Prenatal Nicotine or Cannabis Exposure and Offspring Neurobehavioral Outcomes.

OBJECTIVE: To study the association between nicotine or cannabis metabolite presence in maternal urine and child neurodevelopmental outcomes. METHODS: We conducted a secondary analysis of two parallel multicenter randomized controlled trials of treatment for hypothyroxinemia or subclinical hypothyroidism among pregnant individuals enrolled at 8-20 weeks of gestation. All maternal-child dyads with a maternal urine sample at enrollment and child neurodevelopmental testing were included (N=1,197). Exposure was urine samples positive for nicotine (cotinine) or cannabis 11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) or both metabolites. Primary outcome was child IQ at 60 months. Secondary outcomes included cognitive, motor and language, attention, behavioral and social competency, and differential skills assessments at 12, 24, 36, and 48 months. Quantile regression analysis was performed with confounder adjustment. RESULTS: Of 1,197 pregnant individuals, 99 (8.3%) had positive cotinine samples and 47 (3.9%) had positive THC-COOH samples; 33 (2.8%) were positive for both. Groups differed in self-reported race and ethnicity, education, marital status, insurance, and thyroid status. Median IQ was similar between cotinine-exposed and -unexposed children (90 vs 95, adjusted difference in medians -2.47, 95% CI -6.22 to 1.29) and THC-COOH-exposed and -unexposed children (89 vs 95, adjusted difference in medians -1.35, 95% CI -7.76 to 5.05). In secondary outcome analysis, children with THC-COOH exposure compared with those unexposed had higher attention scores at 48 months of age (57 vs 49, adjusted difference in medians 6.0, 95% CI 1.11-10.89). CONCLUSIONS: Neither prenatal nicotine nor cannabis exposure was associated with a difference in IQ. Cannabis exposure was associated with worse attention scores in early childhood. Longitudinal studies assessing associations between child neurodevelopmental outcomes and prenatal nicotine and cannabis exposure with a focus on timing and quantity of exposure are needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00388297.

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.

SmartTots Outcomes Workshop 2017: Notes From a Round Table Discussion About Outcome Measures.

An important element of designing research studies is the selection of appropriate outcome measures to ensure that the question posed is properly answered given the evidence. The selection of outcome measures is especially important when tackling complex, interdisciplinary problems, where appropriate outcome measures may not be as simple as a blood test or a laboratory value. One such area of study is the research into neurodevelopmental outcomes after early exposure to anesthetic agents. Concern has arisen recently that certain anesthetic agents may be toxic to the developing brain; a public-private partnership, SmartTots, was formed in conjunction with the Food and Drug Administration and various stakeholders to develop safe anesthetic regimens for neonates and infants who require surgery. However, as research has progressed, questions have arisen regarding the best outcome measures to use in order to detect a true effect, as well as the optimal window in which to measure. These issues were discussed in a round table meeting during the SmartTots meeting in September 2017, and a summary of the discussion is presented here.

Systematic review of the neurocognitive outcomes used in studies of paediatric anaesthesia neurotoxicity.

BACKGROUND: Neurotoxicity of anaesthetics in developing brain cells is well documented in preclinical studies, yet results are conflicting in humans. The use of many and different outcome measures in human studies may contribute to this disagreement. METHODS: We conducted a systematic review to identify all measures used to assess long-term neurocognitive outcomes following general anaesthesia (GA) and surgery in children. The quality of studies was assessed according to the Newcastle-Ottawa Scale (NOS) for observational studies. PubMed/MEDLINE, EMBASE, Cinahl, Web of Science, and the Cochrane Library were searched for studies investigating neurocognitive outcome after GA in children <18 yr. RESULTS: Sixty-seven studies were identified from 19 countries during 1990-2017. Most assessments were performed within cognition, sensory-motor development, academic achievement or neuropsychological diagnosis. Few studies assessed other outcomes (magnetic resonance imaging, serum-biomarkers, mortality, neurological examination, measurement of head circumference, impairment of vision). Rating according to the NOS rewarded a mean of six stars out of nine. Some concerns prevail regarding potential inter-rater variability because of equivocal description of rating criteria. Specific features such as stability over lifetime and inter-relations of outcomes (e.g. prediction of subsequent development or diagnosis of neuropsychological conditions) are discussed. The importance of validity and reliability of the various test instruments are described. The studies vary immensely in important characteristics. CONCLUSIONS: Future observational studies should be more consistent in the choice of study population, age at exposure, follow-up, indication for and type of surgery, and outcomes. Assessment of sensory-motor development seems feasible in young children (age <4 yr), and intelligence/cognition in older children.

