Publications

Longitudinal Trajectories of Hair Cortisol: Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Early Childhood

Cynthia R. Rovnaghi, Joseph Rigdon, Jean-Michel Roué, Monica O. Ruiz, Victor G. Carrion, and Kanwaljeet J.S. Anand

Abstract

The objective of this study was to examine if longitudinal trajectories of hair cortisol concentrations (HCC) measured at two or three yearly time points can identify 1-3 year old children at risk for altered hypothalamic-pituitary-adrenal (HPA)-axis function due to early life stress (ELS). HCC was measured (N = 575) in 265 children using a validated enzyme-linked immunosorbent assay. Hair was sampled in Clinic Visits (CV) centered at years 1, 2, and 3 (n = 45); 1 and 2 (n = 98); 1 and 3 (n = 27); 2 and 3 (n = 95).

Log-transformed HCC values were partitioned using latent class mixed models (LCMM) to minimize the Bayesian Information Criterion. Multivariable linear mixed effects models for ln-HCC as a function of fixed effects for age in months and random effects for participants (to account for repeated measures) were generated to identify the factors associated with class membership. Children in Class 1 (n = 69; 9% Black) evidenced declining ln-HCC across early childhood, whereas Class 2 members (n = 196; 43% Black) showed mixed trajectories. LCMM with only Class 2 members revealed Class 2A (n = 17, 82% Black) with sustained high ln-HCC and Class 2B (n = 179, 40% Blacks) with mixed ln-HCC profiles.

Another LCMM limited to only Class 2B members revealed Class 2B1 (n = 65, 57% Black) with declining ln-HCC values (at higher ranges than Class 1), and Class 2B2 (n = 113, 30% Black) with sustained high ln-HCC values. Class 1 may represent hair cortisol trajectories associated with adaptive HPA-axis profiles, whereas 2A, 2B1, and 2B2 may represent allostatic load with dysregulated profiles of HPA-axis function in response to varying exposures to ELS. Sequential longitudinal hair cortisol measurements revealed the allostatic load associated with ELS and the potential for developing maladaptive or dysregulated HPA-axis function in early childhood.

Demographic and Psychosocial Factors Associated With Hair Cortisol Concentrations in Preschool Children

Anand KJS, Rovnaghi CR, Rigdon J, Qin F, Tembulkar S, Murphy LE, Barr DA, Gotlib IH, Tylavsky FA.

Abstract

Background: Early life stress has enduring effects on physical and mental health. Hair cortisol concentrations (HCCs) reflect exposures to contextual stressors in early life, but are understudied in preschool children.

Methods: Hair samples from children (N = 693) during clinic visits (CVs) scheduled at 1-4 years (CV1-CV4) were measured using validated assay methods for HCC.

Results: HCCs were highest at CV1 and decreased at CV2-CV4, with no sex differences. Black children had higher HCC than White/other children; these differences persisted even after adjusting for socioeconomic factors. Bivariable analyses showed significant effects on HCC for Black race, with specific demographic and psychosocial factors at different ages. Multivariable analyses showed that higher HCC at CV1 were associated with Black race and male sex; at CV2 with Black race, lower maternal self-esteem, socioeconomic adversity, and the child's risk for developmental delay; at CV3 with Black race; at CV4 with maternal depression and the child's prior HCC values.

Conclusions: HCCs were higher in Black children than White/other races; differences were related to maternal factors, socioeconomic adversity, and the child's risk for developmental delay. Public health measures to reduce disparities between Blacks and other races must also consider the long-term effects of chronic stress in early life.

Measuring Socioeconomic Adversity in Early Life

Anand KJS, Rigdon J, Rovnaghi CR, Qin F, Tembulkar S, Bush N, LeWinn K, Tylavsky FA, Davis R, Barr DA, Gotlib IH.

Abstract

Aim: Early life adversity leads to enduring effects on physical and mental health, school performance and other outcomes. We sought to identify potentially modifiable factors associated with socioeconomic adversity in early life.

Methods: We enrolled 1503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial and economic variables were analysed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state and national levels.

Results: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education and health insurance. Significantly worse health and social outcomes occurred in the lower versus higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles.

Conclusion: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes.

