association is independent of potential confounding factors including demographic characteristics, maternal factors, and hematologic parameters. The consistency of this trend across different analytical approaches (continuous vs. categorical) and increasing strength of association with more comprehensive adjustment strengthens the biological plausibility of our findings. Subgroup analyses (Table 3) revealed that this dose-response relationship was particularly evident in male neonates (adjusted \u003cem\u003eOR\u003c/em\u003e: 1.08, \u003cem\u003eP\u003c/em\u003e = 0.025), but was not statistically significant in females. The underlying mechanisms for this differential susceptibility remain unclear. Future studies with larger sample sizes should specifically examine these biological pathways to elucidate the basis for this sex-dependent response. The absence of significant interaction by delivery mode (\u003cem\u003eP\u003c/em\u003e = 0.678) indicates that the observed association between HCT and cranial MRI abnormalities is robust across different delivery modes.\u003c/p\u003e\n\u003cp\u003eBiological\u0026nbsp;mechanisms\u003c/p\u003e\n\u003cp\u003eThe association between elevated HCT and cranial MRI abnormalities in NHB likely involves multiple pathways. Elevated HCT increases blood viscosity, impairing cerebral microcirculation and reducing oxygen delivery\u003csup\u003e17\u003c/sup\u003e, as demonstrated by pseudo-continuous arterial spin labeling (pCASL) MRI studies showing an inverse correlation between HCT and cerebral blood flow\u003csup\u003e18\u003c/sup\u003e. This hemodynamic compromise may exacerbate bilirubin-induced neurotoxicity, particularly in neonates with immature cerebral autoregulation\u003csup\u003e19\u003c/sup\u003e. Additionally, high HCT promotes a pro-inflammatory state characterized by elevated cytokines (e.g., IL-6, IL-8)\u003csup\u003e20\u003c/sup\u003e, which may further impair blood-brain barrier function and increase oxidative stress. Bilirubin, in high concentrations, generates reactive oxygen species, further damaging vulnerable neonatal neurons\u003csup\u003e21,22\u003c/sup\u003e. Together, these effects (reduced perfusion, inflammation, and oxidative injury) likely contribute to the observed MRI abnormalities in NHB with elevated HCT.\u003c/p\u003e\n\u003cp\u003eStudy strengths and limitations\u003c/p\u003e\n\u003cp\u003eThis study has several notable strengths, including a well characterized sample of NHB with standardized cranial MRI assessments, comprehensive adjustment for potential confounders (including maternal, neonatal, and hematological factors), and demonstration of a clear dose-response relationship between HCT and cranial MRI abnormalities. However, the study has several limitations. First, due to its cross-sectional design, we cannot establish temporal relationships or definitively prove causality between HCT and neurological injury. Second, the single center design may limit generalizability to other populations. Third, while we adjusted for multiple potential confounders, residual confounding from unmeasured factors cannot be excluded. These limitations warrant careful consideration when interpreting the findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study found that high levels of HCT were significantly associated with a higher risk of incident cranial MRI abnormalities among NHB.