Publications

Objective Detection of Newborn Infant Acute Procedural Pain Using EEG and Machine Learning Algorithms.

Roue, J. M., Avnit, A., Gholami, B., Haddad, W. M., & Anand, K. J. S. (2025).

Abstract

Observer-dependent infant pain scales have limitations including discontinuous assessments and the lack of healthcare professionals' availability. We hypothesized that applying agnostic machine learning approaches to neonatal electroencephalographic (EEG) analysis may reveal features of the infant response to acute pain. EEG was recorded from 30 neonates undergoing acutely painful procedures (18 males, 34.0–41.7 weeks gestation at birth). EEG recordings were randomly assigned to training (n = 20) and testing (n = 10) datasets. Functional connectivity measures were calculated for each infant before and after pain-inducing procedures. A grid search including five machine learning models was conducted on the training dataset, and each model was evaluated using leave-one-subject-out cross-validation. An optimal model, having the highest F-1 score, was obtained and evaluated on the independent testing dataset. A gradient boosting model with 12 features showed optimal performance, with 90% area under the receiver operating characteristic curve suggesting high specificity (0.90) and precision (0.90). The five highest ranked features corresponded to EEG electrode pairs: T7-P4, Fz-CP5, FC1-TP10, CP6-Cz, and Fz-F3, suggesting involvement of the contralateral temporal gyrus, opercular cortex, thalamus, and bilateral insula in infant pain processing. Preliminary changes in functional connectivity indicate infant pain processing. Future machine learning algorithms can integrate physiological and behavioral parameters with EEG changes to accurately assess the complexity of infant pain responses.

Using hair biomarkers to examine social-emotional resilience in adolescence: A feasibility study.

Rovnaghi, C. R., Gupta, A., Ramsundarsingh, S., Newman, R. I., Shen, S., Vedelli, J. K. H., Reichert, E. L., & Anand, K. J. S. (2025).

Abstract

Background

The SKY Schools Program combines breath-based techniques and a social-emotional learning curriculum. We examined its effects on objective physiological biomarkers, including hair cortisol (HCC, chronic stress measure) and hair oxytocin (HOC, social affiliation measure), as well as behavioral (youth risk behaviors) and mental health outcomes (anxiety, depression).

Methods

The SKY Schools program was adapted for post-pandemic restrictions (i.e., staff shortages, no lessons requiring writing, limited weekly follow-ups) and implemented among 7th grade students (daily in-person 40-min sessions for three weeks during physical education classes). Longitudinal assessments were obtained at baseline (T1, February 2022, N = 21), post-intervention (T2, June 2022, N = 20), and follow-up (T3, December 2022, N = 18).

Results

Most of our sample was male (67 %), Hispanic (62 %), and lived in low-income (<$100K) households (75 %). Students reported fewer poor mental health days at follow-up (Friedman test p < 0.01). Log-normal (Ln)-HCC (p < 0.01) were higher post-intervention vs. baseline (median 1.81 (IQR 1.63–2.46) vs. 1.60 (0.91–1.85)) and lower at follow-up (1.23; IQR: 0.64–1.50), with HCC in more students moving into the adaptive range (25th-75th percentile). Ln-HOC (p = 0.04) were higher post-intervention vs. baseline (1.78 (1.54–2.26) vs. 1.50 (0.81–1.70)).

Conclusions

This study uniquely evaluated the impact of the SKY intervention on hair cortisol (HCC) and hair oxytocin concentrations (HOC), which are objective, physiological measures of chronic stress and social affiliation. Results suggest that SKY may improve social affiliation and possibly HPA-axis regulation.

Direct evidence of fetal responses to noxious stimulations: A systematic review of physiological and behavioral reactions.

Bellieni, C. V., & Anand, K. J. S. (2025).