The burden of disease attributable to ambient PM2.5-bound PAHs exposure in Nagpur, India.

Exposure to PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) can elicit several types of cancer and non-cancer effects. Previous studies reported substantial burdens of PAH-induced lung cancer, but the burdens of other cancer types and non-cancer effects remain unknown. Thus, we estimate the cancer and non-cancer burden of disease, in disability-adjusted life years (DALYs), attributable to ambient PM2.5-bound PAHs exposure in Nagpur district, India, using risk-based approach. We measured thirteen PAHs in airborne PM2.5 sampled from nine sites covering urban, peri-urban and rural areas, from February 2013 to June 2014. We converted PAHs concentrations to benzo[a]pyrene equivalence (B[a]Peq) for cancer and non-cancer effects using relative potency factors, and relative toxicity factors derived from quantitative structure-activity relationships, respectively. We calculated time-weighted exposure to B[a]Peq, averaged over 30 years, and adjusted for early-life susceptibility to cancer. We estimated the DALYs/year using B[a]Peq exposure levels, published toxicity data, and severity of the diseases from Global Burden of Disease 2016 database. The annual average concentration of total PM2.5-bound PAHs was 458 ±â€¯246 ng/m3 and resulted in 49,500 DALYs/year (0.011 DALYs/person/year). The PAH-related DALYs followed this order: developmental (mostly cardiovascular) impairments (55.1%) > cancer (26.5%) or lung cancer (23.1%) > immunological impairments (18.0%) > reproductive abnormalities (0.4%).

Evaluating the evidence on genotoxicity and reproductive toxicity of carbon black: a critical review.

Carbon black is produced industrially by the partial combustion or thermal decomposition of gaseous or liquid hydrocarbons under controlled conditions. It is considered a poorly soluble, low toxicity (PSLT) particle. Recently, results from a number of published studies have suggested that carbon black may be directly genotoxic, and that it may also cause reproductive toxicity. Here, we review the evidence from these studies to determine whether carbon black is likely to act as a primary genotoxicant or reproductive toxicant in humans. For the genotoxicity endpoint, the available evidence clearly shows that carbon black does not directly interact with DNA. However, the study results are consistent with the mechanism that, at high enough concentrations, carbon black causes inflammation and oxidative stress in the lung leading to mutations, which is a secondary genotoxic mechanism. For the reproductive toxicity endpoint for carbon black, to date, there are various lung instillation studies and one short-term inhalation study that evaluated a selected number of reproduction endpoints (e.g. gestational and litter parameters) as well as other general endpoints (e.g. gene expression, neurofunction, DNA damage); usually at one time point or using a single dose. It is possible that some of the adverse effects observed in these studies may be the result of non-specific inflammatory effects caused by high exposure doses. An oral gavage study reported no adverse reproductive or developmental effects at the highest dose tested. The overall weight of evidence indicates that carbon black should not be considered a direct genotoxicant or reproductive toxicant.

Inhaled Drugs and Systemic Corticosteroids for Bronchopulmonary Dysplasia.

All definitions of bronchopulmonary dysplasia (BPD) have limitations and a new definition for the purpose of clinical research, benchmarking, and prognostic prediction is needed. Different inhaled and systemic drugs are currently used to prevent or treat BPD. Despite some positive effects on BPD, more information about the effects of inhaled corticosteroids is required to assess overall efficacy and associated risks. One needs to balance the risks of neurodevelopmental impairment owing to systemic corticosteroids against those of BPD itself. Future studies should, therefore, focus on infants with a very high risk of developing BPD and include pharmacokinetics and long-term developmental outcomes.

Role of TLR4 in olfactory-based spatial learning activity of neonatal mice after developmental exposure to diesel exhaust origin secondary organic aerosol.

Exposure to ambient air pollutants has been reported to have various adverse health impacts. Ambient particulate matter comprises primary particles released directly via engine exhaust and secondary organic aerosols (SOAs) formed from oxidative reactions of the ultrafine particle fraction of diesel exhaust (DE). Toll-like receptor 4 (TLR4) is well known to initiate the inflammatory cascade in the central nervous system. However, whether and how DE and DE-SOA exposure influences TLR4 signaling in the immature brain remains unclear. We attempted to evaluate the roles of TLR-4, inflammatory mediators and microglial markers in the impaired spatial learning ability of neonatal mice exposed to DE and DE-SOAs. Pregnant C3H/HeN (TLR4-intact) and C3H/HeJ (TLR4- mutated) mice were exposed to clean air, DE or DE-SOA from gestational day 14 to postnatal day (PND) 10 (5h/day for 5days) in exposure chambers. PND11 neonatal mice were examined for their performance in the olfactory-based spatial learning test. After the spatial learning test, the hippocampi of the mice were removed and real-time RT-PCR analysis was performed to examine the neurological and immunological markers. Both male and female C3H/HeN and C3H/HeJ neonatal mice exposed to DE and DE-SOAs showed poor performance in the test phase of spatial learning as compared to the mice exposed to clean air. However, this spatial learning deficit was prominent in C3H/HeJ neonatal mice. In the neonatal C3H/HeN male mice exposed to DE and DE-SOAs, the mRNA expression levels of the NMDA receptor subunits (NR1, NR2B), proinflammatory cytokines, tumor necrosis factor-α and cyclooxygenase-2, oxidative stress marker, heme oxygenase-1, and microglial marker, Iba1, in the hippocampus were significantly increased, but these changes were not observed in female mice. Our findings indicate that activation of the neuroimmune system and TLR4 signaling may possibly be involved in environmental pollutant-induced spatial learning impairment in neonatal mice.

Anaesthetic considerations for surgery in newborns.

Almost 30 years ago, the American Academy of Pediatrics Committee on Fetus and Newborn coauthored a policy statement strongly advocating for the use of anaesthesia in all neonates stating 'local or systemic pharmacologic agents now available permit relatively safe administration of anesthesia or analgesia to neonates undergoing surgical procedures and that such administration is indicated according to the usual guidelines for the administration of anesthesia to high-risk, potentially unstable patients'. With current techniques and advanced monitoring, preterm and full-term infants routinely undergo surgical procedures under general anaesthesia to repair congenital defects that were lethal in years past. Recent research in immature animal models, however, has shown evidence of enhanced neuroapoptosis and other signs of neurotoxicity with all of the currently used anaesthetic agents. There is also increasing concern about the potential adverse effects of perioperative hypotension and hypocapnia on neurocognitive development in infants. This review outlines the most recent animal and human evidence regarding the effects of general anaesthesia and anaesthetic-related haemodynamic changes on the developing brain of newborns.

Latent Class Analysis of Neurodevelopmental Deficit After Exposure to Anesthesia in Early Childhood.