\u0026nbsp;These findings suggest that HCT measurement could\u0026nbsp;direct\u0026nbsp;current risk stratification protocols for neurological complications in this vulnerable population. The results highlight the potential clinical utility of incorporating hematologic parameters into neuroimaging decision making algorithms for NHB. Further multicenter studies are warranted to validate these findings and investigate their implications for clinical management strategies.\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003eNJLSPH, Nanjing Lishui People\u0026rsquo;s Hospital;\u003c/p\u003e\n\u003cp\u003eChiCTR, Chinese Clinical Trial Registry Center;\u003c/p\u003e\n\u003cp\u003eSTROBE, Strengthening the Reporting of Observational Studies in Epidemiology;\u003c/p\u003e\n\u003cp\u003eNICU, Neonatal Intensive Care Unit;\u003c/p\u003e\n\u003cp\u003eASQ, Ages and stages questionnaire;\u003c/p\u003e\n\u003cp\u003eMRI, Magnetic resonance imaging;\u003c/p\u003e\n\u003cp\u003eT1WI, T1-weighted imaging;\u003c/p\u003e\n\u003cp\u003eT2WI, T2-weighted imaging;\u003c/p\u003e\n\u003cp\u003eT2-FLAIR, T2-fluid-attenuated inversion recovery imaging;\u003c/p\u003e\n\u003cp\u003eT2-Prop, T2-propeller imaging;\u003c/p\u003e\n\u003cp\u003eDWI, Diffusion weighted imaging;\u003c/p\u003e\n\u003cp\u003eADC, Apparent diffusion coefficient mapping;\u003c/p\u003e\n\u003cp\u003eeADC, Exponential apparent diffusion coefficient mapping;\u003c/p\u003e\n\u003cp\u003eSWAN, Susceptibility weighted angiography;\u003c/p\u003e\n\u003cp\u003epCASL, Pseudo-continuous arterial spin labeling;\u003c/p\u003e\n\u003cp\u003ehsCRP, High-sensitivity C-reactive protein;\u003c/p\u003e\n\u003cp\u003eRBC, Red blood cell;\u003c/p\u003e\n\u003cp\u003eHGB, Hemoglobin;\u003c/p\u003e\n\u003cp\u003eHCT, Hematocrit;\u003c/p\u003e\n\u003cp\u003eMCV, Mean corpuscular volume;\u003c/p\u003e\n\u003cp\u003eMCH, Mean corpuscular hemoglobin;\u003c/p\u003e\n\u003cp\u003eRDW-CV, Red cell distribution width coefficient of variation;\u003c/p\u003e\n\u003cp\u003eWBC, White blood cell;\u003c/p\u003e\n\u003cp\u003eNEUT, Neutrophil;\u003c/p\u003e\n\u003cp\u003eLYMPH, Lymphocyte;\u003c/p\u003e\n\u003cp\u003eMONO, Monocyte;\u003c/p\u003e\n\u003cp\u003ePLT, Platelet;\u003c/p\u003e\n\u003cp\u003ePCT, Plateletcrit;\u003c/p\u003e\n\u003cp\u003eMPV, Mean platelet volume;\u003c/p\u003e\n\u003cp\u003ePDW, Platelet distribution width;\u003c/p\u003e\n\u003cp\u003eP-LCR, Platelet large cell ratio;\u003c/p\u003e\n\u003cp\u003eEO, Eosinophil;\u003c/p\u003e\n\u003cp\u003eTBIL, Total bilirubin;\u003c/p\u003e\n\u003cp\u003eDBIL, Direct bilirubin;\u003c/p\u003e\n\u003cp\u003eALT, Alanine aminotransferase;\u003c/p\u003e\n\u003cp\u003eAST, Aspartate aminotransferase;\u003c/p\u003e\n\u003cp\u003eGGT, Gamma-glutamyl transferase;\u003c/p\u003e\n\u003cp\u003eALP, Alkaline phosphatase;\u003c/p\u003e\n\u003cp\u003eALB, Albumin;\u003c/p\u003e\n\u003cp\u003eGLO, Globulin;\u003c/p\u003e\n\u003cp\u003eA/G, Albumin/Globulin ratio;\u003c/p\u003e\n\u003cp\u003eTP, Total protein;\u003c/p\u003e\n\u003cp\u003eGLU, Glucose;\u003c/p\u003e\n\u003cp\u003eCK, Creatine kinase;\u003c/p\u003e\n\u003cp\u003eCK-MB, Creatine kinase MB;\u003c/p\u003e\n\u003cp\u003eLDH, Lactate dehydrogenase;\u003c/p\u003e\n\u003cp\u003eK\u003csup\u003e+\u003c/sup\u003e, Potassium;\u003c/p\u003e\n\u003cp\u003eNa\u003csup\u003e+\u003c/sup\u003e, Sodium;\u003c/p\u003e\n\u003cp\u003eCl\u003csup\u003e-\u003c/sup\u003e, Chloride;\u003c/p\u003e\n\u003cp\u003eCa\u003csup\u003e2+\u003c/sup\u003e, Calcium;\u003c/p\u003e\n\u003cp\u003eCO\u003csub\u003e2\u003c/sub\u003eCP, Carbon dioxide combining power;\u003c/p\u003e\n\u003cp\u003eNHB, Neonatal hyperbilirubinemia;\u003c/p\u003e\n\u003cp\u003eIL-6, Interleukin-6;\u003c/p\u003e\n\u003cp\u003eIL-8, Interleukin-8;\u003c/p\u003e\n\u003cp\u003eBMI, Body mass