Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.

Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.

Environmental enrichment alters neurobehavioral development following maternal immune activation in mice offspring with epilepsy.

Epilepsy is a chronic brain disease affecting millions of people worldwide. Anxiety-related disorders and cognitive deficits are common in patients with epilepsy. Previous studies have shown that maternal infection/immune activation renders children more vulnerable to neurological disorders later in life. Environmental enrichment has been suggested to improve seizures, anxiety, and cognitive impairment in animal models. The present study aimed to explore the effects of environmental enrichment on seizure scores, anxiety-like behavior, and cognitive deficits following maternal immune activation in offspring with epilepsy. Pregnant mice were treated with lipopolysaccharides-(LPS) or vehicle, and offspring were housed in normal or enriched environments during early adolescence to adulthood. To induce epilepsy, adult male and female offspring were treated with Pentylenetetrazol-(PTZ), and then anxiety-like behavior and cognitive functions were assessed. Tumor-necrosis-factor (TNF)-α and interleukin (IL) 10 were measured in the hippocampus of offspring. Maternal immune activation sex-dependently increased seizure scores in PTZ-treated offspring. Significant increases in anxiety-like behavior, cognitive impairment, and hippocampal TNF-α and IL-10 were also found following maternal immune activation in PTZ-treated offspring. However, there was no sex difference in these behavioral abnormalities in offspring. Environmental enrichment reversed the effects of maternal immune activation on behavioral and inflammatory parameters in PTZ-treated offspring. Overall, the present findings highlight the adverse effects of prenatal maternal immune activation on seizure susceptibility and psychiatric comorbidities in offspring. This study suggests that environmental enrichment may be used as a potential treatment approach for behavioral abnormalities following maternal immune activation in PTZ-treated offspring.

Comparison of Protective Effects of Electroacupuncture at ST 36 and LU 5 on Pulmonary and Hypothalamic Pituitary Adrenal Axis Changes in Perinatal Nicotine-Exposed Rats.

BACKGROUND: Maternal smoking and/or exposure to environmental tobacco smoke continue to be significant factors in fetal and childhood morbidity and are a serious public health issue worldwide. Nicotine passes through the placenta easily with minimal biotransformation, entering fetal circulation, where it results in many harmful effects on the developing offspring, especially on the developing respiratory system. OBJECTIVES: Recently, in a rat model, electroacupuncture (EA) at maternal acupoints ST 36 has been shown to block perinatal nicotine-induced pulmonary damage; however, the underlying mechanism and the specificity of ST 36 acupoints for this effect are unknown. Here, we tested the hypothesis that compared with EA at ST 36, EA at LU 5 acupoints, which are on lung-specific meridian, will be equally or more effective in preventing perinatal nicotine-induced pulmonary changes. METHODS: Twenty-four pregnant rat dams were randomly divided into 4 groups: saline ("S"), nicotine ("N"), nicotine + ST 36 (N + ST 36), and nicotine + LU 5 (N + LU 5) groups. Nicotine (1 mg/kg, subcutaneously) and EA (at ST 36 or LU 5 acupoints, bilaterally) were administered from embryonic day 6 to postnatal day 21 once daily. The "S" group was injected saline. As needed, using ELISA, western analysis, q-RT-PCR, lung histopathology, maternal and offspring hypothalamic pituitary adrenal axes, offspring key lung developmental markers, and lung morphometry were determined. RESULTS: With nicotine exposure, alveolar count decreased, but mean linear intercept and septal thickness increased. It also led to a decrease in pulmonary function and PPARγ and an increase of ß-catenin and glucocorticoid receptor expression in lung tissue and corticosterone in the serum of offspring rats. Electroacupuncture at ST 36 normalized all of these changes, whereas EA at LU 5 had no obvious effect. CONCLUSION: Electroacupuncture applied to ST 36 acupoints provided effective protection against perinatal nicotine-induced lung changes, whereas EA applied at LU 5 acupoints was ineffective, suggesting mechanistic specificity and HPA axis' involvement in mediating EA at ST 36 acupoints' effects in mitigating perinatal nicotine-induced pulmonary phenotype. This opens the possibility that other acupoints, besides ST 36, can have similar or even more robust beneficial effects on the developing lung against the harmful effect of perinatal nicotine exposure. The approach proposed by us is simple, cheap, quick, easy to administer, and is devoid of any significant side effects.

Research and policy priorities for addressing prenatal exposure to opioids in Alaska.

The current opioid crisis in Alaska and the USA will negatively affect the health and wellbeing of future generations. The increasing number of infants born with neonatal opioid withdrawal syndrome (NOWS) has had a profound impact on families, health care providers and the child welfare system. This manuscript summarises the main themes of a Symposium held in Anchorage, Alaska with health care providers, researchers, elders and public health officials that focused on identifying emerging challenges, trends and potential solutions to address the increasing number of infants and children affected by maternal opioid use. Five areas of importance for research and policy development that would direct improvement in the care of infants with NOWS in Alaska are outlined with the goal of supporting a research agenda on opioid misuse and child health across the circumpolar north. Abbreviations: NOWS - neonatal opioid withdrawal syndrome; NAS - neonatal abstinence syndrome; MAT - medication-assisted treatment; NICU - neonatal intensive care unit; OATs - opioid agonist treatments; OCS - office of children's services; ANTHC - Alaska Native Tribal Health Consortium; OUD - opioid use disorder; SBIRT - screening, brief intervention and referral to treatment; ISPCTN - IDeA States Pediatric Clinical Trials Network; NIH - National Institutes of Health; ANMC - Alaska Native Medical Center; DHSS - Department of Health and Social Services; AAPP - All Alaska Pediatric Partnership.

The risk for childhood malignancies in the offspring of mothers with previous gestational diabetes mellitus: a population-based cohort study.

The hyperglycemic intrauterine environment has been shown to have long-term effects on offspring. We aimed to evaluate its effect on the long-term risk of childhood malignancies. This was a population-based cohort analysis comparing the risk for long-term childhood malignancies (≤18 years) in children born to mothers with and without gestational diabetes mellitus (GDM). Childhood malignancies were diagnosed by physicians and recorded in hospital medical files according to predefined codes based on ICD-9. Deliveries occurred between the years 1991 and 2014 in a tertiary medical center. Children to mothers with pre-GDM, with fetal congenital malformations, and with benign tumors were excluded from the analysis. Kaplan-Meier survival curve was constructed to compare cumulative oncological morbidity in both groups over time. Cox proportional hazards model was used to control for confounders. During the study period, 236 893 infants met the inclusion criteria; 10 294 (4.3%) of whom were born to mothers with GDM. Hospitalizations involving malignancy diagnoses were comparable between the groups (0.11 vs. 0.12%; P=0.424), as were the cumulative incidences of total oncological morbidity using a Kaplan-Meier survival curve (log-rank P=0.820). In the Cox regression model, maternal GDM was not associated with increased childhood oncological hospitalizations while controlling for maternal age, gestational age, and hypertensive disorders (adjusted hazard ratio: 1.02, 95% confidence interval: 0.58-1.82, P=0.932). Exposure to intrauterine hyperglycemic environment due to maternal GDM does not increase the risk for childhood malignancies.

Gestational age and socioeconomic status as mediators for the impact of prenatal alcohol exposure on development at 6 months.

BACKGROUND: Of the many negative outcomes associated with gestational alcohol use, one that has received relatively little attention is preterm birth and its possible contribution to effects of prenatal alcohol exposure (PAE) on development. To examine the increased risk for premature delivery associated with PAE and the joint influence of preterm birth and alcohol on child outcomes, analysis was carried out in a longitudinal cohort recruited in Western Ukraine. METHODS: Alcohol-using women and low or nondrinking controls were identified prenatally for a clinical trial of multivitamins and minerals (MVM) in ameliorating effects of PAE. Women were interviewed to provide information about medical and social status and other drug use. At delivery, information was collected about infant (N = 686) status including gestational age (GA) in weeks. Finally, 441 infants were followed to 6 months of age and cognitive (Mental Developmental Index [MDI]) and motor development (Psychomotor Developmental Index [PDI]) (measured using the Bayley Scales of Infant Development, second Ed (BSID-II). RESULTS: Seven percent infants were born at <37 weeks GA. The odds ratio for preterm delivery for Alcohol Exposed versus Low/No Alcohol was 2.6 (95% Confidence Interval 1.37, 4.94) (p < .003); MVM supplements were associated with a lower rate of preterm delivery overall, but the relative proportion of preterm births did not vary by MVM supplement status between alcohol exposure groups. In mediation models of 6 month cognitive and motor development with reference to Barron and Kenney in 1986, GA significantly mediated alcohol effects (MDI: Z = -2.64, p < .008; PDI: Z = -2.35, p < .02) although PAE independently affected both outcomes (MDI: t = -5.6, p < .000; PDI: t = -3.19, p < .002). CONCLUSION: Results suggest that PAE is associated with higher rates of preterm birth and that alcohol's effect on development in infancy may be both direct and mediated by shortened length of gestation.

Protective effects of quercetin against brain injury in a rat model of lipopolysaccharide-induced fetal brain injury.

Maternal exposure to lipopolysaccharide (LPS), a bacterial endotoxin produced during infection, leads to disruption in fetal brain development and causes newborn brain injury. Quercetin (QR) is a multipotent flavonoid that functions as an antioxidant and protects against inflammation and neurodegeneration. In this study, we explored the potential functions of QR in alleviating maternal LPS exposure induced fetal brain damage. Pregnant rats at late gestational stages were treated with saline, LPS, QR, LPS and QR. Brain injury biomarker TGF-1ß was assessed in cerebrospinal fluid (CSF) and brain tissue of newborn rats. Pro-inflammatory cytokines, apoptosis markers and oxidative stress indicators were evaluated. We found that LPS treatment induced an increased production of TGF-1ß which was suppressed by QR administration. LPS enhanced pro-apoptotic Bax and inhibited anti-apoptotic Bcl-2 expression. QR reduced that ratio of Bax and Bcl-2 that was high in LPS treated brain tissue. Additionally, QR suppressed oxidative stress induced by LPS. Finally, QR reduced the levels of pro-inflammatory cytokines that were produced as a result of LPS exposure. In summary, our study indicates that QR potently alleviates maternal LPS exposure induced fetal brain injury in rats, making it a potential therapeutic for suppressing infant brain damage as a result of maternal infection.

El recién nacido expuesto a cocaína antenatal: una propuesta de intervención médica y psicosocial integrada / The newborn exposed to antenatal cocaine: a proposal for integrated medical and psychosocial intervention

Introducción: El consumo de cocaína durante la gestación gatilla isquemia, muerte y licuefacción celular en el cerebro fetal, consolidando en la infancia grados variables de retraso mental. El presente estudio busca identificar mediante test de drogas en orina los recién nacidos (RN) expuestos a cocaína en el embarazo y describir el procedimiento clínico y social a seguir. Metodología: Estudio de cohorte prospectivo enero 2016 y enero 2018 en RN con exposición antenatal a cocaína, Unidad de Neonatología del Hospital Clínico San Borja Arriarán. Resultados: Se estudió a 64 RN con test en orina positivo a cocaína. El 42% fue pequeño para la edad gestacional, 33% tenía microcefalia. Se encontraron malformaciones en sistema nervioso y vías urinarias, trastornos del ritmo cardíaco e hipoacusia. Solo 32,8% de las madres controló su embarazo y 52% rechazó la rehabilitación. Servicio Social interpuso medidas de protección a los RN e instó a las madres a programas de rehabilitación. El 12,5% de los RN no tenía familia de apoyo y debió ser derivado a instituciones gubernamentales. Conclusiones: Las consecuencias de la exposición a cocaína antenatal en el RN son devastadoras. Este trabajo permite orientar la pesquisa, estudio y pasos legales a seguir con los RN afectados y sus madres.

Introduction: The consumption of cocaine during pregnancy triggers events such as ischemia, death and cell liquefaction in the fetal brain, consolidating varying degrees of intellectual disability. This study proposed to identify by urine drug test the newborns (NB) with antenatal exposure to and describe the clinical and social procedure to follow with them and their mothers until neonatal discharge. Methodology: Prospective cohort study, conducted in RN who met criteria for risk of antenatal exposure to cocaine, Neonatology Unit of the San Borja Arriaran Clinical Hospital between January 2016 -2018. Results: Antenatal exposure to cocaine was confirmed on 64 NB. Forty-two percent of them were small for gestational age and 33% had microcephaly. Malformations were found in the nervous system urinary tract, as well as disorders in the rhythm of the heart and loss of hearing. Only 32% of mothers controlled her pregnancy, none of them was derived to the secondary. Social Services implemented all the NB protective measures in place and urged mothers to participate in rehabilitation programs. Fifty-two percent rejected rehabilitation and 12.5% of the NB have not family support and had to be referred to government institutions. Conclusions: The consequences of exposure to antenatal cocaine in the NB are devastating. This work allows orienting the research with the NB and showing the legal steps should be taken with the RN and their mothers.

Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid.

Neurodevelopmental impairment can affect lifelong brain functions such as cognitive and social behaviour, and may contribute to aging-related changes of these functions. In the present study, we hypothesized that bone marrow-derived mesenchymal stem cells (MSC) administration may repair neurodevelopmental behavioural deficits by modulating adult hippocampal neurogenesis. Indeed, postnatal intracerebral transplantation of MSC has restored cognitive and social behaviour in mice prenatally exposed to valproic acid (VPA). MSC transplantation also restored post-developmental hippocampal neurogenesis, which was impaired in VPA-exposed mice displaying delayed differentiation and maturation of newly formed neurons in the granular cell layer of the dentate gyrus. Importantly, a statistically significant correlation was found between neuronal differentiation scores and behavioural scores, suggesting a mechanistic relation between the two. We thus conclude that post-developmental MSC administration can overcome prenatal neurodevelopmental deficits and restore cognitive and social behaviours via modulation of hippocampal adult neurogenesis.

Developmental origins of NAFLD: a womb with a clue.

Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.

Prenatal Maternal Occupational Exposure and Postnatal Child Exposure to Elemental Mercury.

OBJECTIVES: Young children are highly vulnerable to elemental mercury toxicity, and elementary mercury exposure in young children in China unfortunately occurs regularly because of the wide use of fluorescent lamps, glass thermometers, and other mercury-contained items. This study aimed to summarize such recent cases in a referral clinic and to make recommendations for postexposure treatment and prevention of future exposure. METHODS: Patients were evaluated between January 2007 and December 2009 in environmental health facilities throughout China and were referred to our clinic. A total of 6 children younger than 4 years with significant elemental mercury exposure were included in this case series analysis. The total mercury content in blood and hair (fetal hair if necessary) and average 24-hour urine mercury concentrations were analyzed. Meso-2,3-dimercaptosuccinic acid or surgery was prescribed for the patient if necessary. RESULTS: Young children were found to be exposed in 3 ways as follows: prenatal exposure through maternal occupational contact in compact fluorescent-lamp factories (2 cases), broken thermometers (3 cases), and other causes of accidental inhalation of mercury vapor during the embryonic and lactation periods (1 case). For 3 cases caused by broken thermometers, x-ray images helped to identify the position of mercury residues. Local excision was used to remove mercury from the floor of the mouth in 1 case. One child was prescribed oral meso-2,3-dimercaptosuccinic acid, and a good response was received. CONCLUSIONS: Substitution of mercury-in-glass thermometers and vigilance to prevent women of childbearing age from occupational mercury exposure were suggested. Treatment selection should vary according to patient situations.

Aortopulmonary collateral artery in prenatal exposure to carbamazepine - endovascular therapy and technical considerations: a case report.

INTRODUCTION: Aortopulmonary collateral arteries are an uncommon variant of alternative blood supply in cases of complex congenital heart disease. Although surgery may still be the classic approach for this condition, mini-invasive endovascular occlusion has been recently attempted as an alternative less traumatic procedure. Children born to women with epilepsy are at increased risk of congenital malformations. CASE PRESENTATION: A cardiovascular malformation in a 6-year-old white boy with prenatal exposure to carbamazepine is described. At birth, he underwent atrial-ventricular septal defects repair. At 6 years of age, he was diagnosed to have an aberrant aortopulmonary artery from the descending aorta. He presented with recurrent respiratory infections and no cardiovascular signs, but there was associated right upper lobe hyperperfusion. Collateral percutaneous plug embolization was performed because of risk for cardiorespiratory infections, pulmonary hypertension and atrioventricular dilatation. The post-releasing control showed a complete occlusion of the aberrant artery. A chest radiogram and computed tomography showed normalization of vascular pattern of his right lung at 9-months follow-up. No complications and no respiratory infections in the first follow-up year were observed. A good growth gain was obtained. CONCLUSIONS: Plug embolization in an aortopulmonary collateral artery is an interesting alternative to surgery and is suitable for children with minor congenital heart disease and without severe respiratory and/or cardiovascular symptoms. Management and long-term pediatric multidisciplinary follow-up is recommended. Prenatal exposure to carbamazepine could be considered in the pathogenesis and diagnosis of the malformation.

Effect of iron deficiency anemia in pregnancy on child mental development in rural China.

OBJECTIVE: To determine the impact of iron deficiency anemia (IDA) in pregnancy on young child development. METHODS: A 2-year follow-up of 850 children born to women who participated in a double-blind cluster randomized controlled trial of prenatal micronutrient supplementation in western rural China. These women were randomly assigned to receive either daily folic acid, iron/folic acid (60 mg iron), or multiple micronutrients (with 30 mg iron) during pregnancy. Children were categorized into the prenatal-IDA and prenatal-non-IDA groups based on the mother's hemoglobin in the third trimester. Each group contained 3 subgroups based on mother's treatment: folic acid, iron/folic acid, and multiple micronutrients. Bayley scales of infant development were administered to the children to assess their development at 3, 6, 12, 18, and 24 months of age. RESULTS: Compared with the prenatal-non-IDA group, the prenatal-IDA group showed a significantly lower mental development index at 12, 18, and 24 months of age. The adjusted mean difference was 5.8 (95% confidence interval [CI], 1.1-10.5), 5.1 (95% CI, 1.2-9.0), and 5.3 (95% CI, 0.9-9.7), respectively. Further analysis showed that the mental development indexes in the prenatal-IDA group and prenatal-non-IDA group were similar with supplementation of iron/folic acid but were significantly lower in the prenatal-IDA group with supplementation of folic acid or multiple micronutrients. CONCLUSIONS: Prenatal IDA in the third trimester is associated with mental development of the child. However, prenatal supplementation with sufficient iron protects child development even when the woman's IDA was not properly corrected in pregnancy.

Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone-derived neural stem cells.

Neurobehavioral teratogenicity can be reversed with transplantation of neural stem cells. However, the usefulness of this therapy would be greatly enhanced by employing adult stem cells. In pursuit of this this goal, we developed a model that uses subventricular zone (SVZ) cells. HS/Ibg mice were exposed prenatally to chlorpyrifos on gestational days 9-18 (3 mg/kg/day, SC) in order to induce deficits in their performance in the Morris water maze test. Both the control and the exposed offspring were transplanted with SVZ cells (or vehicle) on postnatal day 35; this actually represents an allogenic transplantation, because the HS/Ibg strain is a heterogeneous stock. The transplanted cells were later observed in the host brain by DiI tracing, and their initial differentiation to cholinergic neurons and astrocytes was ascertained. On postnatal day 80, animals that had been exposed prenatally to chlorpyrifos displayed impaired Morris water maze performance, requiring more time to reach the platform. Transplantation of adult SVZ-derived neural stem cells (NSC) reversed the deficits. Applying autologous transplantation provides an important demonstration that the methodological obstacles of immunological rejection and the ethical concerns related to using embryonic stem cells may be successfully bypassed in developing stem cell therapies for neurodevelopmental disorders.

Children's cognitive-behavioral functioning at age 6 and 7: prenatal drug exposure and caregiving environment.

OBJECTIVE: The aim of this study was to examine how prenatal drug exposure (PDE) and caregiving environment relate to cognitive, academic, and behavioral performance at ages 6 and 7. METHODS: A longitudinal follow-up was conducted of 111 children with PDE and a community cohort of 62 non-drug-exposed children (N = 173). Children completed standardized tests of cognition (Stanford-Binet Intelligence Scales, Fourth Edition [SB-IV]) and academic performance (Wide Range Achievement Test 3). Caregivers completed ratings of child behavior problems (Child Behavior Checklist [CBCL]). Multivariate analyses were conducted, adjusting for gender, prenatal tobacco exposure, number of caregiver placement changes, and 3 caregiver variables assessed at age 7, including depressive symptoms, employment status, and public assistance status. RESULTS: After adjusting for perinatal and environmental variables, there were no significant exposure-group differences in cognition, academic performance, or behavior problems. In comparison with males, females had higher scores on overall IQ and 4 of 8 SB-IV subtests, fewer caregiver-reported attention and aggression problems, and higher reading achievement scores. There were no significant gender-by-group interactions. CONCLUSION: When analyses were adjusted for perinatal and environmental variables, most associations between PDE and cognitive-behavioral functioning were attenuated. Regardless of drug exposure history, males performed more poorly than females on multiple cognitive-behavioral indices. Both exposed and nonexposed children were from low-income families and obtained scores substantially below normative expectations.