Socioeconomic adversity: making sense of measures used for child health research

Ania Zylbersztejn

Abstract

The link between socioeconomic deprivation and adverse health outcomes is widely recognised. In the UK, many reports have shown socioeconomic gradients in measures of poor health at birth (such as preterm birth or low birth weight), adverse health outcomes in childhood (such as asthma, obesity or tooth decay) and poorer educational and social outcomes 1, 2. Similar patterns are observed in other high‐income countries. Despite numerous studies linking the socioeconomic circumstances of families and child health, evidence is still needed to determine which policies aimed at improving child health should be prioritised, and how to best monitor the effectiveness of policies already introduced. In the current issue of Acta Paediatrica , Anand et al. 3 present a new measure of socioeconomic adversity in the population, the Socioeconomic Adversity Index (SAI) which can be used to describe inequalities in child health. What other measures are commonly used for research and how does SAI compare?

Discovering Pain in Newborn Infants

Anand KJS.

Abstract

Randomised Trial of Fentanyl Anesthesia in Preterm Babies Undergoing Surgery: Effects on the Stress Response. By Anand KJ, Sippell WG, and Aynsley-Green A. Lancet 1987; 1:243-8. Reprinted with permission.In a randomised controlled trial, preterm babies undergoing ligation of a patent ductus arteriosus were given nitrous oxide and D-tubocurarine, with (n = 8) or without (n = 8) the addition of fentanyl (10 μg/kg intravenously) to the anesthetic regimen. Major hormonal responses to surgery, as indicated by changes in plasma adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol levels, in the insulin/glucagon molar ratio, and in blood glucose, lactate, and pyruvate concentrations were significantly greater in the nonfentanyl than in the fentanyl group. The urinary 3-methylhistidine/creatinine ratios were significantly greater in the nonfentanyl group on the second and third postoperative days. Compared with the fentanyl group, the nonfentanyl group had circulatory and metabolic complications postoperatively. The findings indicate that preterm babies mount a substantial stress response to surgery under anesthesia with nitrous oxide and curare and that prevention of this response by fentanyl anesthesia may be associated with an improved postoperative outcome.

Maternal Experiences of Trauma and Hair Cortisol in Early Childhood in a Prospective Cohort

Slopen N, Roberts AL, LeWinn KZ, Bush NR, Rovnaghi CR, Tylavsky F, Anand KJS.

Abstract

Background and objective: Maternal trauma can have intergenerational consequences but little is known about whether maternal traumas affect key biological domains associated with mental health in their offspring. The objective of this study was to examine maternal lifetime history of traumatic events through mid-gestation in relation to offspring cortisol production in early childhood.

Methods: The sample was comprised of 660 children (49.9% Black, 44.4% White) from a longitudinal study of mother-offspring dyads in Shelby County, Tennessee, followed from mid-gestation to child age 4 years (enrolled 2006-2011). Maternal lifetime history of traumatic life events were assessed mid-gestation using the Traumatic Life Events Questionnaire. Total cortisol output among offspring was measured using hair cortisol concentrations at ages 1 to 4 years.

Results: Associations of maternal trauma history with child hair cortisol varied by child's age. No association was observed at age 1 or 2. In adjusted regression models, at ages 3 and 4, offspring of mothers in the third (β = 0.99, P < .01), fourth (β=0.72, P < .05), and fifth (β=0.83, P < .01) quintiles of trauma exposure history had elevated (natural log) hair cortisol concentrations, relative to mothers in the lowest quintile (P-trend = 0.003). The associations were not attenuated after adjustment for theorized pathways, including premature birth, maternal postpartum depression, and maternal parenting stress.

Conclusions: Maternal lifetime trauma exposures are associated with offspring hair cortisol concentrations. Future research is needed to determine intermediary mechanisms and functional significance of elevated hair cortisol concentration in young children.

Pathways from Adverse Childhood Experiences to Nervous System Dysregulation

Cynthia R. Rovnaghi and Kanwaljeet J. S. Anand

Abstract

The type, timing, duration, and frequency of exposures to adverse childhood experiences (ACEs) or early life stress (prenatal/postnatal) are likely antecedents of nervous system dysregulation manifesting across multiple systems. These are mediated through multiple neuroendocrine axes (hypothalamicpituitary-adrenal, hypothalamic-pituitary-thyroid, pituitary-growth hormone/insulin-like growth factor-1 (IGF), hypothalamicpituitary-gonadal) and the autonomic system (sympathetic or parasympathetic), but they also affect neuro-immune interactions (innate and adaptive immunity) and the neuroenteric system (gastric, intestinal, and hepato-pancreatic). Even in the absence of abuse or neglect, children are increasingly exposed to three overarching trends: 1) parental use of psychotropic drugs and substances; 2) inconsistent or distracted parenting; and 3) deprivation from natural environments, social engagements, and unstructured play (that is not technology-dependent). Thus, children may fail to acquire developmentally appropriate selfregulation, coping skills, or peer engagement skills; they often receive pharmaceuticals for behavioral compliance, as opposed to mindfulness, self-reflection, or cognitive-behavioral therapy to guide self-development. Children presenting with clinically unexplained symptoms across multiple domains (executive dysfunction, sleep disturbances, autonomic dysregulation, somatization, digestive symptoms, emotional dysregulation) are susceptible to permanent reductions in grey matter volume, cognitive/behavioral problems, and poorer physical and mental health. Early life stress disrupts their first-time learning experiences; acclimatizes them toward pathways of negative (fearmotivated, anxiety-inducing) reinforcement of affiliated experiences, with atypical internalizing or externalizing behaviors, and impaired self-regulation. Positive experiences in the presence of supportive, nurturing parents with consistent parenting styles/practices can reverse this trend and avoid the long-term consequences of nervous system dysregulation.

Clinical Profile Associated With Adverse Childhood Experiences: The Advent of Nervous System Dysregulation

Elbers J, Rovnaghi CR, Golianu B, Anand KJS.

Abstract

Background: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs).

Methods: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients.

Results: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001).

Conclusions: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study.

Defining Pain in Newborns: Need for a Uniform Taxonomy?

Anand KJS.

Abstract

A framework for defining pain terms such as acute, persistent, prolonged or chronic pain to newborns was derived from the scientific literature on neonatal pain assessments, previous attempts to define chronic pain and the clinical and neurophysiological features of neonatal pain. This novel framework incorporates the temporal features, localising characteristics, and secondary effects of the pain experienced, as well as the behavioural and physiological response patterns of newborns.

Conclusion: Although not evidence-based, this framework provides an initial starting point for defining commonly used neonatal pain terms. It will require future revision/refinement based on the accumulating evidence for non-acute pain.

Assessment of Continuous Pain in Newborns Admitted to NICUs in 18 European Countries

Anand KJS, Eriksson M, Boyle EM, Avila-Alvarez A, Andersen RD, Sarafidis K, Polkki T, Matos C, Lago P, Papadouri T, Attard-Montalto S, Ilmoja ML, Simons S, Tameliene R, van Overmeire B, Berger A, Dobrzanska A, Schroth M, Bergqvist L, Courtois E, Rousseau J, Carbajal R; EUROPAIN survey working group of the NeoOpioid Consortium.

Abstract

Aim: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown.

Methods: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission.

Results: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001).

Conclusion: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

Regulation of Inflammatory Biomarkers by Intravenous Methylprednisolone in Pediatric ARDS Patients: Results From a Double-Blind, Placebo-Controlled Randomized Pilot Trial

Schwingshackl A, Kimura D, Rovnaghi CR, Saravia JS, Cormier SA, Teng B, West AN, Meduri UG, Anand KJ.

Abstract

Objective: A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients.

Design: Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7.

Setting: Tertiary care children's hospital.

Patients: Children (0-18years) with ARDS undergoing mechanical ventilation.

Interventions: 35 children were randomized within 72h of mechanical ventilation. The glucocorticoid group received methylprednisolone 2mg/kg loading dose followed by 1mg/kg/day continuous infusion from days 1 to 7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7.

Results: At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson's correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity.