index;\u003c/p\u003e\n\u003cp\u003eIVF, In vitro fertilization;\u003c/p\u003e\n\u003cp\u003eHDP, Hypertensive disorders in pregnancy;\u003c/p\u003e\n\u003cp\u003eGDM, Gestational diabetes mellitus;\u003c/p\u003e\n\u003cp\u003eICP, Intrahepatic cholestasis of pregnancy;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTAPS\u003c/strong\u003e\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eTwin anemia polycythemia sequence;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAUTHOR CONTRIBUTIONS\u003c/p\u003e\n\u003cp\u003eThis study was conceived and designed by all authors.\u0026nbsp;Hongjuan Wei\u0026nbsp;(Principal Investigator) provided overall scientific oversight.\u0026nbsp;Liang Wang\u0026nbsp;drafted the initial manuscript under the direct supervision of the corresponding author,\u0026nbsp;Hongjuan Wei.\u0026nbsp;Rufeng Ji and Yinyan Tang\u0026nbsp;performed the literature search, data extraction, and analysis. All authors critically reviewed, revised, and approved the final manuscript for submission.\u003c/p\u003e\n\u003cp\u003eCOMPETING INTERESTS\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eACKNOWLEDGEMENTS\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge Dr. Jie Liu from the Department of Vascular and Endovascular Surgery, Chinese PLA General Hospital, for providing statistical support for this study. We also thank Dr. Qilin Yang from the Department of Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, for his consultation on study design and critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003ePATIENT CONSENT STATEMENT\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee granted a waiver of written informed consent owing to the retrospective nature of the research and complete anonymization of all data.\u003c/p\u003e\n\u003cp\u003eFUNDING\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo funding.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLewis, J. D.\u003cem\u003e et al.\u003c/em\u003e Automated Neuroprognostication Via Machine Learning in Neonates with Hypoxic-Ischemic Encephalopathy. \u003cem\u003eAnn Neurol\u003c/em\u003e \u003cstrong\u003e97\u003c/strong\u003e, 791-802 (2025).\u003c/li\u003e\n\u003cli\u003eLew, C. O.\u003cem\u003e et al.\u003c/em\u003e Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE). \u003cem\u003eRadiol Artif Intell\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, e240076 (2024).\u003c/li\u003e\n\u003cli\u003eWang, X., Wang, S., Chen, M., Lv, Y., Chen, X. \u0026amp; Yang, C. The value of hematocrit for predicting bronchopulmonary dysplasia in very low birth weight preterm infants. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e \u003cstrong\u003e102\u003c/strong\u003e, e35056 (2023).\u003c/li\u003e\n\u003cli\u003eScholkmann, F., Ostojic, D., Isler, H., Bassler, D., Wolf, M. \u0026amp; Karen, T. Reference Ranges for Hemoglobin and Hematocrit Levels in Neonates as a Function of Gestational Age (22⁻42 Weeks) and Postnatal Age (0⁻29 Days): Mathematical Modeling. \u003cem\u003eChildren (Basel)\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 38 (2019).\u003c/li\u003e\n\u003cli\u003eZucchini, L.\u003cem\u003e et al.\u003c/em\u003e Characterization of a Novel Approach for Neonatal Hematocrit Screening Based on Penetration Velocity in Lateral Flow Test Strip. \u003cem\u003eSensors (Basel)\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 2813 (2023).\u003c/li\u003e\n\u003cli\u003eHo, T. T.\u003cem\u003e et al.\u003c/em\u003e Red blood cell transfusions increase fecal calprotectin levels in premature infants. \u003cem\u003eJ Perinatol\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 837-841 (2015).