INTRODUCTION: Although some studies have reported an association between early exposure to anesthesia and surgery and long-term neurodevelopmental deficit, the clinical phenotype of children exposed to anesthesia is still unknown. METHODS: Data were obtained from the Western Australian Pregnancy Cohort Study (Raine) with neuropsychological tests at age 10 years measuring language, cognition, motor function, and behavior. Latent class analysis of the tests was used to divide the cohort into mutually exclusive subclasses of neurodevelopmental deficit. Multivariable polytomous logistic regression was used to evaluate the association between exposure to surgery and anesthesia and each latent class, adjusting for demographic and medical covariates. RESULTS: In our cohort of 1444 children, latent class analysis identified 4 subclasses: (1) Normal: few deficits (n=1135, 78.6%); (2) Language and Cognitive deficits: primarily language, cognitive, and motor deficits (n=96, 6.6%); (3) Behavioral deficits: primarily behavioral deficits, (n=151, 10.5%); and (4) Severe deficits: deficits in all neuropsychological domains (n=62, 4.3%). Language and cognitive deficit group children were more likely to have exposure before age 3 (adjusted odds ratio [aOR], 2.11; 95% confidence interval [CI], 1.17-3.81), whereas a difference in exposure was not found between Behavioral or Severe deficit children (aOR, 1.00; 95% CI, 0.58-1.73, and aOR, 0.85; 95% CI, 0.34-2.15, respectively) and Normal children. CONCLUSIONS: Our results suggest that in evaluating children exposed to surgery and anesthesia at an early age, the phenotype of interest may be children with deficits primarily in language and cognition, and not children with broad neurodevelopmental delay or primarily behavioral deficits.

Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies.

Environmental exposure to methylmercury (MeHg) during development is of concern because it is easily incorporated in children's body both pre- and post-natal, it acts at several levels of neural pathways (mitochondria, cytoskeleton, neurotransmission) and it causes behavioral impairment in child. We evaluated the effects of prolonged exposure to 10-600nM MeHg on primary cultures of mouse cortical (CCN) and of cerebellar granule cells (CGC) during their differentiation period. In addition, it was studied if prenatal MeHg exposure correlated with altered antioxidant defenses and cofilin phosphorylation in human placentas (n=12) from the INMA cohort (Spain). Exposure to MeHg for 9days in vitro (DIV) resulted in protein carbonylation and in cell death at concentrations ≥200nM and ≥300nM, respectively. Exposure of CCN and CGC to non-cytotoxic MeHg concentrations for 5 DIV induced an early concentration-dependent decrease in cofilin phosphorylation. Furthermore, in both cell types actin was translocated from the cytosol to the mitochondria whereas cofilin translocation was found only in CGC. Translocation of cofilin and actin to mitochondria in CGC occurred from 30nM MeHg onwards. We also found an increased expression of cortactin and LIMK1 mRNA in CGC but not in CCN. All these effects were prevented by the antioxidant probucol. Cofilin phosphorylation was significantly decreased and a trend for decreased activity of glutathione reductase and glutathione peroxidase was found in the fetal side of human placental samples from the highest (20-40µg/L) MeHg-exposed group when compared with the low (<7µg/L) MeHg-exposed group. In summary, cofilin dephosphorylation and oxidative stress are hallmarks of MeHg exposure in both experimental and human systems.

Sex-Specific Alterations of White Matter Developmental Trajectories in Infants With Prenatal Exposure to Methamphetamine and Tobacco.

IMPORTANCE: Methamphetamine is a common illicit drug used worldwide. Methamphetamine and/or tobacco use by pregnant women remains prevalent. However, little is known about the effect of comorbid methamphetamine and tobacco use on human fetal brain development. OBJECTIVE: To investigate whether microstructural brain abnormalities reported in children with prenatal methamphetamine and/or tobacco exposure are present at birth before childhood environmental influences. DESIGN, SETTING, AND PARTICIPANTS: A prospective, longitudinal study was conducted between September 17, 2008, and February 28, 2015, at an ambulatory academic medical center. A total of 752 infant-mother dyads were screened and 139 of 195 qualified neonates were evaluated (36 methamphetamine/tobacco exposed, 32 tobacco exposed, and 71 unexposed controls). They were recruited consecutively from the community. EXPOSURES: Prenatal methamphetamine and/or tobacco exposure. MAIN OUTCOMES AND MEASURES: Quantitative neurologic examination and diffusion tensor imaging performed 1 to 3 times through age 4 months; diffusivities and fractional anisotropy (FA) assessed in 7 white matter tracts and 4 subcortical brain regions using an automated atlas-based method. RESULTS: Of the 139 infants evaluated, 72 were female (51.8%); the mean (SE) postmenstrual age at baseline was 41.5 (0.27) weeks. Methamphetamine/tobacco-exposed infants showed delayed developmental trajectories on active muscle tone (group × age, P < .001) and total neurologic scores (group × age, P = .01) that normalized by ages 3 to 4 months. Only methamphetamine/tobacco-exposed boys had lower FA (group × age, P = .02) and higher diffusivities in superior (SCR) and posterior corona radiatae (PCR) (group × age × sex, P = .002; group × age × sex, P = .01) at baseline that normalized by age 3 months. Only methamphetamine/tobacco- and tobacco-exposed girls showed persistently lower FA in anterior corona radiata (ACR) (group, P = .04; group × age × sex, P = .01). Tobacco-exposed infants showed persistently lower axial diffusion in the thalamus and internal capsule across groups (P = .02). CONCLUSIONS AND RELEVANCE: Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

Neonatal exposure to SERMs disrupts neuroendocrine development and postnatal reproductive function through alteration of hypothalamic kisspeptin neurons in female rats.

Selective estrogen receptor modulators (SERMs) are a class of therapeutic chemicals which present tissue-specific estrogen receptor modulating activity. Neonatal exposure to SERMs has been reported to adversely affect central nervous system development, however, mechanism and involvement of hypothalamic kisspeptin neurone in this impairment remains undetermined. To clarify this uncertainty, neonates from female Donryu rats were subcutaneously injected with raloxifene (RLX) at 0.1, 1, and 10mg/kg or tamoxifen (TMX) at 10mg/kg on postnatal day 0, and then hypothalamic KiSS1 mRNA expression and gonadotropin levels were investigated during young adulthood and estrous cycling was monitored until middle age. Treatment with RLX or TMX at 10mg/kg significantly depressed luteinizing hormone surge levels and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV), the control center of estrous cyclicity. The 10mg/kg TMX group also showed decreased levels of follicle-stimulating hormone and KiSS1 mRNA expression in the arcuate nucleus (ARC). Early cessation of normal estrous cycling was observed in the 10mg/kg RLX group, while the estrous cycle in the 10mg/kg TMX group had ceased by the start of the analysis. The same dose of tamoxifen or raloxifene had either weak-estrogenic or anti-estrogenic activity on the uterus, respectively; however, treatment in adulthood with both SERMs did not affect KiSS1 mRNA expression in either the AVPV or ARC in the present study. These results indicate that neonatal exposure to SERMs could disrupt neuroendocrine development and postnatal reproductive function through the alteration of kisspeptin neurons.

Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: Bevacizumab intravitreal injection, a vascular endothelial growth factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have been raised regarding its systemic absorption and effect on developing tissues including brain. This study compared neurodevelopment at 18 months' corrected age in preterm infants of <29 weeks' gestation treated with bevacizumab versus laser ablation. METHODS: Data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network databases were retrospectively reviewed. Infants born at <29 weeks' in 2010-2011 with treated ROP were studied. Neurodevelopmental outcome at 18 months was assessed by using neurologic examination and the Bayley Scales of Infant and Toddler Development Third Edition. Regression analyses were performed. RESULTS: Of 125 treated infants, 27 received bevacizumab and 98 laser. The bevacizumab group, compared with laser, obtained a median Bayley Scales of Infant and Toddler Development Third Edition motor composite score of 81 (interquartile range, 70-91) versus 88 (79-97), a language composite score of 79 (65-97) versus 89 (74-97), and a cognitive score of 90 (80-100) versus 90 (85-100). Difference was detected on the motor score only (P = .02). Odds of severe neurodevelopmental disabilities (Bayley scores <70, severe cerebral palsy, hearing aids, or bilateral blindness) was 3.1 times higher (95% confidence interval: 1.2-8.4) in infants treated with bevacizumab versus laser after adjusting for gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score, bronchopulmonary dysplasia, sepsis, and severe brain injury. CONCLUSIONS: Preterm infants treated with bevacizumab versus laser had higher odds of severe neurodevelopmental disabilities. Further investigation on the long-term safety of antivascular endothelial growth factor treatment of ROP is needed.

Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome.

OBJECTIVES: Despite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure. METHODS: Cumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane, and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5 years, including full-scale IQ, verbal IQ, performance IQ, and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link. RESULTS: Cumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5 hours). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (P's < .05) alone and after adjusting for relevant covariates. CONCLUSIONS: Increased cumulative MAC-hrs exposure to VAA is associated with worse ND outcomes in certain domains in children with HLHS and variants.

In utero exposure to carcinogens: Epigenetics, developmental disruption and consequences in later life.

The uterine environment is often viewed as a relatively safe haven, being guarded by the placenta which acts as a filter, permitting required materials to enter and unwanted products to be removed. However, this defensive barrier is sometimes breached by potential chemical hazards to which the mother may be subjected. Many of these toxins have immediate and recognisable deleterious effects on the embryo, foetus or neonate, but a few are insidious and leave a legacy of health issues that may emerge in later life. Several substances, falling into the categories of metals and metalloids, endocrine disruptors, solvents and other industrial chemicals, have been implicated in the development of long-term health problems in the offspring following maternal and subsequent in utero exposure. The mechanisms involved are complex but often involve epigenetic changes which disrupt normal cell processes leading to the development of cancers and also dysregulation of biochemical pathways.

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

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

Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants.

OBJECTIVE: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. METHODS: A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. RESULTS: Total midazolam dose predicted decreased hippocampal volumes (ß = -1.8, p < 0.001) and increased MD (ß = 0.002, p = 0.02), whereas invasive procedures did not (ß = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (ß = -0.31, p = 0.003), midazolam dose (ß = -0.27, p = 0.03), and surgery (ß = -8.32, p = 0.04). INTERPRETATION: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.

Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.

UNLABELLED: Risk assessments of arsenic have focused on skin, bladder, and lung cancers and skin lesions as the sensitive cancer and non-cancer health endpoints, respectively; however, an increasing number of epidemiologic studies that can inform risk assessment have examined neurodevelopmental effects in children. We conducted a systematic review and risk assessment based on the epidemiologic literature on possible neurodevelopmental effects at lower arsenic exposures. Twenty-four cross-sectional, case-control, and cohort studies were identified that report on the association between low-level arsenic exposure (i.e., largely <100 µg/L of arsenic in drinking water) and neurological outcomes in children. Although the overall evidence does not consistently show a causal dose-response relationship at low doses, the most rigorously conducted studies from Bangladesh indicate possible inverse associations with cognitive function, predominantly involving concurrent arsenic exposure as measured by biomarkers (i.e., arsenic in urine or blood) and raw verbal test scores at ages 5-11 years. Issues such as non-comparability of outcome measures across studies; inaccuracies of biomarkers and other measures of inorganic arsenic exposure; potential effect modification by cultural practices; insufficient adjustment for nutritional deficiencies, maternal IQ, and other important confounders; and presence of other neurotoxicants in foreign populations limit generalizability to U.S. POPULATIONS: Of the few U.S. studies available, the most rigorously conducted study did not find a consistent dose-response relationship between arsenic concentrations in tap water or toenails and decrements in IQ scores. Assuming that the strongest dose-response relationship from the most rigorous evidence from Bangladesh is generalizable to U.S. populations, possible reference doses were estimated in the range of 0.0004-0.001 mg/kg-day. These doses are higher than the U.S. Environmental Protection Agency reference dose for chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks.

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats.

Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum.