Neurodevelopmental Parameters Research Articles

Effect of Gender on Metabolic and Neurodevelopmental Parameters of Postnatally Growth-Restricted Rats Undergoing Catch-Up Growth.

To determine the long-term effects of early postnatal malnutrition and various degrees of catch-up growth on metabolic (serum glucose, leptin, triacylglycerides) and neurodevelopmental parameters (learning and memory) among male and female rodent models, mimicking human preterm infants. Randomized controlled trial. Place and Duration of the Study: CMH Multan Insitute of Medical Sciences, from September 2021 to December 2021. This study included 142 neonatal Wister rats, stratified into subgroups to mimic the human preterm infant model of postnatal malnutrition and catch-up growth. Metabolic consequences were assessed via serum analysis of glucose, leptin, and triacylglycerides. The neurocognitive comparison was made among subgroups via a passive avoidance test. Gender-specific comparison of all quantitative parameters was made among subgroups. Malnourished rats with accelerated catch-up growth achieved similar weight gain as normally fed rats when provided with adlibitum feeding in both males (p = 0.92) and females (p >0.99). Rats undergoing accelerated catch-up growth exhibited higher fasting serum glucose levels compared to those undergoing no, or normal catch-up growth (p <0.001). Malnourished female rats undergoing accelerated (p = 0.007), or no catchup growth (p = 0.004) exhibited significant deficits in learning and memory as compared to normally fed rats. Female malnourished rats with normal catchup growth exhibited no neurocognitive deficit as compared to normally fed rats (p = 0.08). Accelerated catch-up growth effectively addresses somatic growth disparities, while normal catch-up growth offers more favourable metabolic and neurodevelopmental outcomes. Particularly, female malnourished rats exhibited poor neurodevelopment in response to both accelerated and no catch-up growth. Gender-specific variations in neurodevelopment underscore the need for personalised care approaches for preterm nutritional care. Growth retardation, Leptin, Extrauterine growth restriction, Malnutrition, Neurodevelopment.

Effects of paternal ionizing radiation exposure on fertility and offspring's health.

The intergenerational effects of ionizing radiation remain controversial. Extensive insights have been revealed for DNA mutations and cancer incidence in progeny, yet many of these results were obtained by immediate post-radiation mating. However, conception at short times after radiation exposure is likely to be avoided. After a long period of fertility recovery, whether unexposed sperm derived from exposed spermatogonia would challenge the health of the offspring is not yet clearly demonstrated. Ten-week-old C57BL/6J males underwent whole-body acute γ irradiation at 0 and 6.4 Gy. Testes and sperm were collected at different times after radiation to examine reproductive changes. The reproductive, metabolic, and neurodevelopmental parameters were measured in the offspring of controls and the offspring derived from irradiated undifferentiated spermatogonia. Paternal fertility was lost after acute 6.4 Gy γ radiation and recovered at 10-11 weeks post irradiation in mice. The reproductive, metabolic, and neurodevelopmental health of offspring born to irradiated undifferentiated spermatogonia were comparable to those of controls. The male mice could have healthy offspring after recovery from the damage caused by ionizing radiation.

Predictive Value of MRI in Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a severe pathology, and no unique predictive biomarker has been identified. Our aims are to identify associations of perinatal and outcome parameters with morphological anomalies and ADC values from MRI. The secondary aims are to define a predictive ADC threshold value and detect ADC value fluctuations between MRIs acquired within 7 days (MR0) and at 1 year (MR1) of birth in relation to perinatal and outcome parameters. Fifty-one term children affected by moderate HIE treated with hypothermia and undergoing MRI0 and MRI1 were recruited. Brain MRIs were evaluated through the van Rooij score, while ADC maps were co-registered on a standardized cerebral surface, on which 29 ROIs were drawn. Statistical analysis was performed in Matlab, with the statistical significance value at 0.05. ADC0 < ADC1 in the left and right thalami, left and right frontal white matter, right visual cortex, and the left dentate nucleus of children showing abnormal perinatal and neurodevelopmental parameters. At ROC analysis, the best prognostic ADC cut-off value was 1.535 mm2/s × 10-6 (sensitivity 80%, specificity 86%) in the right frontal white matter. ADC1 > ADC0 in the right visual cortex and left dentate nucleus, positively correlated with multiple abnormal perinatal and neurodevelopmental parameters. The van Rooij score was significantly higher in children presenting with sleep disorders. ADC values could be used as prognostic biomarkers to predict children's neurodevelopmental outcomes. Further studies are needed to address these crucial topics and validate our results. Early and multidisciplinary perinatal evaluation and the subsequent re-assessment of children are pivotal to identify physical and neuropsychological disorders to guarantee early and tailored therapy.

