Neurodevelopmental and behavioral outcomes of very preterm infants: latent profile analysis in the Environmental influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Very preterm infants are at high risk for neurodevelopmental impairments. We used a child-centered approach (latent profile analysis [LPA]) to describe 2-year neurobehavioral profiles for very preterm infants based on cognitive, motor, and behavioral outcomes. We hypothesized that distinct outcome profiles would differ in the severity and co-occurrence of neurodevelopmental and behavioral impairment. METHODS: We studied children born <33 weeks' gestation from the Environmental influences on Child Health Outcomes Program with at least one neurobehavioral assessment at age 2 (Bayley Scales of Infant and Toddler Development, Child Behavior Checklist, Modified Checklist for Autism in Toddlers, cerebral palsy diagnosis). We applied LPA to identify subgroups of children with different patterns of outcomes. RESULTS: In 2036 children (52% male; 48% female), we found four distinct neurobehavioral profiles. Most children (~85%) were categorized into one of two profiles characterized by no/mild neurodevelopmental delay and a low prevalence of behavioral problems. Fewer children (~15%) fell into one of two profiles characterized by severe neurodevelopmental impairments. One profile consisted of children (5%) with co-occurring neurodevelopmental impairment and behavioral problems. CONCLUSION: Child-centered approaches provide a comprehensive, parsimonious description of neurodevelopment following preterm birth and can be useful for clinical and research purposes. IMPACT: Most research on outcomes for children born very preterm have reported rates of impairment in single domains. Child-centered approaches describe profiles of children with unique combinations of cognitive, motor, and behavioral strengths and weaknesses. We capitalized on data from the nationwide Environmental influences on Child Health Outcomes Program to examine these profiles in a large sample of children born <33 weeks gestational age. We found four distinct neurobehavioral profiles consisting of different combinations of cognitive, motor, and behavioral characteristics. This information could aid in the development of clinical interventions that target different profiles of children with unique developmental needs.

Developmental characteristics and accuracy of autism screening among two-year-old toddlers in the ECHO program.

BACKGROUND: The Modified Checklist for Autism in Toddlers (M-CHAT) is a common pediatric screening tool with mixed accuracy findings. Prior evidence supports M-CHAT screening for developmental concerns, especially in toddlers born preterm. This study examined M-CHAT accuracy in a large, nationwide sample. METHODS: 3393 participants from the Environmental influences on Child Health Outcomes (ECHO) program were included. Harmonized M-CHAT (M-CHAT-H) results were compared with parent-reported autism diagnosis and autism-related characteristics to assess accuracy for term and preterm children, together and separately. Generalized estimating equations, clustering for ECHO cohort and controlling for demographic covariates, were used to examine associations between developmental and behavioral characteristics with M-CHAT-H accuracy. RESULTS: Sensitivity of the M-CHAT-H ranged from 36 to 60%; specificity ranged from 88 to 99%. Positive M-CHAT-H was associated with more developmental delays and behavior problems. Children with severe motor delays and more autism-related problems were more likely to have a false-negative M-CHAT-H. Children with fewer behavior problems and fewer autism-related concerns were more likely to have a false-positive screen. CONCLUSION: The M-CHAT-H accurately detects children at low risk for autism and children at increased risk with moderate accuracy. These findings support use of the M-CHAT-H in assessing autism risk and developmental and behavioral concerns in children. IMPACT: Previous literature regarding accuracy of the Modified Checklist for Autism in Toddlers (M-CHAT) is mixed but this study provides evidence that the M-CHAT performs well in detecting children at low risk for autism and consistently detects children with developmental delays and behavioral problems. The M-CHAT moderately detects children at increased risk for autism and remains a useful screening tool. This study examines M-CHAT accuracy in a large-scale, nationwide sample, examining associations between screening accuracy and developmental outcomes. These findings impact pediatric screening for autism, supporting continued use of the M-CHAT while further elucidating the factors associated with inaccurate screens.

Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes. METHODS: DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews. RESULTS: The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes. CONCLUSIONS: These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific. IMPACT: This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.

Neurobehavioral and Medical Correlates of Autism Screening: 2-Year Outcomes for Infants Born Very Preterm.

OBJECTIVE: To identify neonatal characteristics and 2-year neurodevelopmental outcomes associated with positive screening for risk of autism. STUDY DESIGN: Nine university-affiliated neonatal intensive care units (NICUs) enrolled infants born at <30 weeks of gestation. Infants underwent the NICU Network Neurobehavioral Scale examination before discharge and the Bayley Scales of Infant and Toddler Development, Third Edition, the Child Behavior Checklist, and the Modified Checklist for Autism in Toddlers, revised with follow-up (M-CHAT-R/F) at 2 years of corrected age. Generalized estimating equations examined associations between M-CHAT-R/F, neurobehavioral test results, and neonatal medical morbidities. RESULTS: At 2 years of corrected age, data were available for 466 of 744 enrolled infants without cerebral palsy. Infants with hypoaroused NICU Network Neurobehavioral Scale profiles were more likely to screen M-CHAT-R/F-positive (OR 2.76, 95% CI 1.38-5.54). Infants with ≥2 medical morbidities also were more likely to screen positive (OR 2.65, 95% CI 1.27-5.54). Children with positive M-CHAT-R/F scores had lower Bayley Scales of Infant and Toddler Development, Third Edition, Cognitive (t [451] = 5.43, P < .001, d = 0.82), Language (t [53.49] = 7.82, P < .001, d = 1.18), and Motor (t [451] = 7.98, P < .001, d = 1.21) composite scores and significantly greater Child Behavior Checklist Internalizing (t [457] -6.19, P < .001, d = -0.93) and Externalizing (t [57.87] = -5.62, P < .001, d = -0.84) scores. CONCLUSIONS: Positive M-CHAT-R/F screens at 2 years of corrected age were associated with neonatal medical morbidities and neurobehavioral examinations as well as toddler developmental and behavioral outcomes. These findings demonstrate the potential utility of the M-CHAT-R/F as a global developmental screener in infants born very preterm, regardless of whether there is a later autism diagnosis.

Maternal Prenatal Risk Phenotypes and Neurobehavioral Outcomes among Infants Born Very Preterm.

OBJECTIVE: To assess whether prenatal risk phenotypes are associated with neurobehavioral impairment for children born <30 weeks of gestation at discharge from the neonatal intensive care unit (NICU) and at 24-month follow-up. STUDY DESIGN: We studied infants from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) study, a multisite investigation of infants born <30 weeks of gestation. There were 704 newborns enrolled in the NOVI study; of these, 679 (96%) had neonatal neurobehavioral data and 556 (79%) had 24-month follow-up data. Maternal prenatal phenotypes (physical and psychological risk groups) were characterized from 24 physical and psychological health risk factors. Neurobehavior was assessed at NICU discharge using the NICU Network Neurobehavioral Scales and at 2-year follow-up using the Bayley Scales of Infant and Toddler Development and the Child Behavior Checklist. RESULTS: Children born to mothers in the psychological risk group were at increased risk for dysregulated neonatal neurobehavior (OR, 2.04; 95% CI, 1.08-3.87) at NICU discharge, and for severe motor delay (OR, 3.80; 95% CI, 1.48-9.75), and clinically significant externalizing problems (OR, 2.54; 95% CI, 1.15-5.56) at age 24 months, compared with children born to mothers in the low-risk group. Children born to mothers in the physical risk group were more likely to have severe motor delay (OR, 2.70; 95% CI, 1.07-6.85) compared with the low-risk group. CONCLUSIONS: High-risk maternal prenatal phenotypes were associated with neurobehavioral impairment for children born very preterm. This information could identify newborns at risk for adverse neurodevelopmental outcomes.

Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program.

BACKGROUND: Single-cohort studies have identified distinct neurobehavioral profiles that are associated with prenatal and neonatal factors based on the NICU Network Neurobehavioral Scale (NNNS). We examined socioeconomic, medical, and substance use variables as predictors of NNNS profiles in a multi-cohort study of preterm and term-born infants with different perinatal exposures. METHODS: We studied 1112 infants with a neonatal NNNS exam from the Environmental influences on Child Health Outcomes (ECHO) consortium. We used latent profile analysis to characterize infant neurobehavioral profiles and generalized estimating equations to determine predictors of NNNS profiles. RESULTS: Six distinct neonatal neurobehavioral profiles were identified, including two dysregulated profiles: a hypo-aroused profile (16%) characterized by lethargy, hypotonicity, and nonoptimal reflexes; and a hyper-aroused profile (6%) characterized by high arousal, excitability, and stress, with low regulation and poor movement quality. Infants in the hypo-aroused profile were more likely to be male, have younger mothers, and have mothers who were depressed prenatally. Infants in the hyper-aroused profile were more likely to be Hispanic/Latino and have mothers who were depressed or used tobacco prenatally. CONCLUSIONS: We identified two dysregulated neurobehavioral profiles with distinct perinatal antecedents. Further understanding of their etiology could inform targeted interventions to promote positive developmental outcomes. IMPACT: Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings. In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated. Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents. Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.

Risk Factors for Postpartum Depression and Severe Distress among Mothers of Very Preterm Infants at NICU Discharge.

OBJECTIVE: To identify psychological, medical, and socioenvironmental risk factors for maternal postpartum depression (PPD) and severe psychological distress (SPD) at intensive care nursery discharge among mothers of very preterm infants. STUDY DESIGN: We studied 562 self-identified mothers of 641 infants born <30 weeks who were enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study (NOVI) conducted in nine university-affiliated intensive care nurseries. Enrollment interviews collected socioenvironmental data, depression, and anxiety diagnoses prior to and during the study pregnancy. Standardized medical record reviews ascertained prenatal substance use, maternal and neonatal medical complications. The Edinburgh Postnatal Depression Scale and Brief Symptom Inventory were administered at nursery discharge to screen for PPD and SPD symptoms, respectively. RESULTS: Unadjusted analyses indicated mothers with positive screens for depression (n = 76, 13.5%) or severe distress (n = 102, 18.1%) had more prevalent prepregnancy/prenatal depression/anxiety, and their infants were born at younger gestational ages, with more prevalent bronchopulmonary dysplasia, and discharge after 40 weeks postmenstrual age. In multivariable analyses, prior depression or anxiety was associated with positive screens for PPD (risk ratio [RR]: 1.6, 95% confidence interval [CI]: 1.1-2.2) and severe distress (RR: 1.6, 95% CI: 1.1-2.2). Mothers of male infants had more prevalent depression risk (RR: 1.7, 95% CI: 1.1-2.4), and prenatal marijuana use was associated with severe distress risk (RR: 1.9, 95% CI: 1.1-2.9). Socioenvironmental and obstetric adversities were not significant after accounting for prior depression/anxiety, marijuana use, and infant medical complications. CONCLUSION: Among mothers of very preterm newborns, these multicenter findings extend others' previous work by identifying additional indicators of risk for PPD and SPD associated with a history of depression, anxiety, prenatal marijuana use, and severe neonatal illness. Findings could inform designs for continuous screening and targeted interventions for PPD and distress risk indicators from the preconception period onward. KEY POINTS: · Preconceptional and prenatal screening for postpartum depression and severe distress may inform care.. · Prior depression, anxiety, and neonatal complications predicted severe distress and depression symptoms at NICU discharge.. · Readily identifiable risk factors warrant continuous NICU screening and targeted interventions to improve outcomes..

Neurodevelopmental profiles of infants born <30 weeks gestation at 2 years of age.

BACKGROUND: Infants born <30 weeks postmenstrual age (PMA) are at increased risk for neurodevelopmental impairment by age 2. Prior studies report rates of impairment for individual outcomes separately. Our objective was to describe neurodevelopmental profiles of children born <30 weeks PMA, using cognitive, language, motor, and behavioral characteristics. METHODS: We studied 587 children from a multi-center study of infants born <30 weeks PMA. Age 2 outcomes included Bayley-III subscale scores, Child Behavior Checklist syndrome scores, diagnosis of cerebral palsy (CP), and positive screen for autism spectrum disorder (ASD) risk. We used latent profile analysis (LPA) to group children into mutually exclusive profiles. RESULTS: We found four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes. Two of the profiles included 72.7% of the sample with most having Bayley scores within the normal range. The other two profiles included the remaining 27.3% of the sample with most having Bayley scores outside of the normal range. Only one profile (11% of sample) was comprised of children with elevated behavioral problems. CONCLUSION: Child-centered analysis techniques could facilitate the development of targeted intervention strategies and provide caregivers and practitioners with an integrative understanding of child behavior. IMPACT: Most studies examining neurodevelopmental outcomes in very preterm children report rates of impairment for individual outcomes separately. Comprehensive, "child-centered" approaches that integrate across multiple domains can be used to identify subgroups of children who experience different types of neurodevelopmental impairments. We identified four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes in very preterm children at 24 months. "Child-centered" analysis techniques may provide clinically useful information and could facilitate the development of targeted intervention strategies for high-risk children.

Virtue and care ethics & humanism in medical education: a scoping review.

PURPOSE: This scoping review explores how virtue and care ethics are incorporated into health professions education and how these factors may relate to the development of humanistic patient care. METHOD: Our team identified citations in the literature emphasizing virtue ethics and care ethics (in PubMed, NLM Catalog, WorldCat, EthicsShare, EthxWeb, Globethics.net , Philosopher's Index, and ProQuest Central) lending themselves to constructs of humanism curricula. Our exclusion criteria consisted of non-English articles, those not addressing virtue and care ethics and humanism in medical pedagogy, and those not addressing aspects of character in health ethics. We examined in a stepwise fashion whether citations: 1) Contained definitions of virtue and care ethics; 2) Implemented virtue and care ethics in health care curricula; and 3) Evidenced patient-directed caregiver humanism. RESULTS: Eight hundred eleven citations were identified, 88 intensively reviewed, and the final 25 analyzed in-depth. We identified multiple key themes with relevant metaphors associated with virtue/care ethics, curricula, and humanism education. CONCLUSIONS: This research sought to better understand how virtue and care ethics can potentially promote humanism and identified themes that facilitate and impede this mission.

Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants.

BACKGROUND: Preterm birth places infants at higher risk of adverse long-term behavioral and cognitive outcomes. Combining biobehavioral measures and molecular biomarkers may improve tools to predict the risk of long-term developmental delays. METHODS: The Neonatal Neurobehavior and Outcomes in Very Preterm Infants study was conducted at nine neonatal intensive care units between April 2014 and June 2016. Cries were recorded and buccal swabs collected during the neurobehavioral exam. Cry episodes were extracted and analyzed using a computer system and the data were summarized using factor analysis. Genomic DNA was extracted from buccal swabs, quantified using the Qubit Fluorometer, and aliquoted into standardized concentrations. DNA methylation was measured with the Illumina MethylationEPIC BeadArray, and an epigenome-wide association study was performed using cry factors (n = 335). RESULTS: Eighteen CpGs were associated with the cry factors at genome-wide significance (α = 7.08E - 09). Two CpG sites, one intergenic and one linked to gene TCF3 (important for B and T lymphocyte development), were associated with acoustic measures of cry energy. Increased methylation of TCF3 was associated with a lower energy-related cry factor. We also found that pitch (F0) and hyperpitch (F0 > 1 kHz) were associated with DNA methylation variability at 16 CpG sites. CONCLUSIONS: Acoustic cry characteristics are related to variation in DNA methylation in preterm infants. IMPACT: Preterm birth is a major public health problem and its long-term impact on health is not well understood. Cry acoustics, related to prematurity, has been linked to a variety of medical conditions. Biobehavioral measures and molecular biomarkers can improve prediction tools for long-term developmental risks of preterm birth. Variation in epigenetic modulation in preterm infants provides a potential link between preterm birth and unfavorable developmental outcomes.

Psychosocial and medical adversity associated with neonatal neurobehavior in infants born before 30 weeks gestation.

BACKGROUND: Psychosocial adversity escalates medical risk for poor outcomes in infants born <30 weeks gestation. Neonatal neurobehavior and maternal psychological and socioenvironmental assessments may identify the earliest specific intervention needs. We hypothesized that maternal prenatal anxiety, depression, and adverse medical and socioenvironmental conditions would be associated with less optimal neonatal neurobehavior at neonatal intensive care unit (NICU) discharge. METHODS: We studied 665 infants at 9 university NICUs. Risk indices of socioenvironmental, maternal, and neonatal medical factors were obtained from standardized, structured maternal interviews and medical record reviews. Brain injuries were classified by consensus ultrasonogram readings. NICU Network Neurobehavioral Scale (NNNS) exams were conducted at NICU discharge. RESULTS: On the NNNS, generalized estimating equations indicated infants of mothers with prenatal anxiety had less optimal attention, and those born to mothers with prenatal depression had increased lethargy. Maternal medical complications predicted suboptimal reflexes. Socioenvironmental risk predicted lower self-regulation and movement quality. Infants with more severe neonatal medical complications had lower attention, increased lethargy, and suboptimal reflexes. CONCLUSIONS: Combined information from the observed associations among adverse prenatal maternal medical and psychosocial conditions, and neonatal complications may assist in the early identification of infants at elevated neurobehavioral risk.

The Natal Journey and Perinatal Palliative Care.

Doctors often focus on the science of medicine involved in matters of reproductive health and childbirth, at times to the exclusion of the psychosocial and spiritual dimensions of health. Pregnancy and childbirth are clothed in mystery when it comes to the question of why a pregnancy goes well or is fraught with complications. And while explanations may abound in this age of increasing genetic understanding, the meaning attached to these matters is beyond the scope of medicine alone-especially when the newborn's very survival is in question. Perinatal palliative care can bring solace to such troubling realities.

Anticipation, Accompaniment, and a Good Death in Perinatal Care.

The ethics of perinatal care, and the experiences of families who receive such care, remains a nascent area of inquiry. It can be hard to see how existing "good death" constructs apply to the experiences of fetal patients and their families. In this paper, we explore two themes raised by a case at our fetal health center: anticipation and accompaniment. In this case, a mother presented to our fetal health center; her unborn son, our fetal patient, was diagnosed with life-threatening hypoplastic left heart syndrome and endocardial fibroelastosis. The parents were told that their son's life expectancy, upon birth, was short. For us, this case raised important questions around what sorts of things we might, together with the family, anticipate with respect to their son's birth and death, and what it meant to really accompany this family on their journey. Alongside conventional lessons in the philosophical literature and palliative care practice, the process of anticipating together and of mutual accompaniment helped us to guide this family to what they ultimately determined to be a good death for their son.

Quality predictors of parental satisfaction after birth of infants with life-limiting conditions.

AIM: This study examines parental satisfaction with care received in the context of a life-limiting foetal diagnosis and subsequent birth. METHODS: Survey methods were utilised to embed the Quality Indicators (QI) and Parental Satisfaction of Perinatal Palliative Care Instrument in a survey: 'The Voice of Parents'. RESULTS: The web-based survey had a final sample of N = 405 parent responders. Overall, parents reported satisfaction with care (80.2%; n = 393). Parents satisfied with care reported higher agreement with quality indicator items for all subscales. In total, 17 items from the 41-item instrument revealed the ability to predict higher parental satisfaction when particular QI are reported. CONCLUSION: This study has led to credible insights into parental satisfaction with care given after the birth of an infant with a life-limiting condition. The findings contribute to development of a model with a good fit in ascertaining the importance of compassion, unhurried provider-patient communication and bereavement interventions.

Ethical issues in pediatric face transplantation.

Facial transplantation has become a reality in adult medicine. Children are subject to congenital craniofacial differences, disease-related, traumatic, or thermochemical craniofacial changes and might be suitable for face transplantation. This manuscript addresses unique ethical issues in considering potential pediatric face transplant. These challenges are operant at the individual, technologic, and psychosocial level for clinicians, investigators, and society.