Microstructural white matter changes in infants with transient neonatal hypoglycemia revealed by diffusion tensor imaging: a preliminary cross-sectional study

Introduction

Neonatal hypoglycemia (NH) is a common metabolic disorder during the neonatal period and has been associated with various neurodevelopmental impairments, including executive dysfunction and deficits in visual-motor function (1-5). Although the precise definition of NH remains a subject of debate (6), it is commonly defined as a blood glucose concentration below 2.6 mmol/L on single or repeated measurements (2,4,5,7-10). Following birth, the continuous maternal glucose supply ceases, leading to a physiological decline in blood glucose that typically reaches its nadir within one to two hours (11). This transition activates counter-regulatory mechanisms that promote glucose homeostasis in healthy newborns. However, as documented in numerous studies, symptomatic or moderate to severe hypoglycemia can adversely affect brain development (1,5).

Conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) have been employed to investigate hypoglycemia-related brain injury. Existing neuroimaging studies have primarily linked NH to injuries in the occipital lobe (4,12-14), as well as diffuse cortical and subcortical white matter damage, thalamic injury, and involvement of the globus pallidus (14,15). Recent prospective cohort studies following children at risk of NH into mid-childhood (9–10 years) have reported reduced volume in deep grey matter regions, thinning of the occipital cortex, and decreased caudate volume—the latter being correlated with emotional and behavioral challenges (16,17).

To date, neuroimaging research has largely focused on severe, symptomatic, or prolonged hypoglycemic episodes. This raises concerns regarding potential selection bias, as such cases may not be representative of infants experiencing transient hypoglycemia. Consequently, it remains unclear whether transient NH influences early brain development.

Diffusion tensor imaging (DTI) is a non-invasive, quantitative MRI technique that enables precise evaluation of white matter microstructure through metrics such as fractional anisotropy (FA), which reflects the integrity of fiber tracts and directional coherence of water diffusion (18-21). Microstructural alterations in white matter can lead to changes in water diffusion properties, thereby affecting FA values (21).

This study aims to investigate whether DTI-derived FA can detect subtle microstructural white matter changes associated with NH, thereby exploring its potential as an early indicator of brain vulnerability in this population. A secondary objective was to examine the correlation between FA values and glucose variability during the first 48 hours of life. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2212/rc).

Methods

Study subjects

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by ethics board of the Third Affiliated Hospital of Zhengzhou University (approval No. 2022-390-01) and individual consent for this analysis was waived owing to the retrospective nature of the study.

We performed a systematic search of the electronic medical records and Picture Archiving and Communication Systems (PACS) at the Third Affiliated Hospital of Zhengzhou University to identify neonates with transient NH between February 16, 2020, and October 17, 2023. Transient hypoglycemia was defined as a single glucose measurement <2.6 mmol/L, followed by a subsequent value above this threshold. All infants included in the study underwent structural MRI and DTI for clinical evaluation of brain development. Moreover, no abnormalities were found in the structural imaging of these infants on MRI.

A total of 20 infants with transient NH and 22 sex- and gestational age (GA)-matched normoglycemic controls were enrolled in this cohort study. Control infants were matched to cases primarily on GA and gender to minimize the confounding effect of prematurity on white matter development. Inclusion criteria were: (I) singleton birth with GA >28 weeks; (II) complete and detailed blood glucose monitoring records; (III) a single documented episode of hypoglycemia (<2.6 mmol/L); and (IV) availability of complete prenatal and perinatal clinical data. Exclusion criteria included fetal distress, 5-minute Apgar score <7, chromosomal abnormalities, cardiac or central nervous system malformations, congenital infections, inherited metabolic disorders, and hypoxic-ischemic encephalopathy.

In clinical practice, infants with a blood glucose level <2.6 mmol/L received prompt glucose supplementation and underwent intensive monitoring until normoglycemia was restored.