Conclusion: This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

The social ecology of childhood and early life adversity

Marcela Lopez, Monica O Ruiz, Cynthia R Rovnaghi, Grace K-Y Tam, Jitka Hiscox, Ian H Gotlib, Donald A Barr, Victor G Carrion, Kanwaljeet J S Anand

Abstract

An increasing prevalence of early childhood adversity has reached epidemic proportions, creating a public health crisis. Rather than focusing only on adverse childhood experiences (ACEs) as the main lens for understanding early childhood experiences, detailed assessments of a child's social ecology are required to assess "early life adversity." These should also include the role of positive experiences, social relationships, and resilience-promoting factors. Comprehensive assessments of a child's physical and social ecology not only require parent/caregiver surveys and clinical observations, but also include measurements of the child's physiology using biomarkers. We identify cortisol as a stress biomarker and posit that hair cortisol concentrations represent a summative and chronological record of children's exposure to adverse experiences and other contextual stressors. Future research should use a social-ecological approach to investigate the robust interactions among adverse conditions, protective factors, genetic and epigenetic influences, environmental exposures, and social policy, within the context of a child's developmental stages. These contribute to their physical health, psychiatric conditions, cognitive/executive, social, and psychological functions, lifestyle choices, and socioeconomic outcomes. Such studies must inform preventive measures, therapeutic interventions, advocacy efforts, social policy changes, and public awareness campaigns to address early life adversities and their enduring effects on human potential. IMPACT: Current research does not support the practice of using ACEs as the main lens for understanding early childhood experiences. The social ecology of early childhood provides a contextual framework for evaluating the long-term health consequences of early life adversity. Comprehensive assessments reinforced with physiological measures and/or selected biomarkers, such as hair cortisol concentrations to assess early life stress, may provide critical insights into the relationships between early adversity, stress axis regulation, and subsequent health outcomes.

What is the definition of acute episodic and chronic pain in critically ill neonates and infants? A global, four-stage consensus and validation study

Marcela Lopez, Monica O Ruiz, Cynthia R Rovnaghi, Grace K-Y Tam, Jitka Hiscox, Ian H Gotlib, Donald A Barr, Victor G Carrion, Kanwaljeet J S Anand

Abstract

Objectives: To define and validate types of pain in critically ill neonates and infants by researchers and clinicians working in the neonatal intensive care unit (NICU) and high dependency unit (HDU).

Design: A qualitative descriptive mixed-methods design.

Procedure/s: Each stage of the study was built on and confirmed the previous stages. Stage 1 was an expert panel to develop definitions; stage 2 was a different expert panel made up of neonatal clinicians to propose clinical characteristics associated with the definitions from stage 1; stage 3 was a focus group of neonatal clinicians to provide clinical case scenarios associated with each definition and clinical characteristics; and stage 4 was a survey administered to neonatal clinicians internationally to test the validity of the definitions using the clinical case scenarios.

Results: In stage 1, the panel (n=10) developed consensus definitions for acute episodic pain and chronic pain in neonates and infants. In stage 2, a panel (n=8) established clinical characteristics that may be associated with each definition. In stage 3, a focus group (n=11) created clinical case scenarios of neonates and infants with acute episodic pain, chronic pain and no pain using the definitions and clinical characteristics. In stage 4, the survey (n=182) revealed that the definitions allowed an excellent level of discrimination between case scenarios that described neonates and infants with acute episodic pain and chronic pain (area under the receiver operating characteristic=0.87 and 0.89, respectively).

Conclusions: This four-stage study enabled the development of consensus-based and clinically valid definitions of acute episodic pain and chronic pain. There is a need to define and validate other pain types to inform a taxonomy of pain experienced by neonates and infants in the NICU and HDU.

Hyperoxemia among Pediatric Intensive Care Unit Patients Receiving Oxygen Therapy

Azadeh R. Fayazi, Matteo Sesia , Kanwaljeet J. S. Anand

Abstract

Supratherapeutic oxygen levels consistently cause oxygen toxicity in the lungs and other organs. The prevalence and severity of hyperoxemia among pediatric intensive care unit (PICU) patients remain unknown. This was the first study to examine the prevalence and duration of hyperoxemia in PICU patients receiving oxygen therapy. This is a retrospective chart review. This was performed in a setting of 36-bed PICU in a quaternary-care children's hospital. All the patients were children aged <18 years, admitted to the PICU for ≥24 hours, receiving oxygen therapy for ≥12 hours who had at least one arterial blood gas during this time.