\u003c/li\u003e\n\u003cli\u003eGoel, R., Cushing, M. M. \u0026amp; Tobian, A. A. Pediatric Patient Blood Management Programs: Not Just Transfusing Little Adults. \u003cem\u003eTransfus Med Rev\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 235-241 (2016).\u003c/li\u003e\n\u003cli\u003ede la Vega Muns, G., Quencer, R., Ezuddin, N. S. \u0026amp; Saigal, G. Utility of Hounsfield unit and hematocrit values in the diagnosis of acute venous sinus thrombosis in unenhanced brain CTs in the pediatric population. \u003cem\u003ePediatr Radiol\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, 234-239 (2019).\u003c/li\u003e\n\u003cli\u003ePeng, K., Adegboro, A. A., Li, Y., Liu, H., Xiong, B. \u0026amp; Li, X. The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 11694 (2024).\u003c/li\u003e\n\u003cli\u003eSubspecialty Group of Neonatology, t. S. o. P., Chinese Medical, A., Editorial Board, C. J. o. P. \u0026amp; . [Guidelines on the clinical management of neonatal hyperbilirubinemia (2025)]. \u003cem\u003eZhonghua Er Ke Za Zhi\u003c/em\u003e \u003cstrong\u003e63\u003c/strong\u003e, 338-350 (2025).\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eHarrell, F. E. Jr\u003c/strong\u003e. \u003cem\u003eRegression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis\u003c/em\u003e. New York: Springer, 2015, p.20-24.\u003c/li\u003e\n\u003cli\u003eRosen, H.\u003cem\u003e et al.\u003c/em\u003e Fetal and neonatal brain injury in twins complicated by twin anemia polycythemia sequence. \u003cem\u003ePrenat Diagn\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 978-984 (2022).\u003c/li\u003e\n\u003cli\u003eSpruijt, M. S.\u003cem\u003e et al.\u003c/em\u003e Fetal and neonatal neuroimaging in twin-twin transfusion syndrome. \u003cem\u003eUltrasound Obstet Gynecol\u003c/em\u003e \u003cstrong\u003e63\u003c/strong\u003e, 746-757 (2024).\u003c/li\u003e\n\u003cli\u003eTang, Z. Z., Zhou, C. L., Wang, H. M., Hou, X. L., Liu, Y. F. \u0026amp; Jiang, Y. [Relationship between neonatal polycythemia and brain damage]. \u003cem\u003eZhonghua Er Ke Za Zhi\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 845-849 (2006).\u003c/li\u003e\n\u003cli\u003eGire, C.\u003cem\u003e et al.\u003c/em\u003e Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children. \u003cem\u003eChildren (Basel)\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 209 (2023).\u003c/li\u003e\n\u003cli\u003eKalteren, W. S., Verhagen, E. A., Mintzer, J. P., Bos, A. F. \u0026amp; Kooi, E. Anemia and Red Blood Cell Transfusions, Cerebral Oxygenation, Brain Injury and Development, and Neurodevelopmental Outcome in Preterm Infants: A Systematic Review. \u003cem\u003eFront Pediatr\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 644462 (2021).\u003c/li\u003e\n\u003cli\u003eKameneva, M. V., Watach, M. J. \u0026amp; Borovetz, H. S. Rheologic dissimilarities in female and male blood: potential link to development of cardiovascular diseases. \u003cem\u003eAdv Exp Med Biol\u003c/em\u003e \u003cstrong\u003e530\u003c/strong\u003e, 689-696 (2003).\u003c/li\u003e\n\u003cli\u003eIbaraki, M., Nakamura, K., Matsubara, K., Shinohara, Y. \u0026amp; Kinoshita, T. Effect of hematocrit on cerebral blood flow measured by pseudo-continuous arterial spin labeling MRI: A comparative study with (15)O-water positron emission tomography. \u003cem\u003eMagn Reson Imaging\u003c/em\u003e \u003cstrong\u003e84\u003c/strong\u003e, 58-68 (2021).\u003c/li\u003e\n\u003cli\u003eWatchko, J. F. \u0026amp; Tiribelli, C. Bilirubin-induced neurologic damage--mechanisms and management approaches. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e369\u003c/strong\u003e, 2021-2030 (2013).\u003c/li\u003e\n\u003cli\u003eJain, A.\u003cem\u003e et al.\u003c/em\u003e Aberrant expression of cytokines in polycythemia vera correlate with the risk of thrombosis. \u003cem\u003eBlood Cells Mol Dis\u003c/em\u003e \u003cstrong\u003e89\u003c/strong\u003e, 102565 (2021).\u003c/li\u003e\n\u003cli\u003eLiu, C.\u003cem\u003e et al.\u003c/em\u003e Alleviation of Microglia Mediating Hippocampal Neuron Impairments and Depression-Related Behaviors by Urolithin B via the SIRT1-FOXO1 Pathway. \u003cem\u003eCNS Neurosci Ther\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, e70379 (2025).\u003c/li\u003e\n\u003cli\u003eLee, Z. M., Chang, L. S., Kuo, K. C., Lin, M. C. \u0026amp; Yu, H. R. Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants. \u003cem\u003eChildren (Basel)\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 926 (2023).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hematocrit, Magnetic resonance imaging, Brain diseases, Neonatal hyperbilirubinemia","lastPublishedDoi":"10.21203/rs.3.rs-6875215/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6875215/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The association between hematocrit (HCT) and cranial MRI abnormalities continues to be a topic of controversy. At present, the available evidence regarding the relationship between HCT and cranial MRI abnormalities is inadequate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eThis study aims to elucidate the relationship between HCT and cranial MRI abnormalities in neonatal hyperbilirubinemia (NHB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a retrospective cross-sectional study of 410 neonates with hyperbilirubinemia. Neonatal blood parameters, maternal prenatal data, and cranial MRI findings were extracted from the electronic medical record system. Logistic regression and smooth curve fitting were used to analyze the associations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After adjusting for confounding factors, multivariate logisticregression analysis showed that \u003cstrong\u003eeach\u003c/strong\u003e 1% increase in HCT is associated with a 6% \u003cstrong\u003ehigher\u003c/strong\u003e in the risk of cranialMRI abnormalities. Further exploratory subgroup analyses based on sex and mode of delivery revealed no significant interactions between these subgroups (all \u003cem\u003eP\u003c/em\u003e for interaction \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Among NHB, higher HCT was significantly associated with higher risk of incident cranial MRI abnormalities. These findings suggest that HCT may serve as a potential risk factor for cranial MRI abnormalities and could be a relevant biomarker.\u003c/p\u003e","manuscriptTitle":"Association between Hematocrit and Cranial MRI Abnormalities in Neonatal Hyperbilirubinemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 12:47:08","doi":"10.21203/rs.3.rs-6875215/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"310766c7-dd27-4a1e-a2e3-ea625a9770a4","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51569823,"name":"Health sciences/Medical research"},{"id":51569824,"name":"Health sciences/Medical research/Paediatric research"}],"tags":[],"updatedAt":"2025-09-08T12:53:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 12:47:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6875215","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6875215","identity":"rs-6875215","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}