NICU Network Neurobehavioral Scale Research Articles

Investigation of Prenatal Pesticide Exposure and Neurodevelopmental Deficits in Northern Thailand: Protocol for a Longitudinal Birth Cohort Study.

BackgroundPrenatal exposure to pesticides has been linked to adverse neurodevelopmental outcomes. Gaps exist in the current literature about the timing and magnitude of exposures that result in these adverse outcomes.ObjectiveThe Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) cohort was established to investigate the impact of prenatal exposure to pesticides on early indicators of cognitive and motor skills, inhibitory control, emotion regulation, and memory that have been found to be important in the development of subsequent neurobehavioral and neurodevelopmental diseases. The overarching goal is to find earlier predictors of potential adverse neurologic outcomes in order to enable earlier interventions that could result in better outcome prognoses.MethodsRecruitment of this prospective, longitudinal birth cohort began in July 2017 and was completed in June 2019 in Chom Thong and Fang, 2 farming districts in Chiang Mai Province in northern Thailand. Follow-up of the study participants is ongoing. During pregnancy, 7 questionnaires were administered. Time-resolved biospecimen samples were collected monthly (for urine) and during each trimester (for blood) during antenatal care visits. Medical records were abstracted. Infants were administered the NICU Network Neurobehavioral Scale (NNNS) test at 1 month of age. A total of 322 mother-child pairs completed the NNNS test. All children will be followed until 3 years of age and undergo a series of neurodevelopmental tests. We will complete several additional exposure related analyses.ResultsA total of 1298 women were screened, and of those, 394 (30.35%) women were enrolled. The mean gestational age at enrollment was 9.9 weeks (SD 2.6). Differences in literacy were observed between Chom Thong and Fang participants. In Fang, about 54 of 105 (51.4%) participants reported being able to read in Thai compared to about 206 of 217 (94.9%) participants in Chom Thong. The percentages were comparable for reporting to be able to write in Thai.ConclusionsThis longitudinal birth cohort study will inform risk assessment standards for pregnant women in Thailand and other countries. Building awareness of how insecticide exposure during specific windows of pregnancy affects the neurodevelopmental trajectories of children in developing countries is a specific need recognized by the World Health Organization.International Registered Report Identifier (IRRID)DERR1-10.2196/31696

Prenatal exposure to metal mixtures and newborn neurobehavior in the Rhode Island Child Health Study.

Background:Prenatal exposure to metals can affect the developing fetus and negatively impact neurobehavior. The associations between individual metals and neurodevelopment have been examined, but little work has explored the potentially detrimental neurodevelopmental outcomes associated with the combined impact of coexisting metals. The objective of this study is to evaluate prenatal metal exposure mixtures in the placenta to elucidate the link between their combined effects on newborn neurobehavior.Method:This study included 192 infants with available placental metal and NICU Network Neurobehavioral Scale data at 24 hours–72 hours age. Eight essential and nonessential metals (cadmium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc) detected in more than 80% of samples were tested for associations with atypical neurobehavior indicated by NICU Network Neurobehavioral Scale using logistic regression and in a quantile g-computation analysis to evaluate the joint association between placental metal mixture and neurobehavioral profiles.Results:Individually, a doubling of placental cadmium concentrations was associated with an increased likelihood of being in the atypical neurobehavioral profile (OR = 2.39; 95% CI = 1.05 to 5.71). In the mixture analysis, joint effects of a quartile increase in exposure to all metals was associated with 3-fold increased odds of newborns being assigned to the atypical profile (OR = 3.23; 95% CI = 0.92 to 11.36), with cadmium having the largest weight in the mixture effect.Conclusions:Prenatal exposure to relatively low levels of a mixture of placental metals was associated with adverse newborn neurobehavior. Examining prenatal metal exposures as a mixture is important for understanding the harmful effects of concomitant exposures in the vulnerable populations.

