An Investigation of Signaling Pathways by which Preterm Birth Mediates Neuronal Alterations Associated with Neurodevelopmental Disorders

Abstract

Preterm birth is a global neonatal concern, being one of the leading causes of death in children under 5 years old along with birth defects and Sudden Infant Death Syndrome (SUID) (World Health Organization (WHO), n.d.; March of Dimes, n.d.). Based on one statistical report about preterm birth in the United States, the rate of preterm birth increased from 9.6% to 10.5% from from 2014-2021, decreasing to 10.4% in 2022 (March of Dimes, n.d.; Martin & Osterman, 2019). Over the past couple of decades, along with the maintained rates of preterm birth, medical advancements have contributed to increased survival rates of preterm infants. According to a US study, the survival rates until discharge or one year after birth of preterm infants born at weeks 22-28 of gestation increased from 76% in 2008-2012 to 78.3% in 2013-2018 (Bell et al., 2022). This difference was even more stark for earlier gestational ages; in preterm infants born at 22 weeks, the survival rate increased from 6.6% to 10.9%. With consistent rates of preterm birth and increasing survival rates, it is pertinent to continually work towards a better understanding of the complications that are associated with preterm birth, including neurodevelopmental impairments. Studies have found increased risk for neurodevelopmental disorders (NDDs) in all stages or prematurity, even late prematurity, when compared with term-born counterparts (Nivins et al., 2026; Kong et al., 2025). The exact increase in risk varies between the different disorders, but one study found that, in considering a number of behavioral and emotional disorders, the hazard ratios ranged from 1.20 to 10.7 (Kong et al., 2025). In addition, there are also observed sex-differences in the presentation of multiple NDDs, and these differences often lead to disparities in diagnosing for women. As of yet, the exact mechanisms behind these differences aren’t completely known (Kim et al., 2026). This thesis seeks to explore existing knowledge surrounding the signaling pathways by which preterm birth mediates structural alterations in neural networks that are associated with NDDs. The present work will go through typical neurodevelopment, provide an overview of preterm birth and neurodevelopmental impairments and disorders well known for their sex differences, detail signaling pathways associated with inflammation and neuroprotection, and finish with an exploration of recent research regarding the role of placental endocrine function in sex-differences seen in NDDs.