Background <p>Experiencing early life adversity (ELA) and chronic stress activation early in childhood increases the risk for altered developmental trajectories that lead to lifelong impacts on physical and mental health. This results in a toxic stress response – the dysregulation of neuroendocrine, immune and metabolic functions that causes allostatic load and a higher risk for poor health. Current screening practices for identifying toxic stress is the typical use Adverse Childhood Experience (ACEs) questionnaires, for which higher scores have strong predictability of outcomes at a population level. However, when used as the sole ELA identification tool, the questionnaire has challenges predicting later health outcomes at the individual level. We have proposed that the adaptative processes to ELA converge on mitochondrial health and is measurable in several ways, including the gold standard marker of oxidative stress due to reactive oxygen species, F_2α-Isoprostanes (F2_α -IsoPs). The major initiation of F2_α-IsoPs formation is reactive oxygen species (ROS) accumulation, a major source of which is mitochondria. This study aimed to evaluate the relation between maternal ACEs, child F_2α-IsoPs measures, and child neurodevelopment, establishing how the relations change over early developmental periods.</p> Methods <p>In our ongoing “Family First” longitudinal study, F_2α-IsoPs were measured from child urine samples collected at 6-,12-, and 24 months. Maternal adversity was assessed using the ACEs questionnaire at 6- and scores were confirmed at 12-months. The Bayley Scales of Infant Development (Bayley-4) was administered to assess child neurodevelopment at all study time points.</p> Results <p>Elevated infant F_2α-IsoPs at 6 months correlated significantly with lower language ( <i>r</i>=-0.15,<i>p</i> = 0.02) and motor scores (<i>r</i>=-0.16,<i>p</i> = 0.02) as assessed by the Bayley-4. Assessment of the relation between maternal ACEs on changes in infant F_2α-IsoPs levels over the first year of life demonstrated there were significantly different F_2α-IsoPs (15-F_2t-IsoP, <i>p</i> = 0.003) and (5-F_2t-IsoP, <i>p</i> = 0.001) trajectories for infants whose mothers endorsed either 0, 1–2, or 3 + on ACEs. Changes in child Bayley-4 scores in the second year of life varied by maternal ACEs with children whose mothers had no endorsements of adversity had decreasing language and motor scores and children whose mothers had any endorsements on ACEs had increasing language(<i>p</i> = 0.02) and motor scores (<i>p</i> = 0.02).</p> Conclusions <p>The data indicate that there may be specific physiologic contributions of oxidative stress to a toxic stress response in young children. A broader approach to pediatric screening for toxic stress predictability may be the incorporation of F2_α-IsoPs as one of the physiologic measures in the first two years postnatally.</p>