Effects of Pharmacologic Treatment for Neonatal Abstinence Syndrome on DNA Methylation and Neurobehavior: A Prospective Cohort Study

To determine whether pharmacologic treatment for neonatal abstinence syndrome (NAS) is associated with changes in DNA methylation (DNAm) of the mu-opioid receptor gene (OPRM1) and improvements in neonatal neurobehavior. Buccal swabs were collected from 37 neonates before and after morphine treatment for NAS. Genomic DNA was extracted, and DNAm was examined at 4 cytosine-phosphate-guanine (CpG) sites within the OPRM1 gene. Assessment with the NICU Network Neurobehavioral Scales (NNNS) was also performed before and after NAS treatment. Changes in DNAm (DNAmpost-tx - DNAmpre-tx) and NNNS summary scores (NNNSpost-tx - NNNSpre-tx) were then calculated. Path analysis was used to examine associations among pharmacologic treatment (length of treatment [LOT] and total dose of morphine), changes in DNAm, and changes in NNNS summary scores. DNAm was significantly decreased from pretreatment to post-treatment at 1 of 4 CpG sites within the OPRM1 gene. Neonates also demonstrated decreased excitability, hypertonia, lethargy, signs of stress and abstinence, and increased quality of movement and regulation from pretreatment to post-treatment. Longer LOT and higher morphine dose were associated with greater decreases in DNAm; greater decreases in DNAm were associated with greater decreases in excitability and hypertonia on the NNNS. Pharmacologic treatment of NAS is associated with decreased DNAm of the OPRM1 gene and improved neonatal neurobehavior. Epigenetic changes may play a role in these changes in neonatal neurobehavior.

Pregnancy and Infant Development (PRIDE)\u2014a preliminary observational study of maternal adversity and infant development

BackgroundChildren from socioeconomically disadvantaged families have a markedly elevated risk for impaired cognitive and social-emotional development. Children in poverty experience have a high risk for developmental delays. Poverty engenders disproportionate exposure to psychological adversity which may contribute to impaired offspring development; however the effect may be mitigated by social support and other aspects of resilience. Our objective was to determine the association between maternal stress, adversity and social support and early infant neurobehavior and child behavior at two and three years.MethodsWe conducted a longitudinal mother-infant cohort study nested within a regional home visiting program in Cincinnati, Ohio. Four home study visits were completed to collect measures of maternal stress, adversity and social support and infant and child behavior. A measure of infant neurobehavior (‘high-arousal’ infant) was derived from the NICU Network Neurobehavioral Scale (NNNS) at 1 month and externalizing and internalizing symptoms were measured by the Child Behavior Checklist (CBCL) at 24 and 36 months. Linear and logistic regression identified associations between maternal risk/protective factors and infant and child behavioral measures. We used stratification and multiplicative interaction terms to examine potential interactions.ResultsWe enrolled n = 55 pregnant mothers and follow 53 mother–offspring dyads at 1 month, 40 dyads at 24 months and 27 dyads at 36 months. Maternal adversity and protective factors were not associated with neurobehavior at one month. However, maternal depression and measures of distress in pregnancy were significantly associated with internalizing and externalizing symptoms at 24 and 36 months.ConclusionsThis pilot study established the feasibility of conducting longitudinal research within a community intervention program. In addition, although there were no statistically significant associations between maternal psychosocial factors in pregnancy and infant neurobehavior, there were several associations at 24 months, primarily internalizing symptoms, which persisted through 36 months. Future work will replicate findings within a larger study as well as explore mediators and modifiers of these associations.

Association between placental toxic metal exposure and NICU Network Neurobehavioral Scales (NNNS) profiles in the Rhode Island Child Health Study (RICHS)