Abstract

Fetal pain is usually debated using data extrapolated from physiology and anatomy; whereas direct observation of fetal pain reactions is only marginally used. We present the first systematic review to carefully analyse this direct evidence.Our objective was to summarize the scientific literature based on the direct observation of fetal responses to noxious stimulation.We retrieved 17 clinical studies focused on the direct observation of fetal responses to noxious stimulation. This systematic review suggests that direct trials of fetal responses to acute pain/stress caused by tissue injury are scarce, but nonetheless informative for therapeutic interventions using fetal surgery or fetal invasive procedures. The current evidence indicates that responses to fetal pain develop from mid-gestation onward, but further high-quality research is needed to confirm these findings and guide clinical practice.

Missing Race and Ethnicity Data in Pediatric Studies.

Vedelli, J. K. H., Azizi, Z., & Anand, K. J. S. (2024).

Abstract

Collecting and reporting race and ethnicity data in pediatric studies remains crucial for examining disease risks and outcomes, ensuring the representativeness of scientific research, and equitably allocating health care resources.1 Race and ethnicity are dynamic social constructs shaped by a variety of nonbiological factors, although they may influence gene/environmental interactions with potential clinical and public health implications.2,3

Despite their importance, race and ethnicity data are lacking across the entire health care system, especially among underserved racial and ethnic minority populations, leading to serious consequences for population health research from the exclusion of minorities or misclassification of their data. Even with significant amounts of missing race and ethnicity data, federally funded entities receive minimal guidance on how to overcome this problem. This is particularly exacerbated in childhood-related contexts, leaving researchers and public health workers with no practical framework on how to address the missing data. Here, we describe approaches for addressing this issue through essential phases of data collection and data analysis 

Linear hair growth rates in preschool children

Ruiz, M. O., Rovnaghi, C. R., Tembulkar, S., Qin, F., Truong, L., Shen, S., & Anand, K. J. S. (2024).

Abstract

Background

Human scalp hair is a validated bio-substrate for monitoring various exposures in childhood including contextual stressors, environmental toxins, prescription or non-prescription drugs. Linear hair growth rates (HGR) are required to accurately interpret hair biomarker concentrations.

Methods

We measured HGR in a prospective cohort of preschool children (N = 266) aged 9–72 months and assessed demographic factors, anthropometrics, and hair protein content (HPC). We examined HGR differences by age, sex, race, height, hair pigment, and season, and used univariable and multivariable linear regression models to identify HGR-related factors.

Results

Infants below 1 year (288 ± 61 μm/day) had slower HGR than children aged 2–5 years (p = 0.0073). Dark-haired children (352 ± 52 μm/day) had higher HGR than light-haired children (325 ± 50 μm/day; p = 0.0019). Asian subjects had the highest HGR overall (p = 0.016). Younger children had higher HPC (p = 0.0014) and their HPC-adjusted HGRs were slower than older children (p = 0.0073). Age, height, hair pigmentation, and HPC were related to HGR in multivariable regression models.

Conclusions

We identified age, height, hair pigment, and hair protein concentration as significant determinants of linear HGRs. These findings help explain the known hair biomarker differences between children and adults and aid accurate interpretation of hair biomarker results in preschool children.

Proteins in scalp hair of preschool children.

Rovnaghi, C. R., Singhal, K., Leib, R. D., Xenochristou, M., Aghaeepour, N., Chien, A. S., Ruiz, M. O., Dinakarpandian, D., & Anand, K. J. S. (2024).