Magnetic resonance (MR) image acquisition/DTI

DTI was performed using a 3-T Siemens Magnetom Skyra clinical MRI scanner (Erlangen, Germany) in the Radiology Department of the Third Affiliated Hospital of Zhengzhou University. All infants were scanned in the standard supine position under sedation, with each session limited to 20 minutes. DTI data were acquired at postmenstrual ages (PMAs) ranging from 34.18 to 38.10 weeks, typically within the neonatal period after the resolution of acute hypoglycemic episodes and clinical stabilization. This timing aimed to capture early microstructural changes following the insult. Throughout the scanning procedure, each participant was accompanied by an experienced pediatric neurologist. All acquired images were interpreted by a radiologist specialized in MRI.

Image acquisition was conducted using a 20-channel head coil, with sequences consistent with those applied in our prior study (22).

DTI postprocessing

Automatically, MR images were migrated to Siemens syngo.via after the scan was completed, and FA maps were generated. Regions of interest (ROIs) were manually drawn on the FA map by a single experienced neuroradiologist blind to the clinical history and glucose values. All ROIs, as described formerly (22), were as follows: splenium of corpus callosum (sCC), posterior limb of internal capsule (PLIC), lentiform nucleus (LN), thalamus (Thal), caudate nucleus (Cau), frontal white matter (frontal WM), parietal white matter (parietal WM), occipital white matter (occipital WM), and cerebral peduncle (CP). Each site was measured three times and the average FA value was calculated. The average FA values of symmetrical parts of bilateral cerebral hemispheres were obtained as the final ones. ROIs and color FA maps are shown in Figure 1.

Figure 1 ROIs example diagram. ROIs of DTI are shown in red circle (A-C). ROIs: 1, frontal WM; 2, parietal WM; 3, Cau; 4, Thal; 5, sCC; 6, PLIC; 7, LN; 8, CP; and 9, occipital WM. Color FA maps in the infantile brain (D-F), corresponding to (A-C). Cau, caudate nucleus; CP, cerebral peduncle; DTI, diffusion tensor imaging; FA, fractional anisotropy; LN, lentiform nucleus; PLIC, posterior limb of internal capsule; ROI, region of interest; sCC, splenium of corpus callosum; Thal, thalamus; WM, white matter.

Clinical data collection

Clinical data was obtained for all infants in this cohort by reviewing the electronic medical record system of our hospital. Maternal factors covered maternal age, race, language, living area, maternal infection, and family history of seizures or other neurologic disorders. Neonatal factors included gender, GA, postnatal age (PNA) at DTI scan, PMA, birth weight, 1-minute Apgar, 5-minute Apgar, neonatal respiratory distress syndrome (NRDS), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and neonatal intensive care unit (NICU) hospitalization time. Correspondingly, neonatal blood glucose fluctuation consists of the lowest blood glucose (LBG), the highest blood glucose, the largest amplitude of glycemic excursions, mean blood glucose, and standard deviation of blood glucose.

Data analysis

All statistical analyses were performed using SPSS (version 21, IBM, Armonk, NY, USA) for Windows with P<0.05 considered statistically significant. Wilcoxon Rank Sum test or Chi-squared tests were used for detecting characteristic differences between the two groups. Partial correlation analysis was used to test the association between DTI findings and glucose variability in the first 48 hours of life before and after adjustment for GA, PNA, PMA, birth weight, maternal age, and 5-minute Apgar score. Scatter plots were utilized to assess the linear relationship between FA values and glucose variability.

Results

Study group

Twenty infants with transient NH and 22 gender- and GA-matched unexposed controls were finally recruited to the cohort study who finished 3-T DTI scans and more than 13 times’ blood glucose detection in their first 48 hours of life. The infants with transient NH and control subjects were comparable concerning maternal age, sex, GA, PNA at DTI scan, PMA, birth weight, 1-minute Apgar score, 5-minute Apgar score, NRDS, BPD, NEC, and NICU hospitalization time. Of note, there was a significantly lower “the lowest blood glucose”, “the highest blood glucose”, and mean blood glucose and higher “the largest amplitude of glycemic excursions” and standard deviation of blood glucose in infants with NH than controls. The clinical demographics of the cohort are summarized in Table 1.

Comparison between FA values in infants with transient NH and normoglycaemia group

Hypoglycemic infants showed a significant difference in FA values for sCC when compared with the normoglycaemia group. In contrast, there was no significant difference in FA values for PLIC, LN, Thal, Cau, frontal WM, parietal WM, occipital WM, and CP (Table 2 and Figure 2).