BackgroundPrenatal exposure to heavy metals has been linked to a variety of adverse outcomes in newborn health and later life. Toxic metals such as cadmium (Cd), manganese (Mn) and lead (Pb) have been implicated to negatively affect newborn neurobehavior. Placental levels of these metals may provide additional understandings on the link between prenatal toxic metal exposures and neurobehavioral performances in newborns. ObjectiveTo evaluate associations between placental concentrations of toxic metals and newborn neurobehavioral performance indicated through the NICU Network Neurobehavioral Scales (NNNS) latent profiles. MethodIn the Rhode Island Child Health Study cohort (n = 625), newborn neurobehavioral performance was assessed with NNNS, and a latent profile analysis was used to define five discrete neurobehavioral profiles based on summary scales. Using multinomial logistic regression, we determined whether increased levels of placental toxic metals Cd, Mn and Pb associated with newborns assigned to the profile demonstrating atypical neurobehavioral performances. ResultsEvery doubling in placenta Cd concentration was associated with increased odds of newborns belonging to the atypical neurobehavior profile (OR: 2.72, 95% CI [1.09, 6.79]). Detectable placental Pb also demonstrated an increased odds of newborns assignment to the atypical profile (OR: 3.71, 95% CI [0.97, 13.96]) compared to being in the typical neurobehavioral profile. ConclusionsToxic metals Cd and Pb measured in placental tissue may adversely impact newborn neurobehavior. Utilizing the placenta as a prenatal toxic metal exposure biomarker is useful in elucidating the associated impacts of toxic metals on newborn health.

Association between placental metal exposure and NICU Network Neurobehavioral Scales (NNNS) profiles in the Rhode Island Child Health Study (RICHS)

BACKGROUND AND AIM: Exposure to even low levels of toxic metals has been linked to cognitive and behavioral deficits in children. Our prior work has demonstrated the placenta’s role in programming newborn health, and that placenta function can be affected by metals exposures. In this study, we hypothesized that placental trace metals can lead to poor neurobehavioral performance and so assessed the associations between placental toxic trace metals, cadmium, manganese, and lead, and neurobehavioral performance indicated through the NNNS in newborns. METHODS: A hospital-based birth cohort, RICHS enrolled infants 37 weeks gestation and oversampled for infants born either small or large for gestational age (n= 840). Placental tissue was collected within 2 hours of birth, and 24 metals’, metalloids’, and nutrient elements’ concentrations were determined using inductively couple plasma mass spectrometry. NNNS assessment was carried out by certified psychometrists from 24-72 hours after birth (n=625). Latent profile analysis (LPA) was used to define neurobehavior profiles based on 12 NNNS summary scales. Multinomial regression was used to examine the association between placental metals concentrations and neurobehavioral profile membership controlled for confounders (infant sex, maternal age, race, BMI, education status and tobacco smoking during pregnancy). RESULTS:The optimal LPA fit was a 5-profile model. The 12 NNNS summary scores were significantly different across the five profiles. Adjusted models showed that a doubling of placental cadmium concentration was associated with a 2.4 fold increased odds of newborns belonging to the atypical neurobehavioral profile compared to the typical performing profile (95%CI: [1.4, 3.4]). Participants with detectable placental lead levels also had increased odds of belonging to the atypical profile (OR: 3.4, 95%CI: [2.1, 4.8]). CONCLUSIONS:Placental toxic heavy metals including cadmium and lead were associated with atypical neurobehavioral performance at birth and provided additional evidence of the importance of the placenta in newborn health. KEYWORDS: heavy metals, children's environmental health, neurodevelopmental outcomes, environmental epidemiology

Improving the Assessment of Neonatal Abstinence Syndrome (NAS).

Neonatal Abstinence Syndrome (NAS) is a public health problem of epidemic proportions. The Finnegan Neonatal Abstinence Scoring System (FNASS) is the tool most widely used to evaluate NAS. However, it is limited by its lack of interrater reliability and standardized approach. Surveys to evaluate the FNASS were distributed to nurses at the Women and Infants Hospital in Providence, RI, USA. Infants (n = 78) treated for NAS and born to methadone-maintained mothers were examined to compare items administered from the FNASS and the NICU Network Neurobehavioral Scale (NNNS). All nurses reported that the FNASS was somewhat to very subjective. More than half reported that it was somewhat to not accurate and a new scoring method is needed to accurately diagnose NAS. Correlations between FNASS items and NNNS items showed 9 of 32 (28.1%) correlations were strong (rs > 0.5), 5 of 32 (15.6%) were moderate (0.3 < rs < 0.5), and 10 of 32 (31.3%) were weak (0.1 < rs < 0.3). Principal component factor analysis (PCA) of the NNNS explained more variance (35.1%) than PCA of NNNS and FNASS items combined (33.1%). The nursing survey supported the need for developing a more objective exam to assess NAS. NNNS exam items may be used to improve the evaluation of NAS.

