Programming effects of intrauterine hyperthermia on adrenal gland development.

Maternal heat stress during late pregnancy can lead to intrauterine hyperthermia and affect fetal hypothalamic-pituitary-adrenal axis development and function. Herein, we investigated the effects of chronic environmental heat stress exposure of Holstein cows in the last 2 mo of gestation on their offspring's adrenal gland histomorphology and transcriptome. Cows in their last 54 ± 5 d of gestation were either heat-stressed (i.e., housed under the shade of a free stall barn) or provided heat-stress abatement via active cooling (i.e., via water soakers and fans) during a subtropical summer (Temperature-Humidity Index >68). Respiration rate (RR) and skin temperature (ST) were elevated in heat-stressed dams relative to the cows with access to heat abatement (23 bpm and 2 ◦C higher for RR and ST, respectively). Heifers born to heat-stressed cows experienced heat stress in utero (HS), while heifers born to actively cooled cows did not (CL). The adrenal gland was harvested from 6 heifers per group that were euthanized at birth (d 0; n = 12) or one week after weaning (d 63; n = 12). Circulating cortisol was measured from blood samples collected weekly throughout the pre-weaning period. At d 63, heifers that experienced HS while developing in utero had heavier adrenal glands, with a greater total tissue surface area and thickness of the zona glomerulosa (ZG), fasciculata (ZF), and reticularis (ZR), compared with CL heifers. In addition, the adrenal gland of in utero HS heifers had less cells in the ZG, more and larger cells in the ZF and larger cells in the ZR, relative to CL heifers. Although no changes in circulating cortisol were observed through the pre-weaning period, the transcriptomic profile of the adrenal tissue was altered by fetal exposure to hyperthermia. Both at birth and on d 63, approximately 30 pathways were differentially expressed in the adrenal glands of in utero HS heifers relative to CL. These pathways were associated with immune function, inflammation, prolactin signaling, cell function, and calcium transport. Upstream regulators significantly activated or inhibited in the adrenal glands of heifers exposed to intrauterine hyperthermia were identified. Maternal exposure to heat stress during late gestation caused an enlargement of their offspring's adrenal glands by inducing ZG and ZF cell hypertrophy, and caused gene expression changes. These phenotypic, histological, and molecular changes in the adrenal gland might lead to alterations in stress, immune, and metabolic responses later in life.

Estimating the dynamic early life exposure to PFOA and PFOS of the HELIX children: Emerging profiles via prenatal exposure, breastfeeding, and diet.

In utero and children's exposure to per- and polyfluoroalkyl substances (PFAS) is a major concern in health risk assessment as early life exposures are suspected to induce adverse health effects. Our work aims to estimate children's exposure (from birth to 12 years old) to PFOA and PFOS, using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach. A model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and including individual characteristics and exposure scenarios (e.g., duration of breastfeeding, weight at birth, etc.). Our approach was applied to the HELIX cohort, involving 1,239 mother-child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: maternal and child plasma concentrations (6 to 12 y.o). Our model predicted an increase in plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher plasma concentrations of PFOA than PFOS were predicted until 2 y.o, and then PFOS concentrations gradually became higher than PFOA concentrations. From 2 to 8 y.o, mean concentrations decreased from 3.1 to 1.88 µg/L or ng/mL (PFOA) and from 4.77 to 3.56 µg/L (PFOS). The concentration-time profiles vary with the age and were mostly influenced by in utero exposure (on the first 4 months after birth), breastfeeding (from 5 months to 2 (PFOA) or 5 (PFOS) y.o of the children), and food intake (after 3 (PFOA) or 6 (PFOS) y.o of the children). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the children's exposure over the early life to improve exposure classification. Our approach demonstrates the possibility to simulate individual internal exposures using PBPK models when measured biomarkers are scarce, helping risk assessors in gaining insight into internal exposure during critical windows, such as early life.

Carry-over effects of maternal late-gestation heat stress on granddaughter's growth and mammary gland development.

Maternal (F0) exposure to late-gestation heat stress reduces their daughter's (F1) mammary gland fat pad mass (FP), parenchyma (PAR) mass, and epithelial cell proliferation when evaluated at birth and weaning, and go on to produce less milk in their first lactation. Herein, we investigated the effect of maternal late-gestation heat stress on whole-body growth and mammary development of their granddaughters (F2). Multiparous F0 cows had access to heat abatement (n = 41, shade, and active cooling via fans and water soakers) or not (n = 41, shade only) for the last 56 d of gestation during a subtropical summer. Consequently, the F1 daughters, born to F0 cows, were heat-stressed (HTF1, n = 36) or cooled (CLF1, n = 37) in utero during the last 2 mo of gestation. All F1 heifers were raised as an identically managed cohort until first calving. The F2 granddaughters, born to HTF1 (HTF2, n = 12) or CLF1 (CLF2, n = 17), were raised as an identically managed cohort until 70 d of age. Dry matter intake (DMI), body weight, hip height, wither height, chest girth, head circumference, mammary gland teat length, and left-right and front-rear teat distances were measured. Average daily gain (ADG) was calculated for the pre-weaned period (0-49 d). Mammary ultrasounds were performed on d 21, 49, and 70 (n = 9/group) on the rear left and right quarters to quantify PAR and FP areas. Mammary biopsies were collected for histological evaluation of epithelial structures (H&E staining), and to quantify cells positive for ERα (estrogen receptor, α subunit), cell proliferation (Ki67), and apoptosis (TUNEL). Heifer growth from birth to d 49 was similar between CLF2 and HTF2 for all parameters evaluated. Distances between teats and teat length were not different between groups. On d 70, CLF2 tended to have a greater average PAR (right and left quarters) relative to HTF2. Although the left FP was smaller in HTF2 relative to CLF2, the average FP was not different. The lumenal and non-lumenal epithelial structures in the PAR of HTF2 were significantly smaller than those of CLF2. In addition, HTF2 had a reduced percentage of proliferating cells in the epithelial and stromal compartments and a greater percentage of apoptotic cells, particularly in the stroma. The percentage of ERα positive cells was significantly reduced in HTF2. In summary, although HTF2 heifer's DMI was similar and they grew at the same rate as CLF2 heifers throughout the pre-weaning phase, their mammary glands had smaller PAR areas with fewer epithelial structures characterized by reduced cell turnover and lower ERα expression. These early changes in the microstructure and cellular turnover of the mammary gland may partly explain the reduction in lactation performance relative to CLF2 counterparts at maturity.

Live Imaging of Migrating Neurons and Glial Progenitors Visualized by in Utero Electroporation.

During cortical development, both neurons and glial cells are generated in the germinal zone near the lateral ventricle, migrate in the correct direction, and settle in their appropriate locations. This developmental process can be clearly visualized by introducing fluorescent protein-expression vectors via in utero electroporation. In this chapter, we describe labeling methods for migrating neurons and glial progenitors, as well as methods for slice culture, and time-lapse imaging.

Brain Sample Preparation After Performing in Utero Electroporation to Proliferating and Differentiated Cells in the Developing Mouse Neocortex.

In utero electroporation (IUE) enables labeling and manipulating specific types of cells by introducing DNA plasmids with desired promoters. After the surgery, mouse brains are fixed at any stage and analyzed after staining using specific antibodies. Here, we describe the flow of the IUE experiment from the preparation to microscopic observations.

Ca2+ Imaging in Immature Cortical Neurons.

Ca2+ signaling plays a central role in various neurodevelopmental steps, and immature neurons exhibit spontaneous Ca2+ activity. To analyze Ca2+ dynamics in migrating immature neurons, we developed a method for Ca2+ imaging and offline analysis of Ca2+ dynamics.

Lower Insulin Sensitivity Through 36 Months of Life With in Utero HIV and Antiretroviral Exposure in Botswana: Results From the Tshilo Dikotla Study.

BACKGROUND: There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure. METHODS: The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders. RESULTS: A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P  = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms. CONCLUSIONS: In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life.

Levels of depression and self-esteem in women with cancer of the endometrium and cervix receiving chemotherapy treatment in Türkiye.

OBJECTIVE: Endometrium and cervical cancer is a common and important health problem that affects women in many physical, emotional and psychological aspects. This study aimed to determine the levels of depression and self-esteem in women with endometrial and cervical cancer receiving chemotherapy, determine the factors affecting them, and examine the relationship between the levels of depression and self-esteem. METHODS: This descriptive and cross-sectional study was conducted with 158 women who came to the gynecology-oncology policlinic and chemotherapy unit of a training and research hospital in Izmir, western Türkiye, between April 2022 and April 2023. Data were collected with the "Descriptive Information Form", "Beck Depression Inventory" and "Rosenberg Self-Esteem Scale". Descriptive and inferential statistics were performed to analyse the association between the study variables. RESULTS: In this study, 52.5% of women were diagnosed with endometrial cancer and 47.5% with cervical cancer. Beck Depression Inventory mean total score was 11.28 ±â€¯6.35, and 20.3% of them were at risk of depression (BDI ≥ 17). Rosenberg Self-Esteem Scale mean total score was 21.06 ±â€¯3.85, and 97.5% of them had high self-esteem. There was a statistically significant and strong negative correlation between the mean total scores of the Beck Depression Inventory and Rosenberg Self-Esteem Scale (r = 0.723; p < 0.05). It was determined that an increase in the Rosenberg Self-Esteem Scale mean total score by 1 unit decreased the Beck Depression Inventory mean total score by 1.2 units and was responsible for 52% of the variance (B = -1.192; R2 = 0.523). CONCLUSION: It was determined that one-fifth of women experienced moderate/severe depression and the majority of them had high self-esteem. The increase in women's depression levels decreased their self-esteem. Health professionals and oncology nurses should perform screenings to determine the depression and self-esteem levels of women with endometrial and cervical cancer and provide necessary education, counseling, and care to women.

[Antenatal care for fetuses with congenital diaphragmatic hernia]. / Prise en charge anténatale des fœtus porteurs d'une hernie de coupole diaphragmatique.

Congenital diaphragmatic hernia (CDH) can be diagnosed prenatally and its severity assessed by fetal imaging. The prognosis of a fetus with CDH is based on whether or not the hernia is isolated, the measurement of lung volume on ultrasound and MRI, and the position of the liver. The birth of a child with CDH should take place in a center adapted to the care of such children, and in accordance with the recommendations defined by the French National Diagnosis and Care Protocol. It has recently been demonstrated that for moderate and severe forms of CDH, tracheal occlusion using a balloon placed in utero by fetoscopy (FETO) increases survival until discharge from the neonatal unit, but at the cost of an increased risk of prematurity. At the same time, advances in neonatal resuscitation and the standardization of follow-up of these children within the framework of the "Centre de référence maladies rares: hernie de coupole diaphragmatique" have improved the prognosis of these children and young adults.

Evidence of reduced gestational age in response to in utero arsenic exposure and implications for aging trajectories of the newborn.

Arsenic exposure is associated with a plethora of age-related health outcomes of disparate etiology. However, evidence of the impact of arsenic on aging remains limited. Here, we investigated the utility of epigenetic clocks in two different populations and the impact of maternal arsenic exposure during pregnancy on epigenetic gestational age at birth. To do this, we examined publicly available DNA methylation data and estimated gestational age across five gestational clocks in two unrelated human populations. These populations also differ in the extent of arsenic exposure and the targeted tissue of analysis (cord blood and placental tissue). Our results indicate that same-tissue clocks produce gestational age estimates that are more highly correlated with clinical gestational age. Interestingly, our results also indicate that arsenic exposure is associated with gestational age, with higher arsenic exposures associated with decreased gestational age. We also applied two pediatric clocks to evaluate infant biological age in the same samples. The data is suggestive of higher pediatric age in infants exposed to higher arsenic levels during gestation. Taken altogether, our findings are consistent with past work indicating that that in utero arsenic exposure is associated with decreased gestational maturity as characterized by infant outcomes such as low birthweight and lung underdevelopment and dysfunction in arsenic exposed infants. The findings are also consistent with arsenic exposure setting infants on a trajectory of accelerated epigenetic aging that starts at birth.

NeuroPorator: An open-source, current-limited electroporator for safe in utero gene transfer.

BACKGROUND: Electroporation is an effective technique for genetic manipulation of cells, both in vitro and in vivo. In utero electroporation (IUE) is a special case, which represents a fine application of this technique to genetically modify specific tissues of embryos during prenatal development. Commercially available electroporators are expensive and not fully customizable. We have designed and produced an inexpensive, open-design, and customizable electroporator optimized for safe IUE. We introduce NeuroPorator. METHOD: We used off-the-shelf electrical parts, a single-board microcontroller, and a cheap data logger to build an open-design electroporator. We included a safety circuit to limit the applied electrical current to protect the embryos. We added full documentation, design files, and assembly instructions. RESULT: NeuroPorator output is on par with commercially available devices. Furthermore, the adjustable current limiter protects both the embryos and the uterus from overcurrent damage. A built-in data acquisition module provides real-time visualization and recordings of the actual voltage/current pulses applied to each embryo. Function of NeuroPorator has been demonstrated by inducing focal cortical dysplasia in mice. SIGNIFICANCE AND CONCLUSION: The simple and fully open design enables quick and cheap construction of the device and facilitates further customization. The features of NeuroPorator can accelerate the IUE technique implementation in any laboratory and speed up its learning curve.

Práticas de enfermeiros na prevenção e rastreio do câncer de mama e de colo uterino / Practices performed by nurses in the prevention and screening of breast and cervical cancer / Prácticas de enfermería en la prevención y detección del cáncer de mama y cervicouterino

Objetivo: Identificar como ocorrem as práticas de prevenção e de rastreio do câncer de mama e de colo uterino realizadas por enfermeiros que atuam na Atenção Primária à Saúde do Rio Grande do Sul. Métodos: Trata-se de um estudo de abordagem qualitativa e de natureza analítica e compreensiva. Realizou-se entrevistas semiestruturadas. Os dados foram submetidos à análise de conteúdo do tipo temática proposta por Minayo. Os colaboradores foram 58 enfermeiros atuantes na Atenção Primária à Saúde. Resultados: Os resultados apontam que as práticas se desenvolvem em um contexto de crescente autonomia profissional e de protagonismo da Enfermagem. Aspectos como proximidade e vínculo com a comunidade, outros procedimentos e ações ofertadas nos atendimentos, incluindo a condução clínica/terapêutica, na vigência de sinais e sintomas de infecção, condizem com uma atenção mais ampla às necessidades de saúde e de cuidado às mulheres. Conclusão: O estudo evidencia a importância do respaldo de protocolos para a atuação segura das práticas dos enfermeiros da Atenção Básica, visando a prevenção e rastreio do câncer de mama e de colo uterino. Esses instrumentos devem ser de fácil acesso e constantemente atualizados a fim de garantir a padronização preconizada pelo Ministério da Saúde. (AU)

Objective: To identify how the breast and cervical cancer prevention and screening practices performed by nurses working in Primary Health Care in the state of Rio Grande do Sul occurs. Methods: This is a qualitative study with an analytical and comprehensive nature. The collaborators were 58 nurses working in Primary Health Care. Results: The results indicate that the practices are developed in a context of increasing professional autonomy and the role of Nursing. Aspects such as proximity and bonding with the community, other procedures and actions offered in the consultations, including clinical/therapeutic management in cases of signs and symptoms of infection, are consistent with a broader attention to women's health and care needs. Conclusion: The study highlights the importance of supporting protocols for the safe performance of Primary Care nurses' practices, aiming at the prevention and screening of breast and cervical cancer. These documents must be easily accessible and constantly updated in order to guarantee the standardization recommended by the Ministry of Health. (AU)

Objetivo: Identificar cómo las prácticas de prevención y detección del cáncer de mama y cervicouterino son realizadas por enfermeros que actúan en la Atención Primaria de Salud en Rio Grande do Sul. Métodos: Se trata de un estudio cualitativo de carácter analítico y comprensivo. Los colaboradores fueron 58 enfermeros que actuaban en la Atención Primaria de Salud. Resultados: Los resultados indican que las prácticas se desarrollan en un contexto de aumento de la autonomía profesional y del papel de la Enfermería. Aspectos como la proximidad y el vínculo con la comunidad, otros procedimientos y acciones que se ofrecen en las consultas, incluido el manejo clínico/terapéutico en casos de signos y síntomas de infección, son consistentes con una atención más amplia a las necesidades de salud y cuidado de las mujeres. Conclusión: El estudio destaca la importancia de protocolos para la actuación segura de las prácticas de los enfermeros de Atención Primaria, con el objetivo de la prevención y el tamizaje del cáncer de mama y de cuello uterino. Estos instrumentos deben ser de fácil acceso y constantemente actualizados para garantizar la estandarización recomendada por el Ministerio de Salud. (AU)

Early-life tobacco smoke elevating later-life osteoporosis risk: Mediated by telomere length and interplayed with genetic predisposition.

INTRODUCTION: The growing prevalence of osteoporosis (OP) in an aging global population presents a significant public health concern. Tobacco smoke negatively affects bone turnover, leading to reduced bone mass and heightened OP and fracture risk. However, the impact of early-life tobacco smoke exposure on later-life OP risk remains unclear. OBJECTIVES: This study was to explore the effects of early-life tobacco smoke exposure on incident OP risk in later life. The mediating role of telomere length (TL) and the interaction with genetic predisposition were also studied. METHODS: Data on in utero tobacco smoke exposure (IUTSE) status and age of tobacco use initiation from the UK Biobank were used to estimate early-life tobacco smoke exposure. Incident OP cases were identified according to health-related records. Linear, Cox, and Laplace regression models were mainly used for data analysis. RESULTS: Individuals with IUTSE showed a higher OP risk [hazard ratio (HR): 1.06, 95 % confidence interval (CI): 1.01, 1.11] and experienced earlier OP onset by 0.30 years [50th percentile difference = -0.30, 95 % CI: -0.51, -0.09] compared to those without. Participants initiating tobacco smoke in childhood, adolescence, and adulthood had 1.41 times (95 % CI: 1.23, 1.61), 1.17 times (95 % CI:1.10, 1.24), and 1.14 times (95 % CI: 1.07, 1.20) the risk of OP, respectively, compared to never smokers. They also experienced earlier OP onset by 2.16, 0.95, and 0.71 years, sequentially. The TL significantly mediated the early-life tobacco exposure and OP association. Significant joint and interactive effects were detected between early-life tobacco smoke exposure and genetic elements. CONCLUSIONS: Our findings implicate that early-life tobacco smoke exposure elevates the later-life OP risk, mediated by telomere length and interplayed with genetic predisposition. These findings highlight the importance of early-life intervention against tobacco smoke exposure and ageing status for precise OP prevention, especially in individuals with a high genetic risk.

The utility of combined utero-cervical index in predicting preterm delivery in pregnant women with preterm uterine contractions.

PURPOSE: To evaluate the utility of a novel ultrasound index "combined utero-cervical index (CUCI)" in the prediction of preterm delivery. METHODS: The present prospective cohort study was conducted in Ankara Bilkent City Hospital Perinatology Clinic between January 1, 2023, and March 31, 2023. Pregnant women with uterine contractions between 24 and 36th gestational weeks but did not have dilatation or effacement were included. CUCI was calculated as: (utero-cervical angle)/(anterior cervical lip thickness + fundal thickness + lower uterine segment thickness + cervical length). In the presence of cervical funneling, one point was added to the final result. A ROC analysis was conducted to determine the potential of CUCI in predicting delivery <37 weeks of gestation, <34 weeks of gestation, and <4 weeks after the first admission to the hospital for uterine contractions, respectively. RESULTS: Optimal cut-off values of CUCI were found to be 1.4 (67.1% sensitivity, 67.2% specificity) for predicting delivery at <37th weeks, 1.7 (72.7% sensitivity, 65.7% specificity) for predicting delivery at <34th weeks, and 1.4 (62.5% sensitivity, 61.7% specificity) for predicting delivery at <4 weeks. CONCLUSION: CUCI may be used in the prediction of preterm delivery for pregnant women admitted to hospital with preterm uterine contractions.

Postnatal myelomeningocele closure in smallest reported neonate: illustrative case.

BACKGROUND: Myelomeningocele (MMC) is the most serious form of spina bifida, a congenital defect in neural tube development. Defect closure in a patient with an extremely low birth weight presents unique challenges and risks; lower birth weight is associated with multiple organ system concerns, homeostasis is difficult, and local tissue is underdeveloped. To the authors' knowledge, the present case is the lowest reported weight (490 g) for a neonate with postnatal MMC repair. OBSERVATIONS: A preterm male with a prenatally diagnosed lumbosacral MMC and associated Chiari malformation type II was born at 23 weeks 1 day to a 29-year-old mother, gravidity 6 parity 4. The patient was medically stabilized and underwent MMC closure on day of life 5. His weight was 490 g at the time of this repair, and he did not have any surgical complications. At age 16 months, he underwent endoscopic third ventriculostomy with choroid plexus cauterization; he has not required any further hydrocephalus treatments since the last follow-up at 30 months of age. LESSONS: To the authors' knowledge, this case is the lowest birth weight ex utero MMC closure reported in the literature. Challenges of prematurity and size required appropriate preoperative stabilization, careful hemostasis and temperature regulation, and meticulous surgical technique.

Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries.

Background: The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain. Methods: This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age. Findings: We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small. Interpretation: Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction. Funding: The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).

Arsenic disturbs neural tube closure involving AMPK/PKB-mTORC1-mediated autophagy in mice.

Arsenic exposure is a significant risk factor for folate-resistant neural tube defects (NTDs), but the potential mechanism is unclear. In this study, a mouse model of arsenic-induced NTDs was established to investigate how arsenic affects early neurogenesis leading to malformations. The results showed that in utero exposure to arsenic caused a decline in the normal embryos, an elevated embryo resorption, and a higher incidence of malformed embryos. Cranial and spinal deformities were the main malformation phenotypes observed. Meanwhile, arsenic-induced NTDs were accompanied by an oxidant/antioxidant imbalance manifested by elevated levels of reactive oxygen species (ROS) and decreased antioxidant activities. In addition, changes in the expression of autophagy-related genes and proteins (ULK1, Atg5, LC3B, p62) as well as an increase in autophagosomes were observed in arsenic-induced aberrant brain vesicles. Also, the components of the upstream pathway regulating autophagy (AMPK, PKB, mTOR, Raptor) were altered accordingly after arsenic exposure. Collectively, our findings propose a mechanism for arsenic-induced NTDs involving AMPK/PKB-mTORC1-mediated autophagy. Blocking autophagic cell death due to excessive autophagy provides a novel strategy for the prevention of folate-resistant NTDs, especially for arsenic-exposed populations.

Maternal Mental Health in Pregnancy and Its Impact on Children's Cognitive Development at 18 Months, during the COVID-19 Pandemic (CONCEPTION Study).

BACKGROUND: The COVID-19 pandemic has significantly affected the mental health of pregnant persons. OBJECTIVE: We aimed to evaluate the impact of maternal mental health and antidepressant use on children's cognitive development. METHODS: We followed a cohort of children born during the COVID-19 pandemic. Maternal mental health was self-reported during pregnancy (Edinburgh Postnatal Depression Scale, General Anxiety Disorder-7, stress levels, and antidepressant use). The child's cognitive development was measured using the third edition of the Ages & Stages Questionnaires® (ASQ-3) at 18 months. Multivariate multinomial logistic regression models were built to assess the association between in utero exposure to maternal mental health and ASQ-3 domains: communication, gross motor, fine motor, problem-solving, and personal-social. RESULTS: Overall, 472 children were included in our analyses. After adjusting for potential confounders, a need for further assessment in communication (adjusted odds ratio (aOR) 12.2, 95% confidence interval (CI) (1.60;92.4)), and for improvement in gross motricity (aOR 6.33, 95%CI (2.06;19.4)) were associated with in utero anxiety. The need for improvement in fine motricity (aOR 4.11, 95%CI (1.00; 16.90)) was associated with antidepressant exposure. In utero depression was associated with a decrease in the need for improvement in problem solving (aOR 0.48, 95%CI (0.24; 0.98)). CONCLUSIONS: During the COVID-19 pandemic, maternal mental health appears to be associated with some aspects of children's cognitive development.

Maternal Administration of Busulfan before in Utero Hematopoietic Cell Transplantation Improves Congenic Bone Marrow Cell Engraftment in a Murine Model.

In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative procedure that leads to donor cell chimerism and donor-specific tolerance. However, most clinical applications of IUHCT have failed because of low levels or even no engraftment of donor cells in immunologically normal fetuses. It is likely that the competition from the host hematopoietic compartment is the primary barrier to successful IUHCT, suggesting that conditioning methods that provide a competitive advantage to donor cells may lead to higher-level engraftment following IUHCT. This study aimed to research whether maternal administration of low-dose total body irradiation (TBI) or busulfan (BU) before IUHCT may result in increased donor cell chimerism in postnatal bone marrow transplantation in a congenic murine model. We first determined the birth and mortality rates after maternal administration of low-dose TBI (0, 2 or 4 Gy) or BU (5, 10, 15, or 20 mg/kg) before IUHCT in B6 mice. The mice that received 2 Gy TBI plus IUHCT showed significantly lower birth rate (23.3%) and a 100% 3-day mortality rate. The mice that received 10 mg/kg BU plus IUHCT had similar birth and 3-day mortality rates (58.6% and 0%) compared to mice that received IUHCT alone (61.1% and 4.55%). We then performed maternal administration of BU at 1 of 3 dosages (5, 10, or 15 mg/kg) at 24 hours before intrauterine transplantation of 2.5 × 105 B6GFP Sca-1+ bone marrow cells (BMCs) or 2.5 × 106 B6GFP BMCs on gestational day 14 (E14). Green fluorescent protein (GFP) chimerism in peripheral blood mononuclear cells (PBMCs), RBCs, and platelets of mice at 4 weeks of age was enhanced significantly with an increase in BU dose. Moreover, GFP chimerism of PBMCs from the B6GFP BMC group was significantly higher than that of the B6GFP Sca-1+ BMC group (22.56% versus 7.20%; P = .018). Finally, the pregnant mice were treated with 10 mg/kg of BU at E13, E14, or E15, followed by intrauterine transplantation of 2.5 × 106 B6GFP BMCs 24 hours later. Except for the short-term level of chimerism in PBMCs, which showed no significant difference among the 3 study groups, the results indicate that both short-term (age 4 weeks) and long-term (age 14 weeks) engraftment in PBMCs, RBCs, and platelets was higher in group E16 compared with groups E14 and E15. We also discovered that the engraftment was stable, multilineage, and increased with time. In conclusion, maternal administration of BU, but not of TBI, along with IUHCT could significantly enhance engraftment in a congenic murine model.

Impact of in utero tobacco exposure on fetal growth: Amount of exposure and second trimester fetal growth measurements.

BACKGROUND: Research reveals small and inconsistent findings linking prenatal tobacco exposure and early fetal growth, but failure to consider confounding and amount of exposure many explain inconsistencies. GOAL: To examine whether fetal growth effects following exposure to tobacco are evident in the second trimester, specific to certain growth parameters, and dose dependent. METHODS: Participants were pregnant women (64 smokers, 100 controls) with no other drug use. Available data included background/medical information and ultrasound measurements coded as percentiles. RESULTS: Controlling for background differences, 10+ cig/day predicted a 10+ percentile point reduction in estimated fetal weight, femur length, head circumference, and biparietal diameter compared to non-exposed controls. Exposure to <10 cig/day predicted significant reduction in only biparietal diameter. Exposure was unrelated to abdominal circumference. CONCLUSIONS: Results demonstrate utility of considering amount of exposure when examining/quantifying fetal growth effects, and suggest even reduction in early pregnancy smoking may positively benefit aspects of fetal development.