Figure 2 FA values for NH group and normoglycaemia group. *, P<0.05. Cau, caudate nucleus; CP, cerebral peduncle; FA, fractional anisotropy; LN, lentiform nucleus; NH, neonatal hypoglycemia; PLIC, posterior limb of internal capsule; sCC, splenium of corpus callosum; Thal, thalamus; WM, white matter.

FA and neonatal blood glucose fluctuation correlations

As shown in Figure 3, after adjustment for potential confounders, partial correlation analysis within the cohort between FA values and neonatal blood glucose fluctuation (the LBG, the highest blood glucose, the largest amplitude of glycemic excursions, mean blood glucose, and standard deviation of blood glucose) in sCC showed that there was a positive correlation between FA values and LBG in the region of sCC (P=0.013, r=0.408).

Figure 3 Correlation between FA values and neonatal blood glucose fluctuation (LBG, HBG, LAGE, MBG, SDBG) in sCC. There was a positive correlation between FA values and LBG in the region of sCC. FA values and LAGE, SDBG showed a trend approaching statistical significance. Each dot represents an infant in the cohort. FA, fractional anisotropy; HBG, highest blood glucose; LAGE, largest amplitude of glycemic excursions; LBG, lowest blood glucose; MBG, mean blood glucose; sCC, splenium of the corpus callosum; SDBG, standard deviation of blood glucose.

Discussion

The primary objectives of this study were to investigate whether DTI-detected microstructural white matter integrity differs between infants exposed to transient NH and matched controls, and to analyze the correlation between FA values and glycemic variability during the first 48 hours after birth. Our findings demonstrate that FA values in the splenium of the corpus callosum (sCC) were significantly lower in infants with transient NH compared to the normoglycemic group. Furthermore, after adjusting for potential confounders, sCC FA values exhibited a positive association with the LBG level in the cohort.

Consistent with our results, Zhang et al. [2022] (23) identified the sCC as a vulnerable region in neonates with hypoglycemic brain injury using structural MRI and DWI at different time windows. The susceptibility of the corpus callosum—particularly the sCC—to glycemic variation is supported by earlier studies (24-26), which may partly explain the heightened sensitivity of white matter to hypoglycemia (27). In contrast, some studies have reported no significant differences in cognitive or academic performance between preterm infants and controls (9,28), possibly due to the subjective nature of certain neurobehavioral assessments. In comparison, DTI offers a sensitive and quantitative approach for detecting subtle microstructural white matter abnormalities, making it a valuable tool for studying brain development and neurological disorders at an early stage.

This study holds clinical relevance, particularly as it accounted for prenatal and perinatal covariates, thereby enhancing the robustness of the findings. As previously documented, NH is associated with diverse patterns of brain injury—including involvement of the basal ganglia, thalamus, posterior limb of the internal capsule, watershed regions, occipital lobe, and sCC—most of which represent white matter abnormalities (3,5,24-26). While our results reaffirm the particular vulnerability of the sCC, the underlying reasons remain incompletely understood. Proposed mechanisms of hypoglycemia-induced cellular injury include N-methyl-D-aspartate receptor activation (29,30), impaired cerebral energy metabolism (31), and free radical-mediated mitochondrial alterations (32). Among these injury patterns, white matter damage—including sCC involvement—is the most frequently reported (3).

In line with the work of Lv et al. (33), we observed that white matter alterations in hypoglycemic infants correlate with the LBG level and other glycemic variability indices. Specifically, sCC FA values showed a positive correlation with LBG. In addition, a negative trend—approaching statistical significance—was observed between FA values and both the largest amplitude of glycemic excursions and the standard deviation of blood glucose. Within both the hypoglycemic and normoglycemic groups, FA values demonstrated weak positive correlations with the maximum and mean blood glucose levels, though these were not statistically significant. These trends align with clinical observations. The lowest glucose level, the largest amplitude of glycemic excursions, and the standard deviation of glucose are recognized as sensitive indicators of glycemic variability and are widely employed in glucose metabolism research. Glycemic fluctuation is a critical aspect of glycemic management, and previous studies have identified both early hypoglycemia and early glycemic lability as independent risk factors associated with increased morbidity and mortality (34,35).