Maternal mindfulness during pregnancy predicts newborn neurobehavior.

Newborn neurobehavioral competencies portend a young child's abilities to modulate their arousal and attention in response to dynamic environmental cues. Although evidence suggests prenatal contributions to newborn neurobehavioral differences, no study to date has examined wellness-promoting traits, such as a pregnant woman's mindfulness, in this association. We examined whether a mother's mindfulness while pregnant related to neurobehavioral outcomes in her neonate, as well as whether maternal mindfulness moderated the link between prenatal maternal emotion dysregulation and newborn neurobehavior. Mothers (N=162) reported on their mindfulness and emotion dysregulation while pregnant. Newborn arousal and attention were assessed at least 24h after birth (M=3.8 days, SD=8.3) using the NICU Network Neurobehavioral Scale (NNNS). Highly mindful pregnant women reported lower levels of emotion dysregulation. Newborns of highly mindful mothers exhibited higher levels of arousal (e.g., excitability, motor activity) but did not differ in regards to attention at birth. Maternal emotion dysregulation while pregnant was associated with blunted newborn attention, but only among mothers who were less mindful. Our findings suggest that a mother's mindfulness while pregnant may influence her fetus' neurobehavioral development in ways that are evident at birth.

Randomized clinical trial investigating the effect of consistent, developmentally-appropriate, and evidence-based multisensory exposures in the NICU.

Objective:Evaluate the effect of a manualized multisensory program, applied across NICU hospitalization, on infant and parent outcomes.Study Design:Seventy parent-infant dyads (born ≤ 32 weeks gestation) in a Level IV NICU were randomized at birth to the multisensory program or standard-of-care. Parents in the multisensory group administered prespecified amounts of age-appropriate, evidence-based sensory interventions to their infants each day during NICU hospitalization according to the Supporting and Enhancing NICU Sensory Experiences (SENSE) program.Results:Infants who received the SENSE program had more lethargy on the NICU Network Neurobehavioral Scale (NNNS) (p=0.05), even after controlling for medical and social risk (p=0.043), and had higher Communication scores on the Ages and Stages Questionnaire (p=0.04) at one-year corrected age, but this relationship failed to reach significance after controlling for medical and social risk (p=0.12).Conclusion:The SENSE program shows promise for improving outcomes, but more research with larger sample sizes is needed.

Neurobehaviour of very preterm infants at term equivalent age is related to early childhood outcomes.

To describe neurodevelopmental outcomes during early childhood among infants born very preterm and define the relationships between neurobehaviour of very preterm infants and neurodevelopmental outcomes at 4years. Forty-eight infants born ≤32weeks gestation had neurobehaviour assessed at term equivalent age using the NICU Network Neurobehavioral Scale (NNNS). Outcomes at 4years were assessed with the Ages and Stages Questionnaire (ASQ-3), the Sensory Profile-Short Form (SF) and the Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P). At 4years, 23 (48%) children had at least one below average score on the ASQ-3, 15 (31%) had a below average total score on the Sensory Profile-SF, and 3 (6%) had an abnormal total score on the BRIEF-P. Children with lower fine motor scores at 4years had poorer orientation (P=0.03) and self-regulation (P=0.03), hypertonia (P=0.01), and more sub-optimal reflexes (P=0.02) as neonates. Children with lower gross motor scores at 4years of age had more sub-optimal reflexes (P=0.03) and lethargy (P=0.046) as neonates. Children with tactile sensitivity at 4years of age had poorer orientation (P=0.01) and tolerance of handling (P=0.03) as neonates. Children with decreased responsiveness at 4years of age had low arousal (P=0.02) as neonates, and those with poor auditory filtering at age 4years had hypotonia (P=0.03) as neonates. Early neurobehaviour is related to neurodevelopmental outcome in early childhood.

First trimester pesticide-related exposure behaviors and NNNS scores in infants from the SAWASDEE birth cohort

Background: Prenatal pesticide exposures have been associated with adverse neurodevelopmental outcomes in several studies. A prospective birth cohort, the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) evaluated the association between self-reported pesticide exposure behaviors during early pregnancy and neurodevelopment in infants. We examined behaviors associated with pesticide exposures in occupational settings to further understand potential sources of prenatal pesticide exposure and the implications for neurobehavioral outcomes in infants. Methods: Pregnant women working in agricultural settings provided information on pesticide-related exposures through detailed questionnaires. We investigated their pesticide-related exposure behaviors during the first trimester and their offspring’s neurobehavioral outcomes measured by the NICU Network Neurobehavioral Scales (NNNS). Results: Among those with first trimester exposure information, 272 women reported working since their last menstrual cycle. 58% of working women handled and applied fertilizers and 38% handled containers of pesticides. Common crop types were fruit (tangerines and/or longan; 44.41%) and rice (23.90%). Participants reported wearing long-sleeved shirts (84.93%), other protective clothing (boots, apron, waterproof pants; 67.28%) and face covers (i.e. scarf/handkerchief; 52.94%) for personal protection against pesticide exposures. For NNNS scale scores ranging from 1 to 9, average summary scores were 5.72±0.81 for attention, 3.69±0.54 for arousal, and 6.02±0.60 for regulation. Handling scores ranged between 0 and 1, and the average was 0.20±0.23. Maternal handling of pesticide containers did not increase infant’s OR of having poorer attention (crude OR: 1.06; 95% CI: 0.41, 2.69) or arousal scores (crude OR: 1.02, 95% CI: 0.49, 2.13). However, working with tangerines during the first trimester increased infant’s OR of having poorer handling scores (crude OR: 3.62; 95% CI: 1.44, 9.11). Conclusions: Prenatal pesticide-related behaviors in agricultural settings can lead to poorer neurobehavioral outcomes in the offspring, as demonstrated with the standardized NNNS summary scores.

Selenium-associated decrease of mir-216a and mir-217 expression in placenta and their associations with neurobehavioral development at birth: a genome-wide study of two U.S. birth cohorts

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 neurobehavioral development; however, very few studies have sought to elucidate whether microRNA expression is responsive to selenium in humans. We aimed to investigate the associations between selenium concentration in the placenta, a critical developmental organ, and microRNA expression, and to assess the association between selenium-associated microRNAs and newborns’ neurobehavior. Methods: Our study included 394 newborns (280 from New Hampshire Birth Cohort Study, 114 from Rhode Island Child Health Study). Placental selenium concentrations were quantified using inductively coupled plasma mass spectrometry, and genome-wide microRNA and mRNA transcripts were measured using RNA-seq. Newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales. We fitted generalized additive models with smoothing splines for selenium and microRNAs in the pooled data of the two cohorts, adjusting for covariates. We fitted multiple linear regression and ordinal logistic regression for microRNAs and newborn NNNS summary scores, adjusting for covariates. Results: We identified a reverse J-shaped association between selenium concentration and the expression of mir216a/mir217 cluster (edf = 2, FDR-adjusted p-value = 4.14 × 10-5) in placenta, and we observed that a doubling in mir216a/mir217 expression was associated with a 0.13 and 0.19 decrease in self-regulation score of newborns (p-value = 0.03 and 0.08). Moreover, self-regulation was positively associated with the expression of mir216a/mir217-targeted TXNRD2, a selenoprotein coding gene (β = 0.83, p-value = 0.04). Conclusions: The selenium-associated modification of mir216a/mir217 expression in the placenta might provide a partial mechanism for neurobehavioral developmental effects of prenatal selenium exposure in offspring.

Neurobehavior of newborn infants exposed prenatally to methadone and identification of a neurobehavioral profile linked to poorer neurodevelopmental outcomes at age 24 months.

The abuse of prescription opioids and heroin by women of childbearing age over the past decade has resulted in a five-fold increase in the number of infants born opioid-dependent. Daily opioid substitution treatment with methadone is associated with less maternal illicit opioid use and improved antenatal care. However, research on the neurobehavioral effects of daily prenatal exposure to methadone on the infant is limited. Using the NICU Network Neurobehavioral Scale (NNNS), we compared the neurobehavior at birth of 86 infants born to opioid-dependent mothers receiving methadone treatment (MMT) with 103 infants unexposed to methadone. Generalized linear models, adjusted for covariates, showed methadone exposed infants had significantly poorer attention, regulation, and quality of movement. They were also significantly more excitable, more easily aroused, exhibited more non-optimal reflexes, hypertonicity, and total signs of stress abstinence. Maternal MMT was also associated with more indices of neonatal abstinence, including: CNS, visual, genitourinary (GI), and state. Latent profile analysis of the NNNS summary scores revealed four distinct neurobehavioral profiles with infants characterized by the most disturbed neurobehavior at birth having the poorest clinical outcomes at birth, and poorer cognitive and motor development at 24 months of age.

Neonatal Abstinence Syndrome Severity Index Predicts 18-Month Neurodevelopmental Outcome in Neonates Randomized to Morphine or Methadone

To develop an index to determine which opioid-exposed neonates have the most severe neonatal abstinence syndrome (NAS). 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 18months, 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). 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 18months, 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). Presumptive measures of NAS severity can be aggregated to develop an index that predicts developmental outcomes at age 18months.

Early neurobehavior at 30 weeks postmenstrual age is related to outcome at term equivalent age

AimsTo determine 1) the relationship between infant medical factors and early neurobehavior, and 2) the relationship between early neurobehavior at 30 weeks postmenstrual age (PMA) and neurobehavior at term equivalent age. Study designIn this prospective longitudinal study, 88 very preterm infants born ≤30 weeks estimated gestational age (EGA) had neurobehavioral assessments at 30 weeks PMA using the Premie-Neuro and at term equivalent age using the NICU Network Neurobehavioral Scale (NNNS) and Hammersmith Neonatal Neurological Evaluation (HNNE). ResultsLower Premie-Neuro scores at 30 weeks PMA were related to being more immature at birth (p = 0.01; β = 3.87); the presence of patent ductus arteriosus (PDA; p < 0.01; β = −16.50) and cerebral injury (p < 0.01; β = −20.46); and prolonged exposure to oxygen therapy (p < 0.01; β = −0.01), endotracheal intubation (p < 0.01; β = −0.23), and total parenteral nutrition (p < 0.01; β = −0.35). After controlling for EGA, PDA, and number of days of endotracheal intubation, lower Premie-Neuro scores at 30 weeks PMA were independently related to lower total HNNE scores at term (p < 0.01; β = 0.12) and worse outcome on the NNNS with poorer quality of movement (p < 0.01; β = 0.02) and more stress (p < 0.01; ß = −0.004), asymmetry (p = 0.01; β = −0.04), excitability (p < 0.01; β = −0.05) and suboptimal reflexes (p < 0.01; ß = −0.06). ConclusionMedical factors were associated with early neurobehavioral performance at 30 weeks PMA. Early neurobehavior at 30 weeks PMA was a good marker of adverse neurobehavior at NICU discharge.

Prenatal tobacco and marijuana co-use: Sex-specific influences on infant cortisol stress response

Although tobacco (TOB) and marijuana (MJ) are often co-used in pregnancy, little is known regarding the joint impact of MJ + TOB on offspring development, including the developing neuroendocrine stress system. Further, despite evidence for sex-specific impacts of prenatal exposures in preclinical models, the sex-specific impact of prenatal MJ + TOB exposure on offspring neuroendocrine regulation in humans is also unknown. In the current study, overall and sex-specific influences of MJ + TOB co-use on offspring cortisol regulation were investigated over the first postnatal month. 111 mother-infant pairs from a low-income, racially and ethnically diverse sample participated. Based on Timeline Followback data with biochemical verification, three groups were identified: (1) prenatal MJ + TOB, (2) TOB only, and (3) controls. Baseline cortisol and cortisol stress response were assessed at seven points over the first postnatal month using a handling paradigm in which saliva cortisol was assessed before, during, and following a standard neurobehavioral assessment (NICU Network Neurobehavioral Scale). A significant exposure group by offspring sex interaction emerged for baseline cortisol over the first postnatal month (p = .043); MJ + TOB-exposed males showed 35–36% attenuation of baseline cortisol levels vs. unexposed and TOB-exposed males (ps ≤ .003), while no effects of exposure emerged for females. Both MJ + TOB and TOB-exposed infants showed a 22% attenuation of cortisol stress response over the first postnatal month vs. unexposed infants (ps < .03), with evidence for sex-specific effects in exploratory analyses. Although results are preliminary, this is the first human study to investigate the impact of prenatal MJ exposure on infant cortisol and the first to reveal a sex-specific impact of prenatal MJ + TOB on cortisol regulation in humans. Future, larger-scale studies are needed to elucidate mechanisms and consequences of sex-specific effects of MJ and MJ + TOB on the developing neuroendocrine stress system.

A pilot study demonstrating the impact of the supporting and enhancing NICU sensory experiences (SENSE) program on the mother and infant

AimTo explore differences in maternal mental health and infant neurobehavioral outcome among infants who received and did not receive the Supporting and Enhancing NICU Sensory Experiences (SENSE) program. Study designEighty preterm infants (50 receiving standard-of-care and 30 receiving the SENSE program) born ≤32 weeks gestation were enrolled within the first week of life in a prospective quasi-experimental design, using a historical control group for comparison. Standard-of-care consisted of tactile (skin-to-skin, touch, holding) and olfactory (scent cloth, close maternal contact) interventions as determined to be appropriate by health care professionals and parents. The SENSE group received specific doses of tactile (skin-to-skin care, holding, massage, touch), auditory (human speech, music), olfactory (scent cloth, close maternal contact), kinesthetic/vestibular (movement, rocking/transfers), and visual (dim or cycled light) exposures, based on the infant's postmenstrual age and tailored to medical status and infant cues according to the SENSE program. The SENSE program includes the intentional delivery of positive, age-appropriate sensory exposures by parents (or a sensory support team, when parents are unavailable) each day of NICU hospitalization. Infant neurobehavioral outcome, as well as maternal mental health and confidence, were assessed prior to NICU discharge, using standardized measures. ResultsSeventy-three infants were included in the final analysis. Mothers whose infants received the SENSE program demonstrated higher scores on the Maternal Confidence Questionnaire (p = 0.01). Infants who received the SENSE program demonstrated less asymmetry on the NICU Network Neurobehavioral Scale (p = 0.02; mean difference 0.9) and higher scores on the Hammersmith Neonatal Neurological Evaluation (p < 0.001; mean difference 4.8). DiscussionPreliminary evidence demonstrates improvements in maternal confidence and infant neurobehavioral performance following SENSE implementation.

Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts

Background/AimSelenium (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. MethodsWe 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. ResultsWe 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]). ConclusionsPlacental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.

Sociodemographic and medical influences on neurobehavioral patterns in preterm infants: A multi-center study

BackgroundAmong 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. ObjectiveTo determine associations between demographic, psychosocial and medical risk factors and neonatal neurobehavior. MethodsMulti-center observational study of infants born <30 weeks enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study between April 2014–May 2016. Maternal medical, demographic, and psychological variables and infant medical variables were prospectively collected. Demographic, substance, psychological and medical risk indices were developed. Neurobehavioral assessment was performed using the NICU Network Neurobehavioral Scale (NNNS) at NICU discharge. Results709 infants were enrolled in the NOVI study, and for 679 infants with neurobehavioral assessments, 6 NNNS behavioral profiles were calculated using latent profile analysis. Profile 6 infants (n = 47/679, 7%) were atypical, having poor attention, self-regulation and movement quality, hypertonia and increased stress signs. After adjustment for site, profile 6 infants had significantly smaller head circumferences at birth (β −0.87; −1.59, −0.14), and higher rates of late sepsis (OR 3.38; CI 1.66, 6.92) compared to Profiles 1–5 infants. There were no significant differences in other neonatal morbidities between the two groups. Profile 6 infants had a higher prenatal demographic risk score (1.46 vs 1.07;β 0.34; CI 0.06, 0.61) compared to Profiles 1–5 infants. ConclusionNNNS behavioral profiles identify an atypical behavioral pattern that is associated with early influences of demographic and medical variables. Such behavioral patterns may be seen as early as NICU discharge.

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome

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 18months, 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.