Maternal pre-eclampsia serum increases neurite growth and mitochondrial function through a potential IL-6-dependent mechanism in differentiated SH-SY5Y cells.

Introduction: Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy, which affects 3%-5% of first-time pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Prenatal exposure to PE is associated with an increased risk of neurodevelopmental disorders in affected offspring, although the cellular and molecular basis of this increased risk is largely unknown. Methods: Here, we examined the effects of exposure to maternal serum from women with PE or a healthy uncomplicated pregnancy on the survival, neurite growth and mitochondrial function of neuronally differentiated human SH-SY5Y neuroblastoma cells, which are commonly used to study neurite growth. Neurite growth and mitochondrial function are two strongly linked neurodevelopmental parameters in which alterations have been implicated in neurodevelopmental disorders. Following this, we investigated the pleiotropic cytokine interleukin-6 (IL-6) levels as a potential mechanism. Results: Cells exposed to 3% (v/v) PE serum for 72h exhibited increased neurite growth (p < 0.05), which was validated in the human neural progenitor cell line, ReNcell® VM (p < 0.01), and mitochondrial respiration (elevated oxygen consumption rate (p < 0.05), basal mitochondrial respiration, proton leak, ATP synthesis, and non-mitochondrial respiration) compared to control serum-treated cells. ELISA analysis showed elevations in maternal IL-6 in PE sera (p < 0.05) and placental explants (p < 0.05). In support of this, SH-SY5Y cells exposed to 3% (v/v) PE serum for 24h had increased phospho-STAT3 levels, which is a key intracellular mediator of IL-6 signalling (p < 0.05). Furthermore, treatment with anti-IL-6 neutralizing antibody blocked the effects of PE serum on neurite growth (p < 0.05), and exposure to IL-6 promoted neurite growth in SH-SY5Y cells (p < 0.01). Discussion: Collectively these data show elevated serum levels of maternal IL-6 in PE, which increases neurite growth and mitochondrial function in SH-SY5Y cells. This rationalizes the further study of IL-6 as a potential mediator between PE exposure and neurodevelopmental outcome in the offspring.

Air pollution during the perinatal period and neurodevelopment in children: A national population study in Taiwan.

To evaluate the association between ambient particulate matter no larger than 2.5 μm in diameter (PM2.5 ) during the prenatal and postnatal periods and infant neurodevelopmental parameters. We conducted a population-based birth cohort study using the Taiwan Birth Cohort Study. Participants were assessed for developmental conditions through home interviews at 6 months and 18 months of age. Exposure to PM2.5 of mothers and infants during perinatal periods was estimated using hybrid kriging/land-use regression. The exposure was linked to each participant by home address. Logistic regression was then conducted to determine the risk of neurodevelopmental delay in relation to PM2.5 . A total of 17 683 term singletons without congenital malformations were included in the final analysis. PM2.5 during the second trimester was associated with increased risks of delays in gross motor neurodevelopmental milestones (adjusted odds ratio [aOR] 1.09 per 10 μg/m3 increase in exposure to PM2.5 ). Delayed fine motor development was also found to be related to exposure to PM2.5 in the second and third trimesters (aOR 1.06), as was personal-social skill (aOR 1.11 for the second trimester and 1.06 for the third). These neurodevelopmental parameters were unrelated to postnatal PM2.5 exposure. Exposure to ambient PM2.5 during pregnancy was significantly related to delay in gross motor, fine motor, and personal-social development in this population-based study. Prenatal exposure to higher PM2.5 was associated with increased risk of delayed early neurodevelopment. The critical period for delayed gross motor development was the second trimester. The critical period for fine motor and personal-social development was the second and third trimesters.

Long-Term Persistence of Mitochondrial DNA Instability in HIV-Exposed Uninfected Children during and after Exposure to Antiretroviral Drugs and HIV.

HIV-exposed uninfected (HEU) children show impaired health outcomes during childhood. A high rate of mitochondrial DNA (mtDNA) instability was reported in the blood of HEU at birth. We aimed to explore the relationship between these health outcomes and mtDNA deletions over time in a case series of 24 HEU children. MtDNA instability was assessed by deep sequencing and analyzed by eKLIPse-v2 algorithm at three time points, namely birth, 1 year, and 6 years of age. Association between mtDNA deletion and health outcomes, including growth, clinical, and neurodevelopmental parameters, were explored using univariate statistical analyses and after stratification with relevant variables. HEU children were selected with an equal male:female ratio. An elevated number of mtDNA deletions and duplications events was observed at 7 days’ post-partum. Median heteroplasmy increased at one year of life and then returned to baseline by six years of age. The mtDNA instability was acquired and was not transmitted by the mother. No risk factors were significantly associated with mtDNA instability. In this small case series, we did not detect any association between any health outcome at 6 years and mtDNA instability measures. A significant effect modification of the association between the duration of maternal prophylaxis and child growth was observed after stratification with heteroplasmy rate. Genomic instability persists over time among HEU children but, despite its extension, stays subclinical at six years.

Childhood neurodevelopmental markers and risk of premature mortality: Follow-up to age 60-65 years in the Aberdeen Children of the 1950s study.

BackgroundIndividual neurodevelopmental disorders are associated with premature mortality. Little is known about the association between multiple neurodevelopmental markers and premature mortality at a population level. The ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) approach considers multiple neurodevelopmental parameters, assessing several markers in parallel that cluster, rather than considering individual diagnostic categories in isolation.ObjectivesTo determine whether childhood neurodevelopmental markers, including reduced intellectual functioning, are associated with all-cause premature mortality.Methods and proceduresIn a general population cohort study (n = 12,150) with longitudinal follow up from childhood to middle age, Cox proportional hazard models were used to study the associations between childhood neurodevelopmental markers (Rutter B scale and IQ) and premature all-cause mortality.Outcomes and resultsThe cognitive measures and 21 of the 26 Rutter B items were significantly associated with premature mortality in bivariate analyses with hazard ratios from 1.24 (95% CI 1.05–1.47) to 2.25 (95% CI 1.78–2.90). In the final adjusted model, neurodevelopmental markers suggestive of several domains including hyperactivity, conduct problems and intellectual impairment were positively associated with premature mortality and improved prediction of premature mortality.ConclusionsA wide range of neurodevelopmental markers, including childhood IQ, were found to predict premature mortality in a large general population cohort with longitudinal follow up to 60–65 years of age.ImplicationsThese findings highlight the importance of a holistic assessment of children with neurodevelopmental markers that addresses a range of neurodevelopmental conditions. Our findings could open the door to a shift in child public mental health focus, where multiple and/or cumulative markers of neurodevelopmental conditions alert clinicians to the need for early intervention. This could lead to a reduction in the risk of broad health outcomes at a population level.

A study of clinical, etiological and neurodevelopmental profile of epilepsy in children aged 0-5 years

Background: Seizures constitute the most common neurological problem in children. Appropriate diagnosis and management of childhood epilepsy is essential to improve quality of life in them. Objectives of the study were to study the clinical and etiological profile of early childhood epilepsy and its effect on neurodevelopment.Methods: This was a time bound study; duration being one year from September, 2018 to September 2019. All new patients with acute seizures or status epilepticus admitted in paediatric emergency ward were evaluated and those meeting inclusion criteria were enrolled. On the basis of history, neurological and systemic examination and available investigations primary diagnosis of epilepsy was reached. Neurodevelopmental parameters like vision, hearing, and DQ were assessed. EEG was done in all patients. Other relevant investigations like neuroimaging were carried out when indicated. Collected data was analysed in form of frequency and percentage.Results: A total of 52 patients were enrolled. 60% patients were younger than 2 years. Maximum patients had generalised convulsions; generalised tonic-clonic being the most prevalent. 38% patients had significant perinatal complications like perinatal asphyxia, pyogenic meningitis and kernicterus. Fifty per cent patients had delayed milestones and half of those had severe delay. 67% had abnormal EEG and 20 patients had abnormal neuro-imaging findings. The most common etiologies for epilepsy were hypoxic ischaemic encephalopathy, idiopathic, epilepsy syndromes, metabolic disorders and CNS infections.Conclusions: Majority of early childhood epilepsy is a result of either genetic conditions or perinatal events. They have neurodevelopmental and behavioural associations. While treating epilepsy all these factors should be considered in order to ensure a near-normal life for these patients.

Association of Environmental Tobacco Smoke Exposure and Infant Neurodevelopmental Achievements and Effect Modification by Maternal Overweight and Obesity: Results from the Taiwan Birth Cohort Study

Background: Environmental tobacco smoke (ETS) is a common indoor air pollutant associated with multiple adverse health effects, but it remains unclear regarding effect modifiers and susceptible groups for detrimental neurodevelopmental effect of ETS. We examine the associations between ETS exposure and infant neurodevelopmental parameters in a national-wide representative population. Methods: We extracted the information via structured questionnaires upon home interview from Taiwan Birth Cohort Study (TBCS). The associations between ETS exposure and infant neurodevelopmental milestones were evaluated with multivariate conditional logistic regression and the Cox model and with propensity score (PS) weighting and matching based upon preselected covariates. Results: In this study, 15 987 term singletons were included, and 3598 mother-infant pairs were further selected to PS-matched subpopulation. Higher ETS exposure was associated with increased likelihood of delay in caregiver-reported fine motor (adjusted odds ratio (aOR)=1.29, 95% CI=1.07-1.55; adjusted hazard ratio (aHR)=1.06, 95% CI=1.01-1.11 for clapping hands; aOR=1.21, 95% CI=1.03-1.43; aHR=1.05, 95% CI=1.00-1.10 for scribbling), language-related (aOR=1.25, 95% CI=1.03-1.50; aHR=1.08, 95% CI=1.03-1.13 for waving goodbye; aOR=1.22, 95% CI=1.01-1.47; aHR=1.08, 95% CI=1.04-1.14 for calling a parent meaningfully), and it was consistent in PS-weighted, PS-matched, and among non-smoking families. We also detected positive interaction for both maternal overweight and obesity before pregnancy and after delivery upon the association between high ETS exposure and delayed milestone achievement in scribbling. Conclusions: Maternal peripartum ETS exposure was associated with delayed neurodevelopmental milestone achievement at eighteen months among non-smoking families, and effect modification by maternal overweight and obesity status indicated possible intervention targets for pregnant women.

Successful Management of a Complicated Mirror Syndrome: A Case Presentation

Mirror syndrome is a rare but serious condition of pregnancy characterized by fetal hydrops of any cause and maternal edema that has severe maternal and fetal morbidity and mortality. In most cases, the pregnancy should be terminated to resolve the symptoms. Some cases with mirror syndrome resolve spontaneously due to the demise of the hydropic fetus or fetal infection with parvovirus. This case is a rare complicated mirror syndrome that managed conservatively up to 34 weeks and 3 days of gestation. This case was a unique Dichorionic Diamniotic (DCDA) twin pregnancy with mirror syndrome, that feticide of the hydropic fetus has resolved symptoms of mirror syndrome. Although the mother’s liver enzyme increased after 3 weeks of feticide, we managed to save pregnancy by conservative treatment until 34 weeks and 3 days of gestation. Finally, the mother had a cesarean section delivery. The baby is now 6 months old with normal neurodevelopmental parameters. This case suggests that preeclampsia can happen after feticide due to twin pregnancy and the retained placenta. If we consider this event, we can manage pregnancy conservatively as a preeclamptic patient.

Perioperative neonatal brain injury is associated with worse school‐age neurodevelopment in children with critical congenital heart disease

To assess the impact of perioperative neonatal brain injury and brain volumes on neurodevelopment throughout school-age children with critical congenital heart disease (CHD). Thirty-four survivors of neonatal cardiac surgery (seven females, 27 males) were included. Neonatal preoperative and postoperative cerebral magnetic resonance imaging was performed and neurodevelopment was assessed at 24months (SD 0.7, n=32, using Bayley Score of Infant and Toddler Development, Child Behavior Checklist) and 6years (mean age 5y 11mo; SD 0.3, n=30, using Movement Assessment Battery for Children, Wechsler Preschool and Primary Scale of Intelligence, Child Behavior Checklist, Teacher Report Form). Brain injury, brain volumes, and cortical measures were related to outcome with adjustment for maternal educational level. Two-year cognitive score and 6-year Full-scale IQ were poorer in children with neonatal white matter injury (n=21, all p<0.05), with higher teacher-reported attention problems (p=0.03). Five of six children with involvement of the posterior limb of the internal capsule showed motor problems (p=0.03). Children with a below-average Fulll-scale IQ (<85, n=9) showed smaller volumes of basal ganglia thalami (-8%, p=0.03) and brain stem (-7%, p=0.03). Our findings provide evidence of unfavourable outcome in school-age children with critical CHD who acquire perioperative neonatal brain injury. This paper extends knowledge about neonatal brain injury and long-term outcome in congenital heart disease. Children with white matter injury show lower IQ and more attention problems at school age. Injury of the posterior limb of the internal capsule increases the risk of motor problems. This study provides evidence for worse outcomes in neonates acquiring brain injury around cardiac surgery.

Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae

Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants (BFRs), has resulted in worldwide environmental contamination. TBBPA has been reported as a thyroid endocrine disruptor and a potential neurotoxicant. However, the underlying mechanism is still not clear. In this study, zebrafish (Danio rerio) embryos (2 h post-fertilization, hpf) were exposed to different concentrations of TBBPA (50, 100, 200 and 400 μg/L) alone or in combination with 3,3′,5-triiodo-l-thyronine (T3, 20 μg/L + TBBPA, 200 μg/L). The results confirmed that TBBPA could evoke thyroid disruption by observations of increased T4 contents and decreased T3 contents, accompanied by up-regulated tshβ, tg mRNA and down-regulated ttr and trβ mRNA levels in zebafish larvae. TBBPA-induced neurodevelopmental toxicity was also indicated by down-regulated transcription of genes related to central nervous system (CNS) development (e.g., α1-tubulin, mbp and shha), and decreased locomotor activity and average swimming speed. Our results further demonstrated that treatment with T3 could reverse or eliminate TBBPA-induced effects on thyroidal and neurodevelopmental parameters. Given the above, we hypothesize that the observed neurodevelopmental toxicity in the present study could be attributed to the thyroid hormone disruptions by TBBPA.

706. Wnt/β-Catenin Pathway Contributions to Dendritic Spine and Glutamatergic Synapse Formation Responsive to Lithium-Mediated GSK3 Inhibition

Background A major direct target of lithium is the metalloenzyme GSK3, the central kinase in the Wnt/β-catenin pathway broadly involved in neural development. Methods We have investigated neurodevelopmental and behavioral functions of DIXDC1, which regulates Wnt/β-catenin signaling including late in neural development and postnatally. We have studied a Dixdc1 knock-out (KO) mouse line, applying in vitro and in vivo experimental approaches to assess neurodevelopment, neural activity, dendritic spine dynamics, animal behavior, and responsiveness to lithium and a selective GSK3 inhibitor. This has been accompanied by sequencing of the human DIXDC1 locus in several psychiatric disorders including bipolar disorder, and rescue and gain-of-function experiments involving rare human missense single nucleotide variants (SNVs) that alter the protein׳s signaling activity. Results In mice, loss of Dixdc1 leads to dose-sensitive deficits in behavioral assays including models of depression; this is responsive to lithium as well as to a selective GSK3-inhibitor. Forebrain cortical pyramidal neurons from Dixdc1KO mice have reduced dendritic spine and glutamatergic synapse density correctable by lithium or a selective GSK3 inhibitor. Many of the rare SNVs found more frequently in psychiatric patients affect Wnt/β-catenin activity of the encoded protein. They also alter the above neurodevelopmental parameters when expressed in differentiating pyramidal neurons. Conclusions Our data support a role for DIXDC1 in formation and/or stability of dendritic spines and synapses in forebrain pyramidal neurons upstream of complex behaviors including depression. Our data further suggest that this occurs through the protein’s activity in the Wnt/β-catenin signaling pathway within neurons, and that this responds to GSK3 inhibition by lithium.

Comment on Beltrand et al. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015;38:2033–2041

Beltrand et al. (1) have conducted a prospective single-center clinical study for assessing neurodevelopmental parameters in 18 patients presenting with neonatal diabetes caused by mutations in KCNJ11 or ABCC8 encoding the two ATP-dependent potassium (KATP) channel subunits who were successfully switched from insulin to sulfonylurea (SU) therapy. A standardized normative test battery called NP-MOT (French Neuromotor Functions in Children) performed by a single examiner was used to evaluate the neuromotor functions and developmental parameters before and after 12 months of SU therapy. At the 12-month examination, several patients experienced an improvement or correction of body and visual-spatial motor abnormalities, tone, and attention deficits, with, however, marked differences according to patient age at inclusion. It is well established that the neuromotor clinical abnormalities and patient long-term …

Does route of methamphetamine exposure during pregnancy have an impact on neonatal development and behaviour in rat offspring?

Many preclinical studies have aimed to elucidate the effects of methamphetamine (MA) exposure during pregnancy on the offspring in recent years. However, the severity of effects on the neonate may be related to the subcutaneous (sc) route of administration of the drug that is often employed (88% of preclinical studies) and consequently the delivered dose that the foetus is exposed to. To date there is a paucity of comparative studies investigating different routes of administration for MA during pregnancy and it is not known how these different routes compare when it comes to neonatal outcome. Thus, the aim of this study was to determine if the route of administration of MA (oral gavage or sc injection) during pregnancy at a pharmacological dose affects the magnitude of neurodevelopmental and behavioural effects in the resultant rat offspring. Pregnant Sprague-Dawley dams (n=10 dams/group) received MA (3.75mg/kg) or control (distilled water) via oral gavage or sc injection from gestation day 7–21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. When administered sc, MA significantly reduced maternal weight gain and altered maternal behaviour; mothers spent less time in the nest with pups and spent less time nursing compared to controls. Significant impairments in neurodevelopmental parameters were evident in both MA treatment groups. Somatic development such as pinna unfolding, fur appearance and eye opening were all delayed after MA exposure but these impairments were more pronounced in the MA sc group. Other somatic parameters such as ano-genital distance and body length were only impeded by sc MA. Behavioural development in the surface righting, inclined plane and forelimb grip tests were also altered for both MA treatment groups. This study demonstrates that prenatal MA can have a profound effect on neonatal outcome, but this can be exacerbated if given via the subcutaneous route, as well as producing additional effects not seen with the oral gavage route. Consequently, the route of administration should be considered when interpreting preclinical studies investigating prenatal MA exposure.

The consequences of prenatal and/or postnatal methamphetamine exposure on neonatal development and behaviour in rat offspring

Methamphetamine (MA) has become a popular drug of abuse in recent years not only in the general population but also amongst pregnant women. Although there is a growing body of preclinical investigations of MA exposure during pregnancy, there has been little investigation of the consequences of such exposure via the breast milk during the neonatal period. Therefore, the aim of this study was to determine the consequences of MA exposure during pregnancy and lactation on neurodevelopment and behaviour in the rat offspring. Pregnant Sprague–Dawley dams received MA (3.75mg/kg) or control (distilled water) once daily via oral gavage from gestation day 7–21, postnatal day 1–21 or gestation day 7- postnatal day 21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. Prenatal MA significantly reduced maternal weight gain, with a concomitant reduction in food intake. A significant increase in neonatal pup mortality was observed, being most marked in the prenatal/postnatal MA group. Significant impairments in neurodevelopmental parameters were also evident in all MA treatment groups including somatic development (e.g. pinna unfolding, fur appearance, eye opening) and behavioural development (e.g. surface righting, inclined plane test, forelimb grip). In conclusion, this study demonstrates that exposure to MA during any of these exposure periods (prenatal and/or postnatal) can have a profound effect on neonatal outcome, suggesting that regardless of the exposure period MA is associated with detrimental consequences in the offspring. These results indicate that in the clinical scenario, exposure during lactation needs to be considered when assessing the potential harmful effects of MA on offspring development.

Exposure to artemether-lumefantrine (Coartem) in first trimester pregnancy in an observational study in Zambia.

BackgroundIn general, safety data following exposure to drugs in the first trimester of pregnancy are scarce. More specifically, data on the safety of artemisinin-based combination therapy (ACT) in pregnancy still remain limited. Therefore, pregnant women from Choma, Zambia, who were exposed to artemether-lumefantrine (AL) for the treatment of uncomplicated malaria were followed up and evaluated in a prospective cohort study. This report assessed the longitudinal safety outcomes of the pregnant women inadvertently exposed during the first trimester.MethodsParticipants were classified based on the drug used to treat their most recent malaria episode: artemether-lumefantrine (AL) versus sulphadoxine-pyrimethamine (SP) and/or quinine. All enrolled women were followed up until six weeks post-delivery and the live births for 12 months.ResultsThere were 294 first trimester exposures in the observational cohort (pregnant women: AL = 150, AL and SP = 9 and SP and/or quinine = 135). Similar rates of perinatal mortality (stillbirths and neonatal deaths) were observed for each treatment arm (AL 4.4%, SP and/or quinine 3.9%). At delivery (newborns: AL = 135, AL and SP = 7 and SP and/or quinine = 129), the gestational age (measured using the Dubowitz total scores), length and head circumference of the newborns were similar between the two arms. Low birth weights were reported in 10.2% (95% CI 6.0, 16.6) and 6.7% (95% CI 3.4, 12.6) of newborns in the AL and SP and/or quinine arms, respectively. Overall development (including neurodevelopmental parameters) was similar between the two arms, both at 14 weeks and 12 months of age.ConclusionExposure to AL and SP in the first trimester was not associated with particular safety risks such as perinatal mortality, preterm deliveries or low birth weights. Such outcomes as well as infant neurodevelopmental parameters up to 12 months were similar between the two arms. These findings add to the body of data suggesting that randomized clinical trials could now be the way forward to assess safety and efficacy of ACT in the first trimester of pregnancy.

Modulation of in vitro neuronal development by Fluoxetine and Dexamethasone using an olfactory neurosphere-derived model of neurodifferentiation

INTRODUCTION Investigations of neuropsychiatric and neurodevelopmental disorders provide an unique challenge in that few model systems exist in which neurodevelopmental parameters and treatment response mechanisms can be studied. Here we describe the use of one model system, the olfactory epithelium, which is an accessible neural tissue in adults, to generate neuronal cells of CNS-phenotype. The olfactory epithelium is a major site of neurogenesis in the adult and has been used extensively to model the molecular and cellular aspects of developmental and adult neurogenesis. Moreover, recent studies have shown its utility in investigating the etiology of neuropsychiatric disease. A suggested mechanism of SSRI efficacy in the treatment of neuropsychiatric illnesses, but most specifically major depressive disorder, is their ability to increase neurogenesis and promote neural differentiation in the adult brain. In order to study the underlying mechanisms operating in treatment-induced neural development, we first developed a differentiating culture system to generate neurons of CNS phenotype, including serotonergic neurons, from human and mouse olfactory neurosphere (hONS/mONS)-derived cells. We then used this system to investigate the efficacy of an SSRI to promote neural cell proliferation and differentiation.

The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT

Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children? PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins. Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring. A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS. At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model. Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered. We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins. The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

Dioxin exposure in breast milk and infant neurodevelopment in Vietnam

ObjectivesDioxin levels in the breast milk of mothers residing near hot spots of dioxin contamination areas in South Vietnam remain much higher than in unsprayed areas, suggesting that fetuses and...