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.

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.

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.

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.

DNA methylation in children with prenatal methamphetamine exposure and environmental adversity.

BACKGROUND: Methamphetamine (MA) use during pregnancy is a significant public health concern in the United States and affects long-term brain and behavioral development in children. We hypothesized that prenatal MA exposure would be related to greater DNA methylation of HSD11B2 and postnatal environmental stress. METHODS: The Infant Development, Environment, and Lifestyle Study (IDEAL), a longitudinal study of prenatal MA exposure enrolled mother-infant dyads in California, Hawaii, Iowa, and Oklahoma. Prenatal exposure was defined by maternal self-report and/or meconium toxicology screening. At ages 10-11 years, 100 children were assessed for drug exposure and DNA methylation of HSD11B2. Hierarchical linear models were used to determine the association between prenatal MA exposure and methylation of HSD11B2 at four CpG sites. RESULTS: Prenatal MA exposure (1.4% vs 0.31%, P < 0.01) and early childhood adversity (3.0 vs 2.0, P < 0.01) were associated with greater DNA methylation of HSD11B2 at the CpG2 site. The statistically significant effects of early childhood adversity (B = 0.11, P < 0.01) and prenatal MA exposure (B = 0.32, P = 0.03) on DNA methylation remained after adjusting for covariates. CONCLUSIONS: Prenatal MA exposure is related to postnatal childhood adversity and epigenetic alterations in HSD11B2, an important gene along the stress response pathway suggesting prenatal and postnatal programming effects. IMPACT: Prenatal methamphetamine exposure has been associated with developmental issues in newborns, yet little is known about the stress pathophysiology of methamphetamine on neurobehavior. This is the first evidence that prenatal methamphetamine exposure acts as a stressor, confirming the third pathophysiology of methamphetamine exposure.

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.

Home use of a compact, 12­lead ECG recording system for newborns.

BACKGROUND: An easy-to-operate ECG recorder should be useful for newborn screening for heart conditions, by health care workers - or parents. We developed a one-piece electrode strip and a compact, 12­lead ECG recorder for newborns. METHOD: We enrolled 2582 newborns in a trial to assess abilities of parents to record a 12­lead ECG on their infants (2-4 weeks-old). Newborns were randomized to recordings by parents (1290) or our staff (1292 controls). Educational backgrounds of parents varied, including 64% with no more than a high school diploma. RESULTS: For newborns randomized to parent recorded ECGs, 94% of parents completed a 10-minute recording. However, 42.6% asked for verbal help, and 12.7% needed physical help. ECG quality was the same for recordings by parents versus staff. CONCLUSIONS: By use of a one-piece electrode strip and a compact recorder, 87% of parents recorded diagnostic quality ECGs on their newborn infants, with minimal assistance.

Prenatal exposure: The effects of prenatal cocaine and methamphetamine exposure on the developing child.

Prenatal substance use remains a significant issue in the United States. Initial reports regarding prenatal cocaine and methamphetamine exposure suggested profound adverse effects on child development. However, subsequent prospective, longitudinal investigations have found more subtle effects. What follows is a brief review of the health, growth, behavioral, and intellectual outcomes for children exposed to prenatal cocaine and prenatal methamphetamine. Factors that may mitigate or intensify subtle adverse effects manifested in exposed children will also be discussed. Birth Defects Research (Part C) 108:142-146, 2016. © 2016 Wiley Periodicals, Inc.

School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5-Year Follow-Up from the Infant Development, Environment, and Lifestyle Study.

OBJECTIVE: To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years and the extent to which early adversity mediated this relationship. STUDY DESIGN: The multicenter, longitudinal Infant Development, Environment, and Lifestyle study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5-year follow-up, 290 children with complete Child Behavior Checklist data and an early adversity index score were available for analysis (n = 146 exposed). RESULTS: PME was significantly associated with an increased early adversity index score (P < .001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P < .05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant. CONCLUSIONS: Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems.

Effects of prenatal methamphetamine exposure on behavioral and cognitive findings at 7.5 years of age.

OBJECTIVE: To examine child behavioral and cognitive outcomes after prenatal exposure to methamphetamine. STUDY DESIGN: We enrolled 412 mother-infant pairs (204 methamphetamine-exposed and 208 unexposed matched comparisons) in the Infant Development, Environment, and Lifestyle study. The 151 children exposed to methamphetamine and 147 comparisons who attended the 7.5-year visit were included. Exposure was determined by maternal self-report and/or positive meconium toxicology. Maternal interviews assessed behavioral and cognitive outcomes using the Conners' Parent Rating Scale-Revised: Short Form. RESULTS: After adjusting for covariates, children exposed to methamphetamine had significantly higher cognitive problems subscale scores than comparisons and were 2.8 times more likely to have cognitive problems scores that were above average on the Conners' Parent Rating Scale-Revised: Short Form. No association between prenatal methamphetamine exposure and behavioral problems, measured by the oppositional, hyperactivity, and attention-deficit/hyperactivity disorder index subscales, were found. CONCLUSIONS: Prenatal methamphetamine exposure was associated with increased cognitive problems, which may affect academic achievement and lead to increased negative behavioral outcomes.

A tortuous proximal urethra in urorectal septum malformation sequence?

We observed a newborn boy with urorectal septum malformation sequence. Anomalies of the genitalia and rectum were present. He expired on the first day of life, due to severe lung hypoplasia. Autopsy showed a colon that ended in a blind sac, an enlarged bladder with no grossly visible urethra, and dysplastic kidneys. A cone-shaped tissue at the usual site of the bladder outlet contained tortuous and slit-like lumina, suggesting an undeveloped proximal urethra. The urethral structure was lined by transitional epithelium with squamous metaplasia. Many small buds-lined with columnar epithelium-branched from the urethral structure. These ductal buds lined with columnar epithelium stained for prostatic acid phosphatase. Basal cells surrounding the ductal buds stained for p63 and high molecular weight cytokeratin-supporting an interpretation that the buds were early prostatic ducts with normal histology. To our knowledge, these are the first histological images of an undeveloped, obstructed urethra associated with the urorectal septum malformation sequence.

Risk of neurobehavioral disinhibition in prenatal methamphetamine-exposed young children with positive hair toxicology results.

BACKGROUND: The objective was to evaluate the effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. METHODS: Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa, and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child's neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared with child hair results. RESULTS: A total of 264 children were evaluated. Significantly more PME children (n = 133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n = 131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared with PME children without postnatal exposure. CONCLUSIONS: Child hair testing offered a noninvasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.

Cross-national comparison of prenatal methamphetamine exposure on infant and early child physical growth: a natural experiment.

The current study seeks to compare the effects of prenatal methamphetamine exposure (PME) on infant and child physical growth between the USA and New Zealand (NZ). This cross-national comparison provides a unique opportunity to examine the potential impact of services provided to drug using mothers on child health. The longitudinal Infant Development, Environment and Lifestyle study of PME from birth to 36 months was conducted in the USA and NZ. The US cohort included 204 children with PME and 212 non-PME matched comparisons (NPME); the NZ cohort included 108 children with PME and 115 NPME matched comparisons. Latent growth curve models were used to examine effects of PME, country of origin, and the country × PME interaction on growth in length/height and weight. In regard to length/height, PME and country of origin were associated with initial length and growth over time. There was also a significant interaction effect, such that children with PME in the USA were shorter at birth than children with PME in NZ after controlling for other prenatal exposures, infant set, socioeconomic status, and maternal height. In regard to weight, there was only an effect of country of origin. Effects of PME on infant and child growth were shown to differ across countries, with exposed children in NZ faring better than exposed children in the USA. Implications for prevention programs and public policy are discussed.

Prenatal methamphetamine exposure and neonatal and infant neurobehavioral outcome: results from the IDEAL study.

BACKGROUND: Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown. METHODS: The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. Of the subjects, 17,961 were eligible and 3705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or gas chromatography/mass spectroscopy (GC/MS) confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco, and marijuana use, but excluded use of opiates, lysergic acid diethylamide, or phencyclidine. The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at 1 month to 380 enrollees (185 exposed, 195 comparison). Analysis of variance (ANOVA) tested exposure effects on NNNS summary scores at birth and 1 month. General linear model (GLM) repeated-measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates. RESULTS: By 1 month of age, both groups demonstrated higher quality of movement (P = .029), less lethargy (P = .001), and fewer asymmetric reflexes (P = .012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants (P = .031) and total stress was decreased in exposed infants, with no change in comparison infants (P = .026). CONCLUSIONS: Improvement in total stress and arousal were observed in MA-exposed newborns by 1 month of age relative to the newborn period.

Two-Year Autism Risk Screening and 3-Year Developmental Outcomes in Very Preterm Infants.

Importance: Use of the Modified Checklist for Autism in Toddlers, Revised With Follow-Up, a 2-stage parent-report autism risk screening tool, has been questioned due to reports of poor sensitivity and specificity. How this measure captures developmental delays for very preterm infants may provide support for continued use in pediatric care settings. Objective: To determine whether autism risk screening with the 2-stage parent-report autism risk screening tool at age 2 years is associated with behavioral and developmental outcomes at age 3 in very preterm infants. Design, Setting, and Participants: Neonatal Neurobehavior and Outcomes for Very Preterm Infants was a longitudinal, multisite cohort study. Enrollment occurred April 2014 to June 2016, and analyses were conducted from November 2022 to May 2023. Data were collected across 9 university-affiliated neonatal intensive care units (NICUs). Inclusion criteria were infants born less than 30 weeks' gestational age, a parent who could read and speak English and/or Spanish, and residence within 3 hours of the NICU and follow-up clinic. Exposures: Prematurity and use of the 2-stage parent-report autism risk screening tool at age 2 years. Main Outcomes and Measures: Outcomes include cognitive, language, motor composites on Bayley Scales for Infant and Toddler Development, third edition (Bayley-III) and internalizing, externalizing, total problems, and pervasive developmental disorder (PDD) subscale on the Child Behavior Checklist (CBCL) at age 3 years. Generalized estimating equations tested associations between the 2-stage parent-report autism risk screening tool and outcomes, adjusting for covariates. Results: A total of 467 children (mean [SD] gestational age, 27.1 [1.8] weeks; 243 male [52%]) were screened with the 2-stage parent-report autism risk screening tool at age 2 years, and outcome data at age 3 years were included in analyses. Mean (SD) maternal age at birth was 29 (6) years. A total of 51 children (10.9%) screened positive on the 2-stage parent-report autism risk screening tool at age 2 years. Children with positive screening results were more likely to have Bayley-III composites of 84 or less on cognitive (adjusted odds ratio [aOR], 4.03; 95% CI, 1.65-9.81), language (aOR, 5.38; 95% CI, 2.43-11.93), and motor (aOR, 4.74; 95% CI, 2.19-10.25) composites and more likely to have CBCL scores of 64 or higher on internalizing (aOR, 4.83; 95% CI, 1.88-12.44), externalizing (aOR, 2.69; 95% CI, 1.09-6.61), and PDD (aOR, 3.77; 95% CI, 1.72-8.28) scales. Conclusions and Relevance: Results suggest that the 2-stage parent-report autism risk screening tool administered at age 2 years was a meaningful screen for developmental delays in very preterm infants, with serious delays detected at age 3 years.