Abstract

Background. Early childhood experiences have long-lasting effects on subsequent mental and physical health, education, and employment. The measurement of these effects relies on insensitive behavioral signs, subjective assessments by adult observers, neuroimaging or neurophysiological studies, or retrospective epidemiologic outcomes. Despite intensive research, the underlying mechanisms of these long-term changes in development and health status remain unknown. Methods. We analyzed scalp hair from healthy children and their mothers using an unbiased proteomics platform combining tandem mass spectrometry, ultra-performance liquid chromatography, and collision-induced dissociation to reveal commonly observed hair proteins with a spectral count of 3 or higher. Results. We observed 1368 non-structural hair proteins in children and 1438 non-structural hair proteins in mothers, with 1288 proteins showing individual variability. Mothers showed higher numbers of peptide spectral matches and hair proteins compared to children, with important age-related differences between mothers and children. Age-related differences were also observed in children, with differential protein expression patterns between younger (2 years and below) and older children (3–5 years). We observed greater similarity in hair protein patterns between mothers and their biological children compared with mothers and unrelated children. The top 5% of proteins driving population variability represented biological pathways associated with brain development, immune signaling, and stress response regulation. Conclusions. Non-structural proteins observed in scalp hair include promising biomarkers to investigate the long-term developmental changes and health status associated with early childhood experiences.

An Evidence-Based Discussion of Fetal Pain and Stress.

Mohamed, S. H. M., Reissland, N., & Anand, K. J. S. (2024).

Abstract

Background: The concept of fetal pain results from procedures conducted without anesthesia in preterm newborns and fetuses, which indicate that it is possible to examine fetal pain based on stress hormone, metabolic, and behavioral changes. Anatomical and physiological data suggest that fetuses become capable of processing nociceptive stimuli around midgestation, although the associated changes in fetal brain development remain unclear. What constitutes fetal pain remains controversial in the light of the definition of pain adopted by the International Association for the Study of Pain (IASP), which posits pain as an “unpleasant sensory and emotional experience.” 

Summary: Here, we examine the notion that human fetuses cannot “experience” pain and potential implications of this claim. We highlight the key scientific evidence related to fetal pain, including clinical studies on pain in fetuses and preterm newborns. We argue that consistent patterns of stress hormones, metabolic changes, body movements, hemodynamic changes, and pain-related facial expressions in fetuses exposed to invasive procedures overcome the need for subjective proof of pain as articulated in the IASP definition. No study to date has conclusively proven the absence of fetal pain beyond the age of viability. 

Key Messages: Based on the current evidence, we propose that all fetuses receive anesthesia regardless of the invasive procedures being performed to guarantee the least possible pain and physiological, behavioral, or hormonal responses without exposing the mother or her baby to unnecessary complications.

Unit-based Pathways to Reduce InequitieS for familiEs speaking languages other than English (UPRISE).

Magana-Soto, J. N., Ruiz, M. O., Tawfik, D. S., Rey-Ardila, D., Bonillas, A., Persoglia-Bell, M., Su, F., & Anand, K. J. S. (2024).

Abstract

OBJECTIVE

Health care inequities are common among individuals who speak languages other than English (LOE). Within our PICU, LOE families prefer communication via in-person interpreters (IPI). Spanish-speaking patient families are our largest LOE population; therefore, we sought to increase Spanish IPI utilization for medical updates in the PICU.

METHODS

A quality improvement initiative in a 36-bed PICU included: the addition of a dedicated weekday Spanish-speaking IPI, the creation of communication tools, staff education, optimized identification of LOE families, and development of a language dashboard across multiple Plan, Do, Study, Act cycles. The primary outcome was IPI utilization rates for daily medical updates.

RESULTS

Spanish IPI utilization for daily weekday medical updates among 442 Spanish-speaking patient families increased from a median of 39.4% at baseline to a new centerline median of 51.9% during implementation, exhibiting 66.3% (465 of 701) utilization in the final 6 months of implementation. The greatest sustained increases in Spanish IPI utilization occurred after PICU-based IPI implementation, staff education, electronic health record optimization, and a split work week between 2 PICU-based IPIs.

CONCLUSIONS

This quality improvement initiative increased Spanish IPI utilization for daily weekday medical updates in the PICU across multiple Plan, Do, Study, Act cycles. Future work will adapt these interventions to other languages and other hospital-based units.