There was no intervention. Of 5,251 patients admitted to the PICU, 614 were included in the study. On average, these patients received oxygen therapy for 91% of their time in the PICU and remained hyperoxemic, as measured by pulse oximetry, for 65% of their time on oxygen therapy. Patients on oxygen therapy remained hyperoxemic for a median of 38 hours per patient and only 1.1% of patients did not experience any hyperoxemia. Most of the time (87.5%) patients received oxygen therapy through a fraction of inspired oxygen (FiO2)-adjustable device. Mean FiO2 on noninvasive support was 0.56 and on invasive support was 0.37. Mean partial pressure of oxygen (PaO2) on oxygen therapy was 108.7 torr and 3,037 (42.1%) of PaO2 measurements were >100 torr. Despite relatively low FiO2, PICU patients receiving oxygen therapy are commonly exposed to prolonged hyperoxemia, which may contribute to ongoing organ injury.

Can Translational Social Neuroscience Research Offer Insights to Mitigate Structural Racism in the United States?

Manpreet K Singh, Akua Nimarko, Jennifer Bruno, Kanwaljeet J S Anand, Swaran P Singh

Abstract

Social isolation and conflict due to structural racism may result in human suffering and loneliness across the life span. Given the rising prevalence of these problems in the United States, combined with disruptions experienced during the COVID-19 pandemic, the neurobiology of affiliative behaviors may offer practical solutions to the pressing challenges associated with structural racism. Controlled experiments across species demonstrate that social connections are critical to survival, although strengthening individual resilience is insufficient to address the magnitude and impact of structural racism. In contrast, the multilevel construct of social resilience, defined by the power of groups to cultivate, engage in, and sustain positive relationships that endure and recuperate from social adversities, offers unique insights that may have greater impact, reach, and durability than individual-level interventions. Here, we review putative social resilience-enhancing interventions and, when available, their biological mediators, with the hope to stimulate discovery of novel approaches to mitigate structural racism. We first explore the social neuroscience principles underlying psychotherapy and other psychiatric interventions. Then, we explore translational efforts across species to tailor treatments that increase social resilience, with context and cultural sensitivity in mind. Finally, we conclude with some practical future directions for understudied areas that may be essential for progress in biological psychiatry, including ethical ways to increase representation in research and developing social paradigms that inform dynamics toward or away from socially resilient outcomes.

Prevalence of burnout and its relation to the neuroendocrine system among pediatric residents during the early Covid-19 pandemic: A pilot feasibility study

Daniel S Tawfik, Cynthia Rovnaghi, Jochen Profit, Timothy T Cornell, Kanwaljeet J S Anand

Abstract

Background: Measuring burnout relies on infrequent and subjective surveys, which often do not reflect the underlying factors or biological mechanisms that promote or prevent it. Burnout correlates with cortisol levels and dysregulation of the hypothalamic-pituitary-adrenal axis, but the chronology and strength of this relationship are unknown.

Objective: To determine the prevalence and feasibility of studying burnout in pediatric residents using hair cortisol and hair oxytocin concentrations.

Design: /Methods: Longitudinal observational cohort study of pediatric residents. We assessed burnout using the Stanford Professional Fulfillment Index and hair cortisol (HCC), and hair oxytocin concentrations (HOC) at four 3-month intervals from January 2020-January 2021. We evaluated test-retest reliability, sensitivity to change using Pearson product-moment correlations, and relationships between burnout and hair biomarkers using hierarchical mixed-effects linear regression.

Results: 17 Pediatrics residents provided 78 wellness surveys and 54 hair samples. Burnout symptoms were present in 39 (50%) of the surveys, with 14 (82%) residents reporting burnout in at least one time point. The lowest (41%) and highest (60%) burnout prevalence occurred in 04/2020 and 01/2021, respectively. No significant associations between burnout scores and HCC (β -0.01, 95%CI: 0.14-0.13), HOC (β 0.06, 95%CI: 0.06-0.19), or the HCC:HOC ratio (β -0.04, 95%CI: 0.09-0.02) were noted in separate analyses. Intra-individual changes in hair cortisol concentration were not associated with changes in burnout score.

Conclusions: Burnout was prevalent among Pediatrics residents, with highest prevalence noted in January 2021. This pilot longitudinal study demonstrates the feasibility of evaluating burnout with stress and resilience biomarkers in Pediatrics residents.