Changes in FA values are closely linked to physiological and structural integrity of white matter (36). FA reflects myelin integrity and axonal density, serving as a proxy for white matter microstructural organization. In this cohort, we identified sCC white matter abnormalities and established a correlation between FA values and glucose fluctuations. Using DTI, FA values are expected to successfully detect early brain changes in infants with transient NH. The observed correlations between FA values and glycemic measures suggest that DTI-derived FA is a sensitive tool for detecting subtle microstructural white matter changes associated with NH. While these findings are promising, we acknowledge that establishing FA as a definitive biomarker for brain injury requires further validation through longitudinal studies correlating DTI metrics with conventional MRI findings and long-term neurodevelopmental outcomes. Our study provides foundational evidence that FA changes may precede overt structural abnormalities, highlighting its potential as an early indicator rather than a confirmed biomarker at this stage.

Several limitations of this study should be acknowledged. These include the relatively small sample size and its single-center design. That said, our institution is the largest provincial maternal and child health center, serving a population of over 100 million, which supports the generalizability of the data. Additionally, although blood glucose was measured more than 13 times within the first 48 hours of life—with prompt glucose supplementation and 10-minute interval monitoring upon hypoglycemia detection until normoglycemia was restored—we were unable to determine the exact duration of hypoglycemic episodes or the precise glucose nadir, limiting our ability to fully assess their impact on FA values.

Moreover, we regrettably did not apply the Bonferroni correction in our statistical analysis. Had it been applied, the originally significant P value for the sCC (0.03) would have become non-significant (0.27), a result inconsistent with clinical observations and prior literature. We propose two possible explanations: first, the limited sample size may have undermined the statistical power of the Bonferroni procedure; second, the method is highly conservative and may increase the false negative rate. Future studies with larger sample sizes are needed to enhance statistical power and validate these findings.

Finally, although we matched cases and controls on GA and adjusted for it in our statistical models, our cohort consisted predominantly of preterm infants. Prematurity is associated with its own spectrum of white matter dysmaturation and injury. Despite our efforts, residual confounding by prematurity-related factors cannot be entirely ruled out. The observed microstructural alterations may reflect a compounded effect of hypoglycemia on an already vulnerable preterm white matter substrate.

The timing of DTI acquisition relative to the hypoglycemic episodes is crucial for interpreting our findings. Our scans were performed in the neonatal period, after the acute phase of hypoglycemia had resolved and infants were clinically stable. This timing allows us to investigate early microstructural white matter alterations that may be a consequence of the hypoglycemic insult. However, it is important to consider that the neonatal brain undergoes rapid maturational changes. Therefore, the observed DTI alterations could reflect not only direct injury from hypoglycemia but also potentially altered maturational trajectories influenced by the insult. While our study demonstrates an association between NH and specific white matter microstructural changes, establishing a definitive causal relationship requires further longitudinal studies tracking brain development from the acute phase through later infancy and childhood. Future research could explore the utility of very early DTI to capture acute changes, followed by serial imaging to track their evolution and impact on maturation.

Conclusions

In conclusion, our study reveals that NH is associated with subtle microstructural white matter changes detectable by DTI, particularly in the sCC. These findings suggest that FA values are sensitive to early alterations in brain microstructure and hold potential as an early indicator for further investigation. While our study highlights the vulnerability of the developing brain to hypoglycemia, further longitudinal research is essential to validate FA as a definitive biomarker and to understand its long-term clinical implications.

Acknowledgments

We are grateful to the radiology MRI team of the Third Affiliated Hospital of Zhengzhou University for their assistance with our study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2212/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2212/dss

Funding: This research was funded by the National Natural Science Foundation of China (grant No. 82371929), and Joint Construction Project of Medical Science and Technology Research Program in Henan Province, China (grant No. LHGJ20210464).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2212/coif). All authors report funding from the National Natural Science Foundation of China (grant No. 82371929), and Joint Construction Project of Medical Science and Technology Research Program in Henan Province, China (grant No. LHGJ20210464). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by ethics board of the Third Affiliated Hospital of Zhengzhou University (approval No. 2022-390-01) and individual consent for this analysis was waived owing to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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