Hair cortisol sampling as a measure of physiological stress in youth with acute musculoskeletal pain.

Gaultney, W., O'Brien, J. R., Heierle, J., Battison, E. A. J., Wilson, A., Rovnaghi, C., Anand, K. J. S., & Holley, A. (2024).

Abstract

Stress physiology contributes to health outcomes. Hair cortisol concentration (HCC) is an objective measure of cumulative cortisol secretion associated with health, including pain. The aim of the current study was to describe associations between pre-injury stress physiology (as measured by HCC), acute pain characteristics and relevant demographic factors (i.e., BMI, age, sex, days since injury) in youth with an acute musculoskeletal (MSK) injury. Participants were 58 youth aged 11 to 17 with acute MSK pain. Participants completed self-report measures assessing pain intensity, pain catastrophizing, and pain interference. Hair was collected within 1 month after injury using hair cortisol collection procedures adapted from published research protocols. Correlations examining associations among HCC values and clinical/demographic factors revealed that higher HCC was associated with lower body mass index (BMI) and male sex. HCC was not associated with pain variables or age. Additional research is needed to clarify the relation between HCC and psychosocial variables to aid researchers in studying the role of pre-injury stress in acute MSK injury and pain recovery in youth.

Hyperoxemia among Pediatric Intensive Care Unit Patients Receiving Oxygen Therapy.

Fayazi, A. R., Sesia, M., & Anand, K. J. S. (2024).

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.

Incidence of mental health conditions following pediatric hospital admissions: analysis of a national database.

Daughtrey, H. R., Ruiz, M. O., Felix, N., Saynina, O., Sanders, L. M., & Anand, K. J. S. (2024).

Abstract

Introduction: Despite increasing survival of children following hospitalization, hospitalization may increase iatrogenic risk for mental health (MH) disorders, including acute stress, post-traumatic stress, anxiety, or depression. Using a population-based retrospective cohort study, we assessed the rates of new MH diagnoses during the 12 months after hospitalization, including the moderating effects of ICU exposure.

Study design/methods: This was a retrospective case control study using the Truven Health Analytics insurance database. Inclusion criteria included children aged 3–21 years, insurance enrollment for >12 months before and after hospital admission. We excluded children with hospitalization 2 years prior to index hospitalization and those with prior MH diagnoses. We extracted admission type, ICD-10 codes, demographic, clinical, and service coordination variables from the database. We established age- and sex-matched cohorts of non-hospitalized children. The primary outcome was a new MH diagnosis. Multivariable regression methods examined the risk of incident MH disorder(s) between hospitalized and non-hospitalized children. Among hospitalized children, we further assessed effect modification from ICU (vs. non-ICU) stay, admission year, length of stay, medical complexity, and geographic region.

Results: New MH diagnoses occurred among 19,418 (7%) hospitalized children, 3,336 (8%) ICU-hospitalized children and 28,209 (5%) matched healthy controls. The most common MH diagnoses were anxiety (2.5%), depression (1.9%), and stress/trauma (2.2%) disorders. Hospitalization increased the odds of new MH diagnoses by 12.3% (OR: 1.123, 95% CI: 1.079–1.17) and ICU-hospitalization increased these odds by 63% (OR: 1.63, 95% CI: 1.483–1.79) as compared to matched, non-hospitalized children. Children with non-complex chronic diseases (OR: 2.91, 95% CI: 2.84–2.977) and complex chronic diseases (OR: 5.16, 95% CI: 5.032–5.289) had a substantially higher risk for new MH diagnoses after hospitalization compared to patients with acute illnesses.

Conclusion: Pediatric hospitalization is associated with higher, long-term risk of new mental health diagnoses, and ICU hospitalization further increases that risk within 12 months of the acute episode. Acute care hospitalization confers iatrogenic risks that warrant long-term mental and behavioral health follow-up.

Stress Symptoms Among Children and Their Parents After ICU Hospitalization.

