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Simple Summary: This scoping review provides an overview of the few observational studies that have investigated potential risk factors for acute lymphoblastic leukaemia in infants. It summarises some well-established associations in the literature, such as maternal exposure to pesticides and high birth weight, and outlines suggestive associations, such as heavy parental smoking, parental use of multiple medications, and maternal exposure to air pollution during pregnancy, that merit further research. The results of this review highlight the lack of research on infant acute lymphoblastic leukaemia, which contrasts with the large number of epidemiological studies investigating risk factors in childhood. Objective: Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer. Infant ALL (<1 year) is rare, but it captures a lot of interest due to its poor prognosis, especially in patients harbouring KMT2A rearrangements, which have been demonstrated to arise prenatally. However, epidemiological studies aimed at identifying specific risk factors in such cases are scarce, mainly due to sample-size limitations. We conducted a scoping review to elucidate the prenatal or perinatal factors associated with infant ALL. Methods: Original articles, letters, or conference abstracts published up to June 2022 were identified using the PubMed, Web of Science, and Embase databases, and 33 observational studies were selected. Results: The study reveals several well-established associations across the literature, such as maternal exposure to pesticides and high birth weight, and outlines suggestive associations, such as parental heavy smoking, parental use of several medications (e.g., dipyrone), and maternal exposure to air pollution during pregnancy. Conclusions: This scoping review summarizes the few observational studies that have analysed the prenatal and perinatal risk factors for ALL in infants diagnosed before the age of 1 year. The results of this review highlight the lack of research into this specific age group, which merits further research. [ABSTRACT FROM AUTHOR]

Prenatal exposure to the toxic metal inorganic arsenic (iAs) is associated with adverse pregnancy and fetal growth outcomes. These adverse outcomes are tied to physiological disruptions in the placenta. Although iAs co-occurs in the environment with other metals such as manganese (Mn), there is a gap in the knowledge of the effects of metal mixtures on the placenta. To address this, we exposed human placental trophoblast cells to iAs, Mn, and an iAs–Mn mixture at 3 concentrations and evaluated transcriptome-wide gene expression and placental migration. We hypothesized that co-exposure to iAs–Mn in a mixture would result in a synergistic/enhanced transcriptomic effect compared to either metal alone. We also anticipated that genes involved in inflammatory or immune-related pathways would be differentially expressed in relation to the mixture compared to single-metals. The results highlight that iAs exposure alone had a stronger genomic response than Mn exposure, with 2-fold the number of differentially expressed genes (DEGs). When analyzing DEGs present across all concentrations of study, the iAs–Mn mixture resulted in the greatest number of DEGs. The results highlight that iAs exposure alone influences the expression of toll-like receptor-initiated response pathways including Triggering Receptor Expressed on Myeloid Cells-1. Exposure to Mn alone influenced the expression of Nicotinamide adenine dinucleotide biosynthesis pathways. In contrast, exposure to the iAs–Mn mixtures resulted in altered expression of inflammatory and immune response-related pathways, including the Nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response pathway. Migration was unaffected by iAs, Mn, or the iAs–Mn mixture. These findings provide novel toxicogenomic insights into iAs- and Mn-induced placental transcriptomic dysregulations at environmentally relevant concentrations, with implications that in utero exposure to metal mixtures can influence inflammatory and immune pathways within the placenta. [ABSTRACT FROM AUTHOR]

Introduction: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation and Mitigation Strategy (REMS) program. It is unclear whether these programs target those medications with the most significant impact on public health and adverse pregnancy outcomes. Objectives: This study aims to develop an innovative decision support tool that uses explicit, quantifiable criteria to facilitate prioritization of teratogenic medications for risk mitigation strategies. Methods: The Teratogenic Risk Impact and Mitigation (TRIM) decision support tool will be developed by a national panel via a modified Delphi approach to define measurable criteria, and a multi-criteria decision analysis to estimate criteria weights within a discrete choice experiment. The TRIM scores will then be calculated for 12 teratogenic drugs with active or eliminated REMS programs and for 12 teratogenic drugs without REMS. These drugs will be identified based on highest prenatal exposure prevalence in claims data of privately and publicly insured individuals. Data for the TRIM criteria levels for these 24 drugs will be identified from evidence searches and ad hoc analyses of the same claims data. Conclusions: Teratogenic Risk Impact and Mitigation is intended to inform regulatory decision making about the need for risk mitigation programs for teratogenic medications by providing explicit, quantifiable, evidence-based criteria. The TRIM scores of 24 teratogenic drugs may provide benchmarks for considering REMS for marketed and new teratogenic medications. [ABSTRACT FROM AUTHOR]

Data are lacking regarding the long-term consequences of SARS-CoV-2 and COVID-19 mRNA vaccine on infants exposed in utero. We aimed to evaluate the neurodevelopment of infants exposed prenatally to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy at 12 months after birth. Infants born to mothers exposed to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy, or unexposed to either the virus or the vaccine were enrolled from 2021 to 2023. Infants with prenatal exposure to the virus or vaccine were compared with infants without prenatal exposure to the virus and/or vaccine. Parents received a neurodevelopmental questionnaire (ages and stages questionnaire third edition) at 12 months after birth assessing five subdomains: communication, gross motor, fine motor, problem-solving, and personal social development. A low score was defined as <2 standard deviations below the normative mean in at least one of the subdomains. A total of 330 infants were included (76 in the SARS-CoV-2 group, 153 in the mRNA-COVID-19 vaccine group, and 101 in the reference group). In utero exposure to the SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one subdomain compared with the reference group. The crude ORs were 1.16 (95% CI, 0.59–2.28) and 1.04 (95% CI, 0.58–1.86), respectively. Results remained consistent in the multivariate analysis, showing no increased risk of a low score for at least one subdomain for infants exposed to the SARS-CoV-2 or mRNA-COVID-19 vaccine, compared with the reference group. The adjusted ORs were 1.74 (95% CI, 0.76–3.99) and 0.76 (95% CI, 0.39–1.49), respectively. In utero exposure to SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one ages and stages questionnaire third edition subdomain at 12 months after birth. Additional studies are needed to confirm our results, especially longer-term evaluation of infant development. [ABSTRACT FROM AUTHOR]

Antibiotics are widely used during pregnancy. Recent epidemiological studies suggest that maternal exposure to antibiotics during pregnancy is associated with increased risks of various diseases in offspring; host-microbiome interactions are considered to be involved in pathogenesis, as antibiotic-induced perturbations (dysbiosis) of the maternal microbiome can be transmitted to offspring. We reviewed the current status of antibiotic usage during pregnancy, transmission of maternal antibiotic-induced dysbiosis to offspring, and several diseases in offspring reported to be associated with maternal antibiotic exposure. Antibiotics must be properly used when necessary. While the adverse effect of maternal antibiotic exposure during pregnancy on the health of offspring has been demonstrated by several studies, more robust clinical evidence is necessary to define the best practice for antibiotic use during pregnancy. Epidemiologic studies have limitations in establishing causal links beyond associations; animal studies provide benefits in examining these links, however, microbiomes, gestation courses, and aging vary between host species. Understanding the underlying mechanisms of epidemiologic findings as well as the healthy microbiome during pregnancy and early life in humans would contribute to developing future microbial interventions for restoring antibiotic-induced dysbiosis during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The 2D:4D digit ratio (DR), representing the relative length of the index finger to the ring finger, is an anthropometric marker that shows sexual dimorphism, with males typically having a lower ratio than females. This parameter is linked to prenatal androgen exposure (PAE), which influences sexual differentiation of the brain and behavior. This study aimed to investigate the correlation between PAE and sleep among young adults. Methods: Anthropometric measurements were used to assess PAE, while sleep was evaluated using the Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ), actigraphy, and polysomnography (PSG). Data was collected from 720 participants via surveys, with 290 completing all questionnaires. Of these, 138 underwent anthropometric measurements, and 38 were further recruited for actigraphy, PSG. Results: Men exhibited a lower 2D:4D ratio than women, indicating higher PAE. The average PSQI score was 6.94 ± 2.98, and the MEQ score was 35.43 ± 19.59, with no significant gender differences in sleep quality or chronotype. Low PAE was associated with better sleep efficiency and a morning chronotype, but worse sleep quality in males. Actigraphy results showed no significant differences based on PAE. PSG data revealed that males with longer 2nd fingers and higher 2D:4D ratios were more likely to suffer from mild sleep apnea, a pattern not observed in women. PAE did not significantly impact other sleep architecture parameters. Conclusions: PAE, indicated by the 2D:4D ratio, is linked to sleep efficiency and chronotype, with significant gender differences. Men with lower PAE exhibited poorer sleep quality, and those with certain finger length patterns were more prone to mild sleep apnea. These findings underscore the potential long-term impacts of PAE on sleep health and emphasize the need for further research into gender-specific sleep regulation mechanisms. [ABSTRACT FROM AUTHOR]

Background: Prenatal maternal smoking, lower birthweight, and shorter breastfeeding duration have all been associated with an earlier age at menopause in daughters. We estimated the extent to which birthweight-for-gestational-age z-score and breastfeeding duration mediate the effect of prenatal maternal smoking on time to natural menopause in daughters. Methods: Using pooled data from two prospective birth cohort studies – the 1970 British Cohort Study (n = 3,878) followed-up to age 46 years and the 1958 National Child Development Study (n = 4,822) followed-up to age 50 years – we perform mediation analysis with inverse odds weighting implemented in Cox proportional-hazards models. Results: Prenatal maternal smoking was associated with lower birthweight z-scores [β: -0.29; 95% CI -0.34, -0.24] and reduced breastfeeding duration [RRR< 1month: 0.90; 95% CI 0.79, 1.02; RRR≥ 1 month: 0.66; 95% CI 0.59, 0.73 relative to women who were never breastfed]. Greater z-score for birthweight [HR: 0.96; 95% CI 0.91, 1.01] and longer breastfeeding duration [HR≥ 1 month: 0.84; 95% CI 0.74, 0.96] were associated with lower hazards for earlier age at natural menopause. The total effect of prenatal maternal smoking on the time to natural menopause in daughters was estimated as a HR of 1.13 [95% CI 1.02, 1.24]. Birthweight z-score and breastfeeding duration jointly explained an estimated 14% of the total effect [HRNIE: 1.02; 95% CI 0.99, 1.05]. Conclusions: The consequences of smoking during pregnancy on the earlier experience of natural menopause in daughters may partly be offset by intrauterine growth and longer breastfeeding duration to the extent that they mediate the risk of earlier menopause. However, since the extent of mediation by birthweight z-score and breastfeeding duration is small, other factors, including the direct effect of maternal smoking in utero, may play a more important role. [ABSTRACT FROM AUTHOR]

Background: Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders. Methods: We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses. Results: Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., βwork = − 0.01 [95%CI: − 0.02, − 0.01]), earlier birth (e.g., βwork = − 0.04 [95%CI: − 0.04, − 0.03])), and more emotional (e.g., βevents = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., βrelationship = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally. Conclusions: Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed. [ABSTRACT FROM AUTHOR]

Significance: Women are at increased risk for mood disorders, which may be partly attributed to exposure to endocrine-disrupting chemicals (EDCs) during sensitive periods such as pregnancy. Exposure during these times can impact brain development in the offspring, potentially leading to mood disorders in later life. Additionally, fluctuating levels of endogenous estrogens, as seen during pregnancy, or the use of oral contraceptives, can further elevate this risk. This study examines the cumulative effects of prenatal EDC exposure combined with chronic low-dose 17β-estradiol (E2) treatment in adulthood on neurobehavioral outcomes. Methods: Pregnant Sprague-Dawley rats were orally dosed with vehicle, bisphenol A (BPA) (5 μg/kg body weight (BW)/day), low-dose (LD) diethylhexyl phthalate (DEHP) (5 μg/kg BW/day), high-dose (HD) DEHP (7.5 mg/kg BW/day), or a combination of the two (BPA+DEHP) from gestational days 6-21. At 3 months of age, female offspring were implanted with slow-release E2 pellets or were sham-implanted. Following a 90-day treatment period, behavioral testing was conducted, and serum hormones and brain monoamine levels were analyzed. Results: Chronic E2 treatment in controls increased anxiety and reduced active coping behaviors. In DEHP- and BPA+DEHP-exposed offspring, E2 treatment reversed some of these effects. Dose-dependent alterations in circulating hormone levels and brain monoamines were observed. Dysregulation of the stress axis was particