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Cranial ultrasound (CUS) findings are routinely used to identify preterm infants at risk for impaired neurodevelopment, and neurobehavioral examinations provide information about early brain function. The associations of abnormal findings on early and late CUS with neurobehavior at neonatal intensive care unit (NICU) discharge have not been reported.To examine the associations between early and late CUS findings and infant neurobehavior at NICU discharge.This prospective cohort study included infants enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study between April 2014 and June 2016. Infants born before 30 weeks' gestational age were included. Exclusion criteria were maternal age younger than 18 years, maternal cognitive impairment, maternal inability to read or speak English or Spanish, maternal death, and major congenital anomalies. Overall, 704 infants were enrolled. The study was conducted at 9 university-affiliated NICUs in Providence, Rhode Island; Grand Rapids, Michigan; Kansas City, Missouri; Honolulu, Hawaii; Winston-Salem, North Carolina; and Torrance and Long Beach, California. Data were analyzed from September 2019 to September 2021.Early CUS was performed at 3 to 14 days after birth and late CUS at 36 weeks' postmenstrual age or NICU discharge. Abnormal findings were identified by consensus of standardized radiologists' readings.Neurobehavioral examination was performed using the NICU Network Neurobehavioral Scale (NNNS).Among the 704 infants enrolled, 675 had both CUS and NNNS data (135 [20.0%] Black; 368 [54.5%] minority race or ethnicity; 339 [50.2%] White; 376 [55.7%] male; mean [SD] postmenstrual age, 27.0 [1.9] weeks). After covariate adjustment, lower attention (adjusted mean difference, -0.346; 95% CI, -0.609 to -0.083), hypotonicity (mean difference, 0.358; 95% CI, 0.055 to 0.662), and poorer quality of movement (mean difference, -0.344; 95% CI, -0.572 to -0.116) were observed in infants with white matter damage (WMD). Lower attention (mean difference, -0.233; 95% CI, -0.423 to -0.044) and hypotonicity (mean difference, 0.240; 95% CI, 0.014 to 0.465) were observed in infants with early CUS lesions.In this cohort study of preterm infants, certain early CUS lesions were associated with hypotonicity and lower attention around term-equivalent age. WMD was associated with poor attention, hypotonicity, and poor quality of movement. Infants with these CUS lesions might benefit from targeted interventions to improve neurobehavioral outcomes during their NICU hospitalization.

Background: As an essential micronutrient, selenium plays a vital role in fetal development. MicroRNA expression modification is a potential mechanism linking dietary exposures and fetal neurobehav...

Background Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities. Methods This study included 532 infants born Results We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose–response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing. Conclusions Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.

BACKGROUND AND OBJECTIVES: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS. METHODS: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks’ gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions. RESULTS: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%–100%), medication-assisted treatment (5.9%–100%), and prenatal counseling (1.9%–75.5%). Sites varied in the proportion of infants with toxicology screening (50%–100%) and proportion of infants receiving pharmacologic therapy (6.7%–100%), secondary medications (1.1%–69.2%), and nonpharmacologic interventions including fortified feeds (2.9%–90%) and maternal breast milk (22.2%–83.3%). The mean length of stay varied across sites (2–28.8 days), as did the proportion of infants discharged with their parents (33.3%–91.1%). CONCLUSIONS: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development.

BACKGROUND AND OBJECTIVES: The effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine. METHODS: Subjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance. At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory. RESULTS: Analyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior. By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age. Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores. CONCLUSIONS: Behavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.

To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial.Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL).Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P .01) and continued maternal substance use (P .01).Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment.ClinicalTrials.gov: NCT01958476.

This study investigates parental perceptions of cries of 1-month-old infants later diagnosed with autism spectrum disorder (ASD) and non-ASD controls. Parents of children with and without ASD listened to cry recordings of infants later diagnosed with ASD and comparison infants and rated them on cry perception scales. Parents completed the Broad Autism Phenotype Questionnaire (BAPQ) to assess the potential relations between traits associated with autism and cry perception. Across parents, ASD infant cries were rated as more distressed, less typical, and reflecting greater pain, with no significant differences between parent groups. Parents of children with ASD scored higher on the BAPQ compared to parents of children without ASD. Follow up analyses explored the relations between BAPQ score and cry ratings.

To compare length of hospital stay (LOS), LOS due to neonatal abstinence syndrome (NAS), and duration of pharmacologic treatment in community or academic settings. One hundred-two infants exposed to opioids in utero at two community hospitals were compared to 256 from eight academic centers. All infants were managed with non-pharmacologic care followed by similar pharmacologic treatment options. Two hundred-twelve infants received pharmacologic treatment for NAS. Mean LOS (24.7 ± 8.5 vs. 24.5 ± 11.3 days), LOS due to NAS (24.0 ± 8.2 vs. 23.3 ± 9.2 days), and duration of NAS treatment (19.3 ± 8.0 vs. 18.9 ± 9.2 days) were similar in community compared to academic medical centers. No significant differences were found in infants managed in the community compared to academic care settings. These findings support caring for opioid-exposed infants in both community and academic settings with the use of standardized care protocols.

Prenatal programming models have rarely been applied to research on children with prenatal substance exposure, despite evidence suggesting that prenatal drug exposure is a form of stress that impacts neurodevelopmental outcomes and risk for psychopathology. Utilizing data from two longitudinal multisite studies comprising children prenatally exposed to substances as well as a nonexposed comparison group (Maternal Lifestyle Study, n = 1,388; Infant Development, Environment, and Lifestyle study, n = 412), we tested whether early phenotypic indicators of hypothesized programming effects, indexed by growth parameters at birth and infant temperament, served as a link between prenatal substance exposure and internalizing and externalizing behavior at age 5. Latent profile analysis indicated that individual differences in reactivity and regulation for infants prenatally exposed to substances was best characterized by four temperament profiles. These profiles were virtually identical across two independent samples, and demonstrated unique associations with adjustment difficulties nearly 5 years later. Results of path analysis using structural equation modeling also showed that increased prenatal substance exposure was linked to poorer growth parameters at birth, profiles of temperamental reactivity in infancy, and internalizing and externalizing behavior at age 5. This pathway was partially replicated across samples. This study was among the first to link known individual-level correlates of prenatal substance exposure into a specific pathway to childhood problem behavior. Implications for the developmental origins of a child's susceptibility to psychopathology as a result of intrauterine substance exposure are discussed.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.

Caregivers play a critical role in scaffolding infant stress reactivity and regulation, but the mechanisms by which this scaffolding occurs is unclear. Animal models strongly suggest that epigenetic processes, such as DNA methylation, are sensitive to caregiving behaviors and, in turn, offspring stress reactivity. We examined the direct effects of caregiving behaviors on DNA methylation in infants and infant stress reactivity. Infants and mothers (N = 128) were assessed during a free play when infants were 5 months old. Maternal responsiveness and appropriate touch were coded. and infant buccal epithelial cells were sampled to assess for DNA methylation of the glucocorticoid receptor gene, NR3c1 exon 1F. Infant cortisol reactivity was assessed in response to the still-face paradigm. Greater levels of maternal responsiveness and appropriate touch were related to less DNA methylation of specific regions in NR3c1 exon 1F, but only for females. There was no association with maternal responsiveness and appropriate touch or DNA methylation of NR3c1 exon 1F on prestress cortisol or cortisol reactivity. Our results are discussed in relation to programming models that implicate maternal care as an important factor in programing infant stress reactivity.Los cuidadores juegan un papel esencial en el andamiaje de la reactividad y regulación del estrés infantil pero los mecanismos por medio de los cuales aparece este andamiaje no están claros. Los modelos animales fuertemente sugieren que los procesos epigenéticos, tales como la metilación del ADN, son sensibles a los comportamientos de prestaciones de cuidado y por consiguiente a la reactividad al estrés por parte de los hijos. Examinamos los efectos directos que los comportamientos de prestaciones de cuidado tienen sobre la metilación de ADN en infantes y, por consiguiente, la reactividad del estrés infantil. Los infantes y sus madres (N = 128) fueron evaluados durante una sesión de juego libre cuando los infantes tenían 5 meses de edad. Se codificó la sensibilidad materna y la apropiada forma de tocar y se obtuvo muestra de las células epiteliales bucales del infante para analizar la metilación de ADN del gen receptor glucocorticoide, NR3c1, exón 1F. Se evaluó la reactividad del infante al cortisol como respuesta al paradigma de la cara quieta. Niveles mayores de sensibilidad materna y apropiada forma de tocar se relacionaron con menos metilación de ADN de regiones específicas en NR3c1 exón 1F, aunque sólo en las niñas. No se presentó ninguna asociación con la sensibilidad materna y la apropiada forma de tocar, o metilación de ADN de NR3c1 exón 1F en el cortisol pre-estrés o la reactividad del cortisol. Nuestros resultados se discuten en relación con modelos de programación que implican cuidado materno como un importante factor en la programación de la reactividad del estrés del infante.Les personnes prenant soin des enfants jouent un rôle critique dans l’échafaudage de la réaction au stress du nourrisson et la régulation mais les mécanismes selon lesquels cet échafaudage se bâtit ne sont pas clairs. Les modèles animaux suggèrent fortement que des processus épigénétiques, comme la méthylation de l'ADN, sont sensibles au comportements de qui prend soin d'eux et en conséquence déclenchent un réaction au stress. Nous avons examiné les effets directs des comportements soignants sur la méthylation de l'ADN chez les bébés, en ensuite sur la réaction au stress du nourrisson. Des nourrissons et leurs mères (N = 128) ont été évalués au moyen d'un jeu libre quand les bébés avaient 5 mois d’âge. La réaction maternelle et le toucher approprié ont été codés et des cellules épithéliales buccales du bébé ont été prélevées afin d’évaluer la méthylation de l'ADN du gène récepteur glucocorticoïde, le NR3c1 exon 1F. La réaction du cortisol du bébé a été évaluée en réponse au paradigme du visage immuable. Des niveaux plus élevés de réaction maternelle et de toucher approprié étaient liés à une méthylation de l'ADN des régions spécifiques de NR3c1 exon 1F moindre, mais seulement chez les filles. On n'a trouvé aucun lien avec la réaction maternelle et le toucher approprié ou de méthylation NR3c1 exon 1F de l'ADN sur le cortisol pré-test ou de réaction du cortisol. Nos résultats sont discutés en relation aux modèles de programme qui impliquent que le soin maternel en tant que facteur important dans la programmation de la réaction au stress du bébé.Die Bezugspersonen spielen eine entscheidende Rolle für die Herausbildung der Reaktionsfähigkeit und Regulierung von Säuglingen, aber die Mechanismen, wie diese entstehen, sind unklar. Tiermodelle deuten stark darauf hin, dass epigenetische Prozesse, wie z.B. die DNA-Methylierung, sensitiv auf das Verhalten der Bezugspersonen reagieren und wiederum die Reaktivität der Nachkommen beeinflussen. Wir untersuchten die direkten Auswirkungen des Verhaltens der Bezugspersonen auf die DNA-Methylierung bei Säuglingen und damit wiederum auf die Stressreaktivität von Säuglingen. Säuglinge und Mütter (N = 128) wurden während eines freien Spiels im Alter von 5 Monaten beurteilt. Die mütterliche Responsivität und die entsprechende Berührung wurden kodiert und bukkale Epithelzellen von Säuglingen wurden untersucht, um die DNA-Methylierung des Glukokortikoid-Rezeptorgens NR3c1-Exon 1F zu beurteilen. Die Reaktivität des Säuglings auf Cortisol wurde als Antwort auf das Still-Face-Paradigma bewertet. Ein höheres Ausmaß an mütterlicher Responsivität und passenden Berührungen waren mit einer geringeren DNA-Methylierung bestimmter Regionen im NR3c1-Exon 1F verbunden, jedoch nur für das weibliche Geschlecht. Es gab keinen Zusammenhang für die mütterliche Responsivität und passende Berührungen oder DNA-Methylierung des NR3c1-Exons 1F mit der Reaktivität von Cortisol oder dem Cortisol vor der Belastung. Unsere Ergebnisse werden in Bezug auf Programmiermodelle diskutiert, die die mütterliche Fürsorge als einen wichtigen Faktor bei der Programmierung der Stressreaktivität von Säuglingen beinhalten.乳幼児期のNR3c1のＤＮＡメチル化:母親の養育と乳幼児の性別の関連 養育者は乳幼児のストレス反応性と調節の土台に大切な役割を果たすが、この土台が生じるメカニズムは明らかでない。動物モデルはＤＮＡメチル化のような、養育行動や、子どものストレス反応性に敏感である後成的なプロセスを強く示唆する。我々は養育行動が乳幼児のＤＮＡメチル化と、乳幼児のストレス反応性に直接与える影響を検討した。乳幼児が 5 ヶ月のとき、乳幼児と母親 （N=128） を自由遊び中に評価した。母親の応答性と適切な接触をコード化し、糖質コルチコイド受容体遺伝子である NR3cI エクソン 1F の DNA メチル化を評価するために乳幼児の頬粘膜細胞を標本抽出した。乳幼児のコルチゾール反応性は still face の反応性パラダイムに応じて評価した。より大きなレベルの母親の反応性と適切な接触は、 NR3cI エクソン 1F の特定領域の DNA メチル化に関連が少なかったが、それは女児だけにあてはまった。母親の反応性と適切な接触もしくは NR3cI エクソン 1F の DNA メチル化と、ストレス前のコルチゾールやコルチゾール反応性との関連は認めなかった。我々の研究結果を母親の養育が、乳幼児のストレス反応性のプログラミングにおける重要な因子であると示唆するプログラミングモデルとの関連から議論する。.嬰兒期NR3c1的DNA甲基化:母親照顧與兒童性別的關係 護理人員在支架嬰兒對壓力反應和調節方面發揮著關鍵作用， 但這種支架發生的機制尚不清楚。動物模型強烈表明， 表觀遺傳過程， 如 DNA 甲基化， 對護理行為和後代壓力反應敏感。我們檢查護理行為對嬰兒 DNA 甲基化的直接影響， 進而檢測嬰兒對壓力反應。當嬰兒 5 個月大時， 在自由遊戲期間評估嬰兒和母親 （N = 128）。對母體反應性和適當的觸覺進行編碼， 並對嬰兒頰上皮細胞進行取樣， 以評估糖皮質激素受體基因 NR3c1 外顯子 1F 的 DNA 甲基化。評估嬰兒皮質醇反應性以響應靜止面觀範例。較高水平的母體反應性和適當的觸覺， 與 NR3c1 外顯子1F中特定區域的較少 DNA 甲基化相關， 但僅限於女嬰。母親反應和適當接觸或 NR3c1 外顯子 1F 的 DNA 甲基化， 與壓力前皮質醇或皮質醇反應性無關。我們討論結果與編程模型的關係， 這些編程模型將孕產婦護理作為影響嬰兒對壓力反應的重要因素。.ميثيل الحمض النووي لNR3c1 في مرحله الرضاعة: الارتباطات بين رعاية الامومة وجنس الرضع مقدمو الرعاية يلعبون دورا حاسما في تدعيم استجابة الرضع للإجهاد والتنظيم ولكن الآليات التي يحدث بها هذا التدعيم غير واضحة. النماذج الحيوانية تشير بقوة إلى ان العمليات الوراثية ، مثل ميثيل الحمض النووي ، حساسة لسلوكيات الرعاية وبدورها تولد الاستجابة التفاعلية للإجهاد العصبي. درسنا الآثار المباشرة لسلوكيات الرعاية علي ميثيل الحمض النووي في الرضع وكذلك الاستجابة التفاعلية للرضع. وتم تقييم الرضع والأمهات (العدد = 128) اثناء اللعب الحر عندما كان عمر الرضع 5 أشهر. وتم ترميز الاستجابة الاموميه واللمس المناسب وعينت الخلايا الظهاريه للرضع لتقييم ميثيل الحمض النووي من الجينات مستقبلات جلوكورتيكويد ، NR3c1 اكسون 1F. وتم تقييم تفاعل الكورتيزول للرضع استجابه لنموذج الوجه الثابت. وكانت المستويات الأكبر من الاستجابة الاموميه واللمس المناسب مرتبطة بمستوى أقل من ميثيل الحمض النووي في مناطق محدده في NR3c1 اكسون 1F ، ولكن فقط للإناث. ولم يكن هناك ارتباط مع استجابه الام واللمس المناسب أو ميثيل الحمض النووي من NR3c1 اكسون 1Fعلي الكورتيزول قبل الإجهاد أو الاستجابة التفاعلية للكورتيزول. وتناقش نتائجنا فيما يتعلق بنماذج البرمجة التي تضع رعاية الامومه كعامل مهم في برمجه استجابة الرضع التفاعلية للإجهاد العصبي.

Background Little is known about how prenatal exposure to substances (alcohol, tobacco, marijuana, and cocaine) may contribute to heterogeneous childhood trajectories of internalizing symptoms (i.e., depression, withdrawal, anxiety). The present study aimed to identify developmental trajectories of internalizing symptoms in children using gender-separate analyses and to examine whether trajectories differ by prenatal substance exposure (PSE) and other environmental and biological correlates. Methods Data from two large community-based birth cohorts with PSE were integrated (N = 1,651, 848 boys, 803 girls): the Cleveland cohort and the Maternal Lifestyle Study (MLS). Internalizing symptoms were assessed with the Child Behavior Checklist at ages 2, 4, 6, 9, 10, 11, and 12 in the Cleveland study and at ages 3, 5, 7, 9, 11, and 13 in the MLS. Results Gender-separate group-based trajectory modeling yielded five distinctive developmental trajectories of internalizing symptoms from ages 2 to 13 in both boys and girls: low-risk group (14.4% girls, 28.8% boys); normative-decreasing group (35.3% girls, 33.1% boys); increasing risk group (14.4% girls, 13.0% boys); early-high group (22.3% girls, 17.9% boys); and chronic group (13.8% girls, 7.2% boys). Prenatal tobacco exposure, maternal psychological distress, and postnatal maternal alcohol use differentiated the longitudinal courses of internalizing symptoms. Boys were more likely to follow the low-risk trajectory, whereas girls were more likely to follow the chronic trajectory. Conclusions Prenatal tobacco exposure was associated with suboptimal developmental trajectories of internalizing symptoms in the context of prenatal poly-drug exposure, highlighting a need for continued and increased effort toward prevention of prenatal tobacco use.

OBJECTIVE: To develop an index to determine which opioid-exposed neonates have the most severe neonatal abstinence syndrome (NAS). STUDY DESIGN: Full-term neonates with NAS (n = 116) from mothers maintained on methadone or buprenorphine were enrolled from 8 sites into a randomized clinical trial of morphine vs methadone. Ninety-nine (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale (NNNS). At 18 months, 83 of 99 (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and 77 of 99 (77.7%) were evaluated with the Child Behavior Checklist (CBCL). RESULTS: Cluster analysis was used to define high (n = 21) and low (n = 77) NAS severity. Compared with infants in the low NAS severity cluster, infants in the high NAS severity cluster had a longer length of stay (P < .001), longer length of stay due to NAS (P < .001), longer duration of treatment due to NAS (P < .001), and higher total dose of the study drug (P < .001) and were more likely to have received phenobarbital (P < .001), to have been treated with morphine (P = .020), and to have an atypical NNNS profile (P = .005). The 2 groups did not differ in terms of maximum Finnegan score. At 18 months, in unadjusted analyses, compared with the high-severity cluster, the low-severity cluster had higher scores on the Bayley-III Cognitive (P = .013), Language (P < .001), and Motor (P = .041) composites and less total behavior problems on the CBCL (P = .028). In adjusted analyses, the difference in the Bayley-III Language composite remained (P = .013). CONCLUSIONS: Presumptive measures of NAS severity can be aggregated to develop an index that predicts developmental outcomes at age 18 months.

This study examined infants' early visual attention (at 1 month of age) and social engagement (4 months) as predictors of their later joint attention (12 and 18 months). The sample (n = 325), drawn from the Maternal Lifestyle Study, a longitudinal multicenter project conducted at 4 centers of the National Institute of Child Health and Human Development Neonatal Research Network, included high-risk (cocaine-exposed) and matched noncocaine-exposed infants. Hierarchical regressions revealed that infants' attention orienting at 1 month significantly predicted more frequent initiating joint attention at 12 (but not 18) months of age. Social engagement at 4 months predicted initiating joint attention at 18 months. Results provide the first empirical evidence for the role of visual attention and social engagement behaviors as developmental precursors for later joint attention outcome. (PsycINFO Database Record

The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure).Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity.Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale.Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.

Maternal smoking during pregnancy (MSDP) remains one of the most common prenatal drug exposures in the US and worldwide. MSDP is associated with medical risk for the fetus and altered behavioral development in infants; however, fewer studies have examined the impact of MSDP on fetal behavior or newborn behavioral state. We investigated associations between MSDP and (a) fetal motor activity and (b) newborn behavioral state following handling. Participants were 79 healthy mother-fetus/newborn pairs (57% MSDP-exposed). MSDP was measured by maternal interview and verified by saliva biomarkers. Mothers completed an observational fetal ultrasound assessment between 24 and 37 weeks gestation (M = 28 weeks), including baseline, vibro-acoustic stimulus and recovery periods. Total fetal motor activity and complex body movements were coded from ultrasound videos. Following delivery, newborn post-handling behavioral state was assessed by direct observational coding. MSDP exposure was associated with higher baseline fetal motor activity, particularly at younger gestational ages. Further, motor reactivity to stimulation emerged at later gestational ages in MSDP-exposed fetuses, while motor reactivity was consistent across gestational ages in unexposed fetuses. Finally, heavy MSDP exposure was associated with more arousal following handling and greater need for soothing interventions in the newborn period. Monitoring of fetal behavior via ultrasound may offer a unique opportunity to identify at-risk infants and provides data for stronger public health messaging regarding risks of MSDP. Associations between MSDP and increased newborn fussiness highlight opportunities for education and anticipatory guidance in the postpartum period.

Key Points Question Can a simplified Finnegan Neonatal Abstinence Scoring Tool (FNAST), composed only of dichotomized items that are independently associated with the decision to initiate pharmacologic therapy, discriminate between infants who did and did not receive therapy as effectively as the original FNAST? Findings In this cohort study of 424 neonates with opioid exposure, the simplified FNAST discriminated between neonates who did and did not receive pharmacologic treatment nearly as well as the original FNAST. Meaning Use of a simplified FNAST may provide an accurate means of identifying neonatal abstinence syndrome and may enhance the clinical utility of the tool., This cohort study identifies items on the Finnegan Neonatal Abstinence Scoring Tool (FNAST) that are independently associated with the decision to use pharmacologic therapy and simplifies the tool while minimizing loss of information for the treatment decision., Importance Observer-rated scales, such as the Finnegan Neonatal Abstinence Scoring Tool (FNAST), are used to quantify the severity of neonatal abstinence syndrome (NAS) and guide pharmacologic therapy. The FNAST, a comprehensive 21-item assessment tool, was developed for research and subsequently integrated into clinical practice; a simpler tool, designed to account for clinically meaningful outcomes, is urgently needed to standardize assessment. Objectives To identify FNAST items independently associated with the decision to use pharmacologic therapy and to simplify the FNAST while minimizing loss of information for the treatment decision. Design, Setting, and Participants This multisite cohort study included 424 neonates with opioid exposure who had a gestational age of at least 36 weeks with follow-up from birth to hospital discharge in the derivation cohort and 109 neonates with opioid exposure from the Maternal Opioid Treatment: Human Experimental Research Study in the validation cohort. Neonates in the derivation cohort were included in a medical record review at the Universities of Louisville and Kentucky or in a randomized clinical trial and observational study conducted at Tufts University (2014-2018); the Maternal Opioid Treatment: Human Experimental Research was conducted from 2005 to 2008. Data analysis was conducted from May 2017 to August 2019. Exposures Prenatal opioid exposure. Main Outcomes and Measures All FNAST items were dichotomized as present or not present, and logistic regression was used to identify binary items independently associated with pharmacologic treatment. The final model was validated with an independent cohort of neonates with opioid exposure. Results Among 424 neonates (gestational age, ≥36 weeks; 217 [51%] female infants), convulsions were not observed, and high-pitched cry and hyperactive Moro reflex had extremely different frequencies across cohorts. Therefore, these 3 FNAST items were removed from further analysis. The 2 tremor items were combined, and 8 of the remaining 17 items were independently associated with pharmacologic treatment, with an area under the curve of 0.86 (95% CI, 0.82-0.89) compared with 0.90 (95% CI, 0.87-0.94) for the 21-item FNAST. External validation of the 8 items resulted in an area under the curve of 0.86 (95% CI, 0.79-0.93). Thresholds of 4 and 5 on the simplified scale yielded the closest agreement with FNAST thresholds of 8 and 12 (weighted κ = 0.55; 95% CI, 0.48-0.61). Conclusions and Relevance The findings of this study suggest that 8 signs of NAS may be sufficient to assess whether a neonate meets criteria for pharmacologic therapy. A focus on these signs could simplify the FNAST tool and may enhance its clinical utility.

Background/Aim: Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns’ neurobehavior. Methods: We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. Results: We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (β-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). Conclusions: Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association. Keywords: Selenium, DNA methylation, Placenta, Neurobehavior, NNNS, Muscle tone

BACKGROUND: Among preterm infants, neurodevelopmental outcomes are influenced by both medical and sociodemographic factors. Less is known about the impact on these factors on neonatal neurobehavioral patterns. OBJECTIVE: To determine associations between demographic, psychosocial and medical risk factors and neonatal neurobehavior. METHODS: Multi-center observational study of infants born

Background & ObjectivesNeonatal neurobehavioral performance measures, such as the NICU Network Neurobehavioral Scale (NNNS), have been developed to assess the neurobehavioral characteristics of infants and provide insights into future developmental trajectories. The identification of molecular biomarkers of very early life neurobehavioral experiences could lead to better predictions of the long-term developmental outcomes of high-risk infants including preterm infants. To this end, we aimed to examine whether variability in DNA methylation (DNAm) or epigenetic age from surrogate tissues are associated with NNNS profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA).MethodsThis study was performed within the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study and included those infants with complete NNNS assessment data and DNAm measured from buccal cells, collected at near term-equivalent age using the Illumina EPIC array (N=536). We tested whether epigenetic age and age acceleration differed between infants based on their NNNS profile classifications. Then we performed an epigenome-wide association study, to test whether DNAm at individual epigenetic loci varied between these NNNS profile groupings. Models were adjusted for recruitment site, infant sex, postmenstrual age, and estimated tissue heterogeneity.ResultsWe found that infants with an optimal NNNS profile had slightly older epigenetic age than other NOVI infants (β1 = 0.201, p-value = 0.026), and that infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). The genes annotated to these differentially methylated CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders.ConclusionsGreater epigenetic age is associated with optimal NNNS responses while altered DNAm of multiple genes are associated with an atypical neurobehavioral profile at near-term equivalent age. These findings build upon the existing evidence that epigenetic variations in buccal cells may serve as markers of neonatal neurobehavior and might facilitate early identification of children at risk for abnormal developmental outcome.

OBJECTIVES: We sought to determine if variations in maternal care alter DNA methylation in term, healthy, 5-month-old infants. This work was based on landmark studies in animal models demonstrating that nurturing care by dams would alter their newborns’ stress responses through epigenetic mechanisms. We used breastfeeding as a proxy for animal maternal behavior. We hypothesized alterations in DNA methylation of the glucocorticoid receptor gene and less hypothalamic stress response in infants of mothers who breastfed their infants versus infants of mothers who did not breastfeed. METHODS: A cohort study of term, healthy infants and their mothers who did (n = 21) or did not (n = 21) breastfeed for the first 5 months was used in this analysis. Cortisol stress reactivity was measured in infant saliva by using a mother-infant interaction procedure and DNA methylation of an important regulatory region of the glucocorticoid receptor gene. Changes in DNA methylation of this gene in humans were compared to homologous regions of the rat gene. DNA samples were prepared from cheek swabs and subjected to quantitative analysis of the extent of methylation by using sensitive sequencing techniques. RESULTS: Breastfeeding was associated with decreased DNA methylation of the glucocorticoid receptor promoter and decreased cortisol reactivity in 5-month-old infants. Decreased DNA methylation occurred in the promoter region involved in regulation of the hypothalamic-pituitary-adrenal and immune system responses. CONCLUSIONS: Maternal care in humans may impact the hypothalamic-pituitary-adrenal stress response through behavioral programming and manifest as offspring epigenetic change. These results explain, in part, some of the positive effects observed in children who are breastfed.

Background/Aim: As a micronutrient, selenium (Se) levels in pregnancy have been linked with the neurobehavioral development of the offspring. DNA methylation is a potential mediator of the effect o...

Deficits in social engagement emerge in autism during the infant and toddler period and may be related to emotion regulation and stress response systems. This study examined patterns of growth in autonomic functioning related to autism diagnosis and addresses the hypothesis that there are differences in autonomic functioning related to autism in infancy. Heart rate (HR) and respiratory sinus arrhythmia (RSA) were measured at 8 time points from 1 to 72 months of age in infants later diagnosed with autism (n = 12) and a non-autistic comparison group (n = 106). Multilevel models were used to describe the developmental course of HR and RSA and to test the effect of autism diagnosis on growth trajectories. Both groups showed an expected age-related decrease in HR and increase in RSA. Groups did not differ in the rate of decrease of HR over time. However, infants with autism demonstrated a smaller linear increase in RSA, indicating slower growth in RSA over time in comparison to controls. These results suggest that differences in physiological regulation may develop with age in autism. The slowed RSA growth in autism was most evident after 18 months of age, at a time when behavioral symptoms become prominent. This is consistent with the view that RSA is a marker of functional status in autism rather than a cause of social deficits in autism.

Global motion processing depends on a network of brain regions that includes extrastriate area V5 in the dorsal visual stream. For this reason, psychophysical measures of global motion perception have been used to provide a behavioural measure of dorsal stream function. This approach assumes that global motion is relatively independent of visual functions that arise earlier in the visual processing hierarchy such as contrast sensitivity and visual acuity. We tested this assumption by assessing the relationships between global motion perception, contrast sensitivity for coherent motion direction discrimination (henceforth referred to as contrast sensitivity) and habitual visual acuity in a large group of 4.5-year-old children (n = 117). The children were born at risk of abnormal neurodevelopment because of prenatal drug exposure or risk factors for neonatal hypoglycaemia. Motion coherence thresholds, a measure of global motion perception, were assessed using random dot kinematograms. The contrast of the stimuli was fixed at 100% and coherence was varied. Contrast sensitivity was measured using the same stimuli by fixing motion coherence at 100% and varying dot contrast. Stereoacuity was also measured. Motion coherence thresholds were not correlated with contrast sensitivity or visual acuity. However, lower (better) motion coherence thresholds were correlated with finer stereoacuity (rho=0.38, p=0.004). Contrast sensitivity and visual acuity were also correlated (rho= −0.26, p=0.004) with each other. These results indicate that global motion perception for high contrast stimuli is independent of contrast sensitivity and visual acuity and can be used to assess motion integration mechanisms in children.

Preterm birth is associated with medical problems affecting the neuroendocrine system, altering cortisol levels resulting in negative effects on newborn neurobehavior. Newborn neurobehavior is regulated by DNA methylation of NR3C1 and HSD11B2. Aim: Determine if methylation of HSD11B2 and NR3C1 is associated with neurobehavioral profiles in preterm infants. Patients & methods: Neurobehavior was measured before discharge from the hospital in 67 preterm infants. Cheek swabs were collected for DNA extraction. Results: Infants with the high-risk neurobehavioral profile showed more methylation than infants with the low-risk neurobehavioral profile at CpG3 for NR3C1 and less methylation of CpG3 for HSD11B2. Infants with these profiles were more likely to have increased methylation of NR3C1 and decreased methylation of HSD11B2 at these CpG sites. Conclusion: Preterm birth is associated with epigenetic differences in genes that regulate cortisol levels related to high-risk neurobehavioral profiles.

Objective To evaluate associations between actigraphic sleep patterns, subjective sleep quality, and daytime functioning (ie, sleepiness, symptoms of depression, and delinquency and other conduct problems) in at-risk adolescents. Design Prospective, observational cohort study. Setting Providence, RI, predominantly home and school and 2 visits to the Brown Center for the Study of Children at Risk. Participants A diverse group of low-income 13-year-olds (n = 49) with and without prenatal drug exposure. Interventions None. Measurements Actigraphy, sleep diaries, and sleep and health questionnaires. Results Above and beyond the effects of prenatal drug exposure and postnatal adversity, actigraphic daytime sleep was a significant predictor of daytime sleepiness and delinquency. Subjective sleep quality was a significant predictor of daytime sleepiness, delinquency, and depressive symptoms. Later bed times predicted increased delinquency. Conclusions There was a unique effect of actigraphic daytime sleep duration, subjective nighttime sleep quality, and bedtime on daytime functioning (ie, sleepiness, symptoms of depression, and delinquency and other conduct problems) of at-risk adolescents. In these vulnerable youth, these problematic sleep patterns may contribute to feeling and behaving poorly. Intervention studies with at-risk teens should be conducted to further explore the role of these sleep parameters on daytime functioning.

Genomic imprinting disorders often exhibit delayed neurobehavioral development, suggesting this unique mechanism of epigenetic regulation plays a role in mental and neurological health. While major errors in imprinting have been linked to adverse health outcomes, there has been little research conducted on how moderate variability in imprinted gene expression within a population contributes to differences in neurobehavioral outcomes, particularly at birth. Here, we profiled the expression of 108 known and putative imprinted genes in human placenta samples from 615 infants assessed by the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). Data reduction identified 10 genes (DLX5, DHCR24, VTRNA2-1, PHLDA2, NPAP1, FAM50B, GNAS-AS1, PAX8-AS1, SHANK2, and COPG2IT1) whose expression could distinguish between newborn neurobehavioral profiles derived from the NNNS. Clustering infants based on the expression pattern of these genes identified 2 groups of infants characterized by reduced quality of movement, increased signs of asymmetrical and non-optimal reflexes, and increased odds of demonstrating increased signs of physiologic stress and abstinence. Overall, these results suggest that common variation in placental imprinted gene expression is linked to suboptimal performance on scales of neurological functioning as well as with increased signs of physiologic stress, highlighting the central importance of the control of expression of these genes in the placenta for neurobehavioral development.

Background Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly. Objectives We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes. Methods The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants. Results We identified 339 loci with an average methylation difference > 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p < 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression. Conclusions EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes. Citation Maccani JZ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, Marsit CJ. 2015. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect 123:723–729; http://dx.doi.org/10.1289/ehp.1408561

Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions.

The combined impact of infant colic and maternal depression on infant, parent, and family difficulties was examined. The sample included 93 consecutive patients seen at an outpatient Colic Clinic. Most mothers had private insurance and completed high school. Infants were approximately 2 months of age. Questionnaires completed by the mother prior to treatment onset were used to measure depressive symptoms in the mothers, infant cry, sleep and temperament, characteristics, parenting stress, maternal self-esteem, social support, and family function. Moderate to severe depressive symptoms were reported by 45.2% of the mothers. More severe depressive symptoms in the mothers were related to fussy/difficult infant temperament, more parenting stress, lower parental self-esteem, and more family-functioning problems. Pediatric health care providers need to be aware that the combined effects of colic and maternal depression can be problematic for the family. ©2005 Michigan Association for Infant Mental Health.

Objective Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes. Study design DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with $2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing. Results Sixty-five percent of infants required treatment for NAS, and 24% required $2 medications. Hypermethylation of the OPRM1 promoter was measured at the � 10 CpG in treated vs nontreated infants (adjusted difference d = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the � 14 (d = 4.9% [95% CI, 1.8%-8.1%], P =. 003),� 10 (d =5 .0% [95% CI, 2.3-7.7%],P = .0005), and +84 (d = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring $2 medications, which remained significant for � 14 and � 10 after multiple testing correction. Conclusions Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing. (J Pediatr 2014;165:472-8).

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.

Background Despite the evidence that women world-wide are using methamphetamine (MA) during pregnancy little is known about the neurodevelopment of their children. Design The controlled, prospective longitudinal New Zealand (NZ) Infant Development, Environment and Lifestyle (IDEAL) study was carried out in Auckland, NZ. Participants were 103 children exposed to MA prenatally and 107 who were not exposed. The Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development, Second Edition (BSID-II) measured cognitive and motor performances at ages 1, 2 and 3, and the Peabody Developmental Motor Scale, Second Edition (PDMS-II) measured gross and fine motor performances at 1 and 3. Measures of the child's environment included the Home Observation of Measurement of the Environment and the Maternal Lifestyle Interview. The Substance Use Inventory measured maternal drug use. Results After controlling for other drug use and contextual factors, prenatal MA exposure was associated with poorer motor performance at 1 and 2 years on the BSID-II. No differences were observed for cognitive development (MDI). Relative to non-MA exposed children, longitudinal scores on the PDI and the gross motor scale of the PDMS-2 were 4.3 and 3.2 points lower, respectively. Being male and of Maori descent predicted lower cognitive scores (MDI) and being male predicted lower fine motor scores (PDMS-2). Conclusions Prenatal exposure to MA was associated with delayed gross motor development over the first 3 years, but not with cognitive development. However, being male and of Maori descent were both associated with poorer cognitive outcomes. Males in general did more poorly on tasks related to fine motor development.

Summary Background Leptin (LEP) is a hormone central for energy homeostasis and has been implicated in neurodevelopment. This adipokine is produced by the placenta and is epigenetically regulated by promoter DNA methylation. Recent evidence has suggested a role for LEP in behavioral development. In this study, we investigated associations between profiles of human newborn neurobehavior and placental LEP DNA methylation. Methods We determined LEP promoter methylation in 444 placental samples from healthy term infants and measured LEP gene expression in a random subset of these samples. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scales (NNNS) and we examined the relationship between LEP promoter methylation and profiles of infant neurobehavior derived from these scores generated using a hierarchical model-based clustering method. Results LEP methylation is negatively correlated with gene expression only in placentas from male infants (r = −0.6, P = 0.006). A 10% increase in LEP DNA methylation was associated with membership in a profile of infant neurobehavior marked by increased lethargy and hypotonicity (OR = 1.9; 95% CI: 1.07–3.4), and consistently with reduced risk of membership in a profile characterized by decreased lethargy and hypotonicity (OR = 0.54; 95% CI: 0.3–0.94) only in male infants (n = 223). No statistically significant associations were observed amongst female infants. Discussion These results suggest that increased placental LEP DNA methylation, related to reduced expression, may play a role in human newborn neurodevelopment, particularly in reactivity to various stimuli, but that these effects may be sexually dimorphic.

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.

The brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging at 8-10 years, was studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 noncocaine-exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, the thalamus and the putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse correlation with exposure levels, thus highlighting effects on dopamine-rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group. A subgroup of these subjects (6 CE, 4 NCE) was also scanned at 13-15 years of age. In subjects who were scanned twice, we found that the trend for smaller structures continued into teenage years. We found that the differences in structural volumes between the CE and NCE groups are largely diminished when the HCs are controlled for or matched by study design. Participants in this study were drawn from a unique longitudinal cohort and, while the small sample size precludes strong conclusions regarding the longitudinal findings reported, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.

Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and cortisol (high RSA and low cortisol or low RSA and high cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline cortisol interaction. Boys with low baseline RSA and high baseline cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents.

In infants, eye constriction—the Duchenne marker—and mouth opening appear to index the intensity of both positive and negative facial expressions. We combined eye constriction and mouth opening that co-occurred with smiles and cry-faces (respectively, the prototypic expressions of infant joy and distress) to measure emotional expression intensity. Expression intensity and heart rate were measured throughout the Face-to-Face/Still Face (FFSF) in a sample of infants with prenatal cocaine exposure who were at risk for developmental difficulties. Smiles declined and cry-faces increased in the still-face episode, but the distribution of eye constriction and mouth opening in smiles and cry-faces did not differ across episodes of the FFSF. As time elapsed in the still face episode potential indices of intensity increased, cry-faces were more likely to be accompanied by eye constriction and mouth opening. During cry-faces there were also moderately stable individual differences in the quantity of eye constriction and mouth opening. Infant heart rate was higher during cry-faces and lower during smiles, but did not vary with intensity of expression or by episode. In sum, infants express more intense negative affect as the still-face progresses, but do not show clear differences in expressive intensity between episodes of the FFSF.

We employed latent growth curve analysis to examine trajectories of respiratory sinus arrhythmia (RSA) from 3 to 6 years among children with varying levels of prenatal substance exposure and early adversity. Data were drawn from a prospective longitudinal study of prenatal substance exposure that included 1,121 participants. Baseline RSA and RSA reactivity to an attention-demanding task were assessed at 3, 4, 5, and 6 years. Overall, there were significant individual differences in the trajectories of RSA reactivity, but not baseline RSA, across development. Greater levels of prenatal substance exposure, and less exposure to early adversity, were associated with increased RSA reactivity at 3 years, but by 6 years, both were associated with greater RSA reactivity. Prenatal substance exposure had an indirect influence through early adversity on growth in RSA reactivity. Results are in support of and contribute to the framework of allostatic load.

Until now, the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in children with prenatal methamphetamine exposure (PME) had been unexamined. Previous research indicates that prenatal exposure to stimulant drugs is associated with dose-response alterations in neural growth and connectivity and consequent neurobehavioral deficits. In addition, children of drug-using parents are at an increased risk for exposure to chronic postnatal stress. In this preliminary study, we examined the associations of PME and postnatal environmental stress with cortisol stress reactivity in children with PME.Participants were 2-year-old children (N = 123; 55.3% male) with PME from a multicenter longitudinal Infant, Development, Environment, and Lifestyle Study. Saliva samples were obtained before and after a stress-inducing separation task. Hierarchical multiple regression analyses examined prenatal drug exposure, methodological and postnatal stress covariates, and interactions between levels of PME and postnatal stress.Mild to moderate potential for child physical abuse moderated increased cortisol reactivity in high exposed children with PME. Blunted cortisol reactivity was associated with caregiver's postnatal alcohol use, child's behavioral dysregulation, and the interaction between higher levels of PME and caregiver's psychopathology.Consistent with the known effects of stimulant drugs and chronically stressful environments on the HPA axis and, thus, the toxic stress and allostatic load phenomena, our results imply that elevated PME may be associated with alterations in the programming of the HPA axis reflecting hyperactivity, which under significant and chronic environmental stress then may become hypoactive.

a b s t r a c t Background: Methamphetamine (MA) abuse is a worldwide problem. Little is known about the co- morbidity of substance use disorders (SUD) and other psychiatric disorders of mothers who use MA prenatally. The Infant Development, Environment and Lifestyle (IDEAL) Study is a prospective, inves- tigation of prenatal MA use and child outcome in the United States (US) and New Zealand (NZ). This study examined prenatal MA use and the co-morbidity of SUD and psychiatric disorders at 1-month postpartum. Method: Mothers who used MA (US = 127, NZ = 97) were compared to a matched comparison group (US = 193, NZ = 110). The Substance Abuse Subtle Screening Inventory-3 was used to measure the prob- ability of a SUD. The Brief Symptom Inventory (BSI) was used to measure the likelihood of a positive diagnosis of a psychiatric disorder. Results: In the US and NZ, MA groups had lower SES, increased single parenting, delayed prenatal care, and increased polydrug use. In the US only, MA mothers had lower income than the comparison group. MA users were 10 times more likely to have a SUD and twice as likely to meet BSI criteria for a diagnosable psychiatric disorder. In NZ, but not the US, MA users were five times more likely to have co-morbidity of both. This disparity may be due to higher quantities of prenatal alcohol use associated with increased psychiatric symptoms. Conclusion: These findings suggest that addressing both substance abuse and psychiatric disorders in mothers who use MA may be required to effectively treat maternal MA use.

BACKGROUND: We determined the role of risk and protective factors on the trajectories of behavior problems associated with high prenatal cocaine exposure (PCE)/polydrug exposure. METHODS: The Maternal Lifestyle Study enrolled 1388 children with or without PCE, assessed through age 15 years. Because most women using cocaine during pregnancy also used other substances, we analyzed for the effects of 4 categories of prenatal drug exposure: high PCE/other drugs (OD), some PCE/OD, OD/no PCE, and no PCE/no OD. Risks and protective factors at individual, family, and community levels that may be associated with behavior outcomes were entered stepwise into latent growth curve models, then replaced by cumulative risk and protective indexes, and finally by a combination of levels of risk and protective indexes. Main outcome measures were the trajectories of externalizing, internalizing, total behavior, and attention problems scores from the Child Behavior Checklist (parent). RESULTS: A total of 1022 (73.6%) children had known outcomes. High PCE/OD significantly predicted externalizing, total, and attention problems when considering the balance between risk and protective indexes. Some PCE/OD predicted externalizing and attention problems. OD/no PCE also predicted behavior outcomes except for internalizing behavior. High level of protective factors was associated with declining trajectories of problem behavior scores over time, independent of drug exposure and risk index scores. CONCLUSIONS: High PCE/OD is a significant risk for behavior problems in adolescence; protective factors may attenuate its detrimental effects. Clinical practice and public health policies should consider enhancing protective factors while minimizing risks to improve outcomes of drug-exposed children.

Using existing longitudinal data from 570 infants in the Maternal Lifestyle Study, we explored the predictive value of maternal and infant affect and maternal vocalizations during 2 minutes of face-to-face interactions at 4 months on IQ scores at 4.5 and 7 years. After controlling for demographic factors, maternal depression, and prenatal drug exposure, maternal positive affect and maternal positive vocalizations emerged as predictors of both verbal and performance IQ at 4.5 and 7 years. Although infant positive affect during the interaction with the mother was not predictive of these outcome measures, infant positive affect towards an examiner predicted verbal but not performance IQ at 4.5 years. These results suggest that maternal positive affect may index emotional engagement in interaction that facilitates both verbal and nonverbal cognitive development, while infant social positive affect is specifically related to the acquisition of verbal reasoning abilities. These findings are significant because they are based on a discrete snapshot of observable behavior in infancy (just 2 minutes of interaction), because they extend the range of maternal behaviors and characteristics known to support positive developmental outcomes, and because they are derived from high-risk infants where prevention efforts may be beneficial. Potential mechanisms for these associations are discussed, as are the clinical implications for identifying dyads most in need of targeted interventions.

Global motion perception is often used as an index of dorsal visual stream function in neurodevelopmental studies. However, the relationship between global motion perception and visuomotor control, a primary function of the dorsal stream, is unclear. We measured global motion perception (motion coherence threshold; MCT) and performance on standardized measures of motor function in 606 4.5-year-old children born at risk of abnormal neurodevelopment. Visual acuity, stereoacuity and verbal IQ were also assessed. After adjustment for verbal IQ or both visual acuity and stereoacuity, MCT was modestly, but significantly, associated with all components of motor function with the exception of gross motor scores. In a separate analysis, stereoacuity, but not visual acuity, was significantly associated with both gross and fine motor scores. These results indicate that the development of motion perception and stereoacuity are associated with motor function in pre-school children.

Developmental psychopathologists face the difficult task of identifying the environmental conditions that may contribute to early childhood behavior problems. Highly stressed caregivers can exacerbate behavior problems, while children with behavior problems may make parenting more difficult and increase caregiver stress. Unknown is: (a) how these transactions originate, (b) whether they persist over time to contribute to the development of problem behavior and (c) what role resilience factors, such as child executive functioning, may play in mitigating the development of problem behavior. In the present study, transactional relations between caregiving stress, executive functioning, and behavior problems were examined in a sample of 1,388 children with prenatal drug exposures at three developmental time points: early childhood (birth to age 5), middle childhood (ages 6 to 9), and early adolescence (ages 10 to 13). Transactional relations differed between caregiving stress and internalizing versus externalizing behavior. Targeting executive functioning in evidence-based interventions for children with prenatal substance exposure who present with internalizing problems and treating caregiving psychopathology, depression, and parenting stress in early childhood may be particularly important for children presenting with internalizing behavior.

The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 × 10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.

Epigenetic mechanisms regulating expression of the glucocorticoid receptor gene (NR3C1) promoter may influence behavioral and biological aspects of stress response in human infants. Acoustic features of infant crying are an indicator of neurobehavioral and neurological status not yet investigated in relation to epigenetic mechanisms. We examined NR3C1 methylation in placental tissue from a series of 120 healthy newborn infants in relation to a detailed set of acoustic features extracted from newborn infant cries. We identified significant associations of NR3C1 methylation with energy variation in infants’ cries as well as with the presence of very high fundamental frequency in cry utterances. The presence of high fundamental frequency in cry (above 1 kHz) has been linked to poor vocal tract control, poor regulation of stress response, and may be an indicator of poor neurobehavioral integrity. Thus, these results add to evidence linking epigenetic alteration of the NR3C1 gene in the placenta to neurodevelopmental features in infants.