Daughtrey, H. R., Lee, J., Boothroyd, D. B., Burnside, G. M., Shaw, R. J., Anand, K. J. S., & Sanders, L. M. (2024).

Abstract

Objective: Child survival after intensive care unit (ICU) hospitalization has increased, yet many children experience acute stress that may precipitate mental/behavioral health comorbidities. Parents report stress after their child's hospitalization. Little is known about the individual and family characteristics that may moderate intergenerational relationships of acute stress. 

Design: Following ICU admission at a large academic medical center, a prospective cross-sectional cohort study assessed the associations between intergenerational characteristics and acute stress among children and families. 

Patients: Parent–child dyads (N = 88) were recruited from the pediatric ICU and pediatric cardiovascular ICU (CVICU) following ICU discharge. Eligible children were between 8 and 18 years old with ICU stays longer than 24 hours. Children with developmental delays were excluded. Caregivers were proficient in English or Spanish. Surveys were collected before hospital discharge. 

Measurements/Main Results: The primary outcome was “child stress” defined as a score≥17, measured by the Children's Revised Impact of Events Scale (CRIES-8). “Parent stress” was defined as an elevated composite score on the Stanford Acute Stress Reaction Questionnaire. We used validated scales to assess the child's clinical and family social characteristics. Acute stress was identified in 34 (39.8%) children and 50 (56.8%) parents. In multivariate linear regression analyses adjusting for social characteristics, parent stress was associated with increased risk of child stress (adjusted odds ratio 2.58, 95% confidence interval 0.69, 4.46, p < .01). In unadjusted analyses, Hispanic ethnicity was associated with greater child stress. In adjusted analyses, race, income, ICU length of stay, and language were not associated with child stress and did not moderate the parent–child stress relationship.

 Conclusions: Parent stress is closely correlated with child stress during ICU hospitalization. Hispanic ethnicity may be associated with increased risk for child stress, but further studies are required to define the roles of other social and clinical measures.

Effects of the COVID-19 Pandemic on Early Childhood Development and Mental Health: A Systematic Review and Meta-Analysis of Comparative Studies

Alcon, S., Shen, S., Wong, H. N., Rovnaghi, C. R., Truong, L., Vedelli, J. K. H., & Anand, K. J. S. (2024)

Abstract

From 2020 to 2023, the coronavirus-19 (COVID-19) pandemic exposed children to a variety of adverse childhood events, including parental loss, abuse, and disruption in services, and it exacerbated societal inequities. Studies evaluating the mental health of older children and adolescents reported increases in depression and anxiety symptoms, but no reviews have addressed the effects of the pandemic on preschool children. This systematic review and meta-analysis is the first to explore these effects. The goal was to analyze and synthesize longitudinal cohort studies to determine impact of the COVID-19 pandemic on the development and mental health of young children. Searches of multiple databases were performed for studies published between 2018 and 2023 with pre- and post-pandemic evaluations of the mental health or development of preschool children (aged 0–6 years) using objective measures and according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Cohen’s d effect sizes were calculated for each study that utilized the Strengths and Difficulties Questionnaire (SDQ), Ages and Stages Questionnaire (ASQ), or the Child Behavior Checklist (CBCL). Random-effects mixed models combined the estimates of effect sizes to calculate the overall mean effect size. The meta-analyses included 22,348 children from 16 countries. The analyses showed small increases in emotional symptoms and conduct problems, as well as increases in emotional reactivity, anxiety/depression, withdrawal symptoms, attention problems, and aggressive behaviors. A decrease in fine motor and personal–social skills was noted. Studies not included in these meta-analyses also showed negative effects on language and executive function. This systematic review characterizes the detrimental effects of the COVID-19 pandemic on the mental health and development of preschool children across the world. Our results suggest the vulnerability of early childhood to pandemic-related disruptions, although the heterogeneity in study design and child characteristics may limit some of these conclusions.

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.