Low Birthweight Associated Long-term Pubertal and Neurodevelopmental Alterations in Preterm Children

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Abstract Submission 

Weibin Ji^1,2, Guanya Li^1,2, Wenchao Zhang^1,2, Yang Hu^1,2, Peter Manza³, Nora Volkow³, Gene-Jack Wang³, Yi Zhang^1,2

¹Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China, ²International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China, ³Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA

Weibin Ji  
Center for Brain Imaging, School of Life Science and Technology, Xidian University|International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University
Xi'an, Shaanxi 710126, China|Xi'an, Shaanxi 710126, China

Guanya Li  
Center for Brain Imaging, School of Life Science and Technology, Xidian University|International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University
Xi'an, Shaanxi 710126, China|Xi'an, Shaanxi 710126, China

Wenchao Zhang  
Center for Brain Imaging, School of Life Science and Technology, Xidian University|International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University
Xi'an, Shaanxi 710126, China|Xi'an, Shaanxi 710126, China

Yang Hu  
Center for Brain Imaging, School of Life Science and Technology, Xidian University|International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University
Xi'an, Shaanxi 710126, China|Xi'an, Shaanxi 710126, China

Peter Manza  
Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism
Bethesda, MD 20892, USA

Nora Volkow  
Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism
Bethesda, MD 20892, USA

Gene-Jack Wang  
Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism
Bethesda, MD 20892, USA

Yi Zhang  
Center for Brain Imaging, School of Life Science and Technology, Xidian University|International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment & Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University
Xi'an, Shaanxi 710126, China|Xi'an, Shaanxi 710126, China

Preterm birth is often associated with low birthweight, and these infants are delivered at a critical time when brain architecture is not fully developed being at higher risk of long-term neurological and cognitive dysfunction (Ji et al., 2023; Mwaniki et al., 2012). In addition, there is also evidence that preterm birth and low birthweight could provoke adaptive changes in endocrine and metabolic processes and influence puberty, particularly early onset of adrenarche during the transition from childhood to adolescence (Charkaluk et al., 2004; Ibanez et al., 1998; Wehkalampi et al., 2011), impacting brain health throughout development (Goddings et al., 2014; Peper et al., 2009; Peper et al., 2008). However, few studies have examined associations among birthweight, pubertal endocrine process and brain and cognitive development.

Data were selected from the Annual Curated Data Release 3.0 from the ABCD consortium (https://abcdstudy.org/index.html). The preterm group included 1706 preterm subjects (gestational age < 37 weeks) and 1865 matched full-term individuals as control group (age, gender, BMI, intracranial volume, race/ethnicity, household income, highest education and sites, P > 0.05). The indicators of onset of adrenarche integrated both perceived physical features (adrenal score) and hormone measures (salivary dehydroepiandrosterone (DHEA)) from the child aged 9-10 years (Herting et al., 2020). We tested the differences in adrenal score and salivary DHEA level between preterm and control group. A linear mined-effect model (LME) was used to test the associations of adrenal score/salivary DHEA level with cognition and brain volumes in preterm and control groups (Ji et al., 2023), all demographic characteristics were included as covariates and all statistical results were corrected for multiple comparisons using FDR correction (P < 0.05). Furthermore, a serial two-mediator analysis was implemented to assess whether adrenal score/salivary DHEA level mediated the association among birthweight, cortical volume and cognition.

Compared to controls, preterm children showed lower birthweight, higher salivary DHEA level and adrenal score (Figure 1A). Salivary DHEA level was negatively associated with birthweight in both preterm and control groups, and two correlations were significantly different (Figure 1B). Adrenal score was negatively associated with birthweight in both preterm and control groups (Figure 1B); and also positively associated with salivary DHEA level in both preterm and control groups and two correlations were significantly different (Figure 1B).
Adrenal score was negatively associated with multiple cortical volumes in preterm children, including lateral orbitofrontal cortex (lOFC), inferior parietal lobule, anterior cingulate cortex, middle temporal gyrus, later occipital and rostral middle frontal cortex, superior parietal lobule, inferior temporal gyrus, lingual, cuneus and precuneus (P < 0.05, FDR; Figure 2A); but not in normal children (P < 0.05, FDR). In addition, there were negative associations between adrenal score and language vocabulary knowledge, cognitive control and attention, cognitive flexibility, as well as Fluid, Cryst and Totalcomp scores in the preterm group (P < 0.05, FDR; Figure 2B), and only working memory score was negatively associated with adrenal score in controls (P < 0.05, FDR; Figure 2B). The adrenal score indirect path, cortical volume in the lOFC path, and cortical volume in the lOFC via adrenal score indirect path all significantly mediated the direct relationship between birthweight and Fluid/Totalcomp score in preterm children (Figure 2C).

These findings highlight the impact of low birthweight on long-term pubertal and neurodevelopmental alterations in preterm children, suggesting that preterm and low birthweight associated abnormal developmental trajectories are observable during the transition from childhood to adolescence. This understanding may help with prevention and treatment.

Neurodevelopmental/ Early Life (eg. ADHD, autism) ¹

Executive Function, Cognitive Control and Decision Making ²

Development

Morphometrics

Other - Preterm birth, Puberty