The metabolic adverse effects of antipsychotic use in individuals with intellectual and/or developmental disability: A systematic review and meta-analysis.

OBJECTIVE: Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population. METHODS: We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta-analyses were used to examine weight gain as both a continuous and dichotomous outcome. RESULTS: Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference = 1.10 kg, [0.79, 1.40], p < 0.00001, I2  = 54%; Dichotomous: odds ratio = 3.94, [2.15, 7.23], p < 0.00001, I2  = 0). Sub-group analysis revealed no significant effect of AP type. Data regarding the effects of APs on other metabolic outcomes were limited. CONCLUSION: This review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long-term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals.

Reproductive and developmental toxicity screening study of an acetone extract of rosemary.

In 2017, JECFA requested reproductive and developmental toxicity studies to finalize an acceptable daily intake for solvent rosemary extracts. Thus, an OECD 421 reproductive/developmental toxicity study was conducted using an acetone rosemary extract that complied with JECFA and EFSA food additive specifications. Rosemary extract was provided to rats at dietary concentrations of 0 (control), 2100, 3600, or 5000 mg/kg, for 14 days before mating, during mating, and thereafter (throughout gestation and up to Lactation Day 13 for females) until necropsy. General toxicity (clinical signs, body weight, food consumption) and reproductive/developmental outcomes (fertility and mating performance, estrous cycles, anogenital distance, thyroid hormones, reproductive organ weights, thyroid histopathology) were assessed. There were no signs of general toxicity and no effects on reproduction; thus, the highest concentration tested (equivalent to mean daily intakes of 316 or 401 mg/kg bw/day [149 or 189 mg/kg bw/day carnosol and carnosic acid] for males and females, respectively) was established as the no-observed-adverse-effect level for general and reproductive toxicity. Dose-related reductions in T4 were observed for Day 13 pups (not seen on Day 4) but were not accompanied by thyroid weight changes or histopathological findings; further investigations are required to determine the biological relevance of these T4 reductions.

Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure.

BACKGROUND: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1ß, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-ß, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

In utero exposure to analgesic opioids and language development in 5-year old children.

PURPOSE: An increasing consumption of opioids has been reported. The primary aim of the present study was follow-up of neurocognitive development in children exposed to analgesic opioids during pregnancy, using three different validated instruments to assess language and communication development at 5 years. METHODS: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women 1999 to 2008. Participants reported medication use at pregnancy week 17/18 and 30, and 6 months after birth. Children's language competence and communication skills at 5 years were reported by mothers on three different validated scales; The Ages and Stages Questionnaire (ASQ), The Speech and Language Assessment Scale (SLAS) and The Twenty Statements about Language-Related Difficulties list (Language20Q). RESULTS: A total of 27 428 women with 33 407 singleton pregnancies were included. Use of analgesic opioids was reported in 584 pregnancies (1.7%). No associations between opioid use and lower language competence or communication skills were found. For ASQ, the OR of being in the lowest category vs the group with maximum mean score was 0.82 (95%CI 0.57, 1.17), for SLAS the OR of scoring worse than typical for age vs better than typical for age was 0.84 (0.61, 1.17) in children exposed to opioids in utero. For Language20Q using the best performance category as reference, the OR of scoring in the lower performance category was 0.57 (0.35, 0.91) with exposure to opioids. CONCLUSION: Use of analgesic opioids in pregnant women does not seem to negatively affect language development or communication skills in children at 5 years.

Leveraging complementary computational models for prioritizing chemicals of developmental and reproductive toxicity concern: an example of food contact materials.

The evaluation of developmental and reproductive toxicity of food contact materials (FCMs) is an important task for food safety. Since traditional experiments are both time-consuming and labor-intensive, only a small number of FCMs have sufficient toxicological data for evaluating their effects on human health. While computational methods such as structural alerts and quantitative structure-activity relationships can serve as first-line tools for the identification of chemicals of high toxicity concern, models with binary outputs and unsatisfied accuracy and coverage prevent the use of computational methods for prioritizing chemicals of high concern. This study proposed a genetic algorithm-based method to develop a weight-of-evidence (WoE) model leveraging complementary methods of structural alerts, quantitative structure-activity relationships and in silico toxicogenomics models for chemical prioritization. The WoE model was applied to evaluate 623 food contact chemicals and identify 26 chemicals of high toxicity concern, where 13 chemicals have been reported to be developmental or reproductive toxic and further experiments are suggested for the remaining 13 chemicals without toxicity data related to developmental and reproductive effects. The proposed WoE model is potentially useful for prioritizing chemicals of high toxicity concern and the methodology may be applied to toxicities other than developmental and reproductive toxicity.

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.

Developmental outcomes following prenatal exposure to methamphetamine: A Western Australian perspective.

AIM: To describe neurodevelopmental outcomes among a cohort of Western Australian infants exposed to maternal methamphetamine use during pregnancy and to determine whether the Ages and Stages Questionnaire is a reliable screening tool for this population. METHODS: Methamphetamine-using women were approached for participation when referred to the state-wide perinatal specialist drug and alcohol service for pregnancy care. Drug use during pregnancy was self-reported in each trimester using a standardised questionnaire. Ages and Stages Questionnaires were completed by infant care givers at 4 and 12 months, and development was formally assessed at 12 months using the Griffiths Mental Development Scales. Griffiths results for term-born infants in our cohort were compared to a Western Australian historical cohort of 443 healthy 1-2-year-olds. RESULTS: A total of 112 methamphetamine-using pregnant women participated in the study, who gave birth to 110 live-born infants. Ages and Stages Questionnaires were completed for 89 (81%) and 78 (71%) of the infants at 4 and 12 months, respectively. The Ages and Stages assessment identified 30 infants (33.7%) as having a potential developmental delay at 4 months and 29 infants (38.7%) as having a potential developmental delay at 12 months. Griffiths assessments were performed on 64 (58%) of the infants, with a mean general quotient of 92.7. This was significantly lower in term-born babies compared to the historical cohort (who had a median general quotient of 113.0). There was a weak correlation between 12-month Ages and Stages scores and Griffiths general quotients (r = 0.322) and no correlation between 4-month Ages and Stages Questionnaire scores and later Griffiths results. CONCLUSIONS: Infants born to women reporting methamphetamine use during pregnancy are at increased risk of developmental delay and may warrant enhanced developmental follow-up. However, they are a challenging group to follow due to complex psychosocial factors. Ages and Stages Questionnaires at 4 and 12 months were not helpful in screening for infants who had a developmental delay at 12 months.

Impact of anesthesia exposure in early development on learning and sensory functions.

Each year, millions of children undergo anesthesia, and both human and animal studies have indicated that exposure to anesthesia at an early age can lead to neuronal damage and learning deficiency. However, disorders of sensory functions were not reported in children or animals exposed to anesthesia during infancy, which is surprising, given the significant amount of damage to brain tissue reported in many animal studies. In this review, we discuss the relationship between the systems in the brain that mediate sensory input, spatial learning, and classical conditioning, and how these systems could be affected during anesthesia exposure. Based on previous reports, we conclude that anesthesia can induce structural, functional, and compensatory changes in both sensory and learning systems. Changes in myelination following anesthesia exposure were observed as well as the neurodegeneration in the gray matter across variety of brain regions. Disproportionate cell death between excitatory and inhibitory cells induced by anesthesia exposure can lead to a long-term shift in the excitatory/inhibitory balance, which affects both learning-specific networks and sensory systems. Anesthesia may directly affect synaptic plasticity which is especially critical to learning acquisition. However, sensory systems appear to have better ability to compensate for damage than learning-specific networks.

A Birth Cohort Study on the Genetic Modification of the Association of Prenatal Methylmercury With Child Cognitive Development.

Genetic predisposition might affect neurodevelopmental outcomes of prenatal methylmercury exposure. We examined suspected heterogeneities for modification of exposure-related neurodevelopment in children from the Avon Longitudinal Study of Parents and Children (1991-2000), Bristol, United Kingdom. A subgroup (n = 1,127 from a pilot study and 1,045 from the present study) was identified based on the availability of the mercury concentration of cord tissue as a measure of prenatal methylmercury exposure, data on 247 single-nucleotide polymorphisms (SNPs), and Wechsler Intelligence Scale for Children intelligence quotient (IQ) scores. Log10-transformed mercury concentration was positively associated with IQ, but adjustment for confounding cofactors attenuated this association. A finding of enhanced interaction with methylmercury was replicated in this study for the minor allele of rs1042838 (progesterone receptor) (ß = -11.8, 95% confidence interval: -23.0, -0.6; P for interaction = 0.004) and weakly for rs662 (paraoxonase 1) (ß = -3.6, 95% confidence interval: -11.4, 4.3; P = 0.117). In the joint sample, new interacting single-nucleotide polymorphisms were discovered in relation to superoxide dismutase 2, ATP binding cassette subfamily A member 1, and metallothionein 1M genes. While the low-level prenatal exposure to methylmercury was not associated with child cognition, progesterone receptor rs1042838 minor alleles revealed a negative association of mercury exposure with IQ.

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds.

INTRODUCTION: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. MATERIAL AND METHODS: Data on AED exposure, pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. RESULTS: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. CONCLUSIONS: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information.

Serum NGF levels may be associated with intrauterine antiepileptic exposure-related developmental problems.

OBJECTIVE: It has been shown that maternal epilepsy and antiepileptic drug use during pregnancy have adverse developmental outcomes in children. The aim of this study was to investigate the developmental outcomes of maternal epilepsy and prenatal antiepileptic exposure. We also looked for the associations between serum levels of glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) and developmental outcomes. METHODS: This is a retrospective, nonrandomized, case-controlled study. Fifty-three children aged two to six years old with maternal epilepsy were included in the case group. Fifty-three age- and gender-matched children without maternal epilepsy were included in the control group. Developmental assessment was conducted using the Denver II Developmental Screening Test (DDST-II). Serum levels of NGF and GDNF were measured using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Multiple regression analysis revealed that prenatal antiepileptic exposure was significantly associated with lower global developmental scores (B = -7.5, confidence interval (CI): -13.1; -1.9, p = 0.009) while periconceptional folate use was associated with a reduced risk for adverse developmental outcomes (B = 6.6, CI: 0.91; 12.3, p = 0.024). Children with prenatal antiepileptic exposure are at increased risk for global developmental delay (GDD) particularly for language domain (p = 0.018). We found a statistically significant positive correlation between NGF levels and global developmental scores (r = 0.302, p = 0.009). Serum levels of GDNF in children with maternal epilepsy were significantly lower than the children without maternal epilepsy (p = 0.025). CONCLUSIONS: Prenatal antiepileptic exposure was related with the increased risk of GDD while periconceptional folate use was related with lower risk. Clinicians should inform all women in reproductive age with epilepsy about the possible benefits and risks of antiepileptic drug use during a possible pregnancy. Periconceptional folate use has protective effect on child development, and all women on antiepileptic drugs should be encouraged for periconceptional folate use. Serum NGF levels may be a promising biomarker for monitoring global development delay in at-risk population.

Parental perception on the effects of early exposure to anaesthesia on neurodevelopment.

Several studies have investigated the effects of general anaesthesia on neurodevelopment in children, with conflicting results. The potential for early general anaesthesia exposure to impact neurodevelopment in children may cause significant concern for parents. Administering a questionnaire in 200 parents, we aimed to explore their knowledge, concerns and perceptions, and determine factors which influence parents' willingness for their children to participate in relevant research studies. A significant proportion of parents (40%) were concerned that general anaesthesia may affect their child's neurodevelopment. Generally these concerns arose from the parents' own beliefs or preconceived ideas and only 25.5% had encountered prior information in this domain. Parents with children aged 2 years or younger, those whose children had previous general anaesthesia exposure, and those who had encountered information about potential neurodevelopmental effects were most likely to be concerned. The majority of parents (68%) would agree to participate in research studies, especially if they were able to receive the test results. Anaesthetists should pre-emptively initiate discussions to address any potential misconceptions regarding the effects of general anaesthesia on neurodevelopment in children.

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.

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.

Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year-old Vietnamese children.

BACKGROUND: We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children's eating behavior, which is often altered in those with developmental disorders. METHODS: A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children's Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children's gestational age at delivery, and children's age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores. RESULTS: There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-p-dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9-octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls. CONCLUSIONS: Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure.

The reproductive and developmental toxicity of nanoparticles: A bibliometric analysis.

Because of the advantages of nanoparticles (NPs) in a variety of industrial, biomedical, and consumer applications, they are intentionally (such as in medicine) or unintentionally (environment exposure) introduced into the human body. However, to date, the detrimental effects of NPs are still unclear, especially in reproductive and developmental toxicity. In this study, we researched 266 articles related to the reproductive and developmental toxicity of NPs from 2006 to December 2016 based on the database of the Web of Science. According to the bibliometric analysis, we found that China and the United States were the leading countries in this field and the major research trends might focus on the pathogenesis of NPs, such as oxidative stress, inflammation, and DNA damage. By this analysis, we provide new insights into the research trends and characteristics of the field.

The risks associated with the use of lamotrigine during pregnancy.

OBJECTIVE: This paper reviewed the relevant literature on the effects of lamotrigine on pregnancy outcomes to provide useful information regarding lamotrigine use in pregnant women with bipolar disorder. METHODS: A systematic search of electronic databases and other original sources was conducted that examined the effects of lamotrigine on pregnancy outcomes. RESULTS: It is not clear that foetuses of lamotrigine-exposed pregnant women are at higher risk of malformation or neurodevelopmental delay. When treating pregnant women with bipolar disorder, the risks associated with lamotrigine use have to be balanced with the risks of uncontrolled maternal symptoms. The information obtained from our review of psychotropic medications will assist clinicians in managing pregnant women with bipolar disorder. CONCLUSIONS: Although lamotrigine has emerged as the safest mood stabiliser for use during pregnancy based on the clinical evidence thus far, further studies are needed to inform the best clinical practice when treating bipolar disorder in pregnant women.

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.

From Shortage to Surge: A Developmental Switch in Hippocampal-Prefrontal Coupling in a Gene-Environment Model of Neuropsychiatric Disorders.

Cognitive deficits represent a major burden of neuropsychiatric disorders and result in part from abnormal communication within hippocampal-prefrontal circuits. While it has been hypothesized that this network dysfunction arises during development, long before the first clinical symptoms, experimental evidence is still missing. Here, we show that pre-juvenile mice mimicking genetic and environmental risk factors of disease (dual-hit GE mice) have poorer recognition memory that correlates with augmented coupling by synchrony and stronger directed interactions between prefrontal cortex and hippocampus. The network dysfunction emerges already during neonatal development, yet it initially consists in a diminished hippocampal theta drive and consequently, a weaker and disorganized entrainment of local prefrontal circuits in discontinuous oscillatory activity in dual-hit GE mice when compared with controls. Thus, impaired maturation of functional communication within hippocampal-prefrontal networks switching from hypo- to hyper-coupling may represent a mechanism underlying the pathophysiology of cognitive deficits in neuropsychiatric disorders.

Intelligence quotient scores at the age of 6 years in children anaesthetised before the age of 5 years.

We analysed the association of independent variables with non-verbal cognition at 6 years in children with complete data (3441 from a cohort of 9901), of whom 415 were anaesthetised before the age of 5 years. Using multivariable regression, cognition was reduced by a mean (95% CI) score for children: anaesthetised before the age of 5 years, 2.1 (0.7-3.5), p = 0.004; born prematurely, 9.8 (4.1-15.4), p = 0.001; whose mothers smoked while pregnant, 2.3 (0.8-3.8), p = 0.004; whose mothers had lower IQ scores, 0.3 (0.2-0.3) for each unit reduction in maternal IQ, p < 0.0001. The association of child IQ with exposure to anaesthetic drugs was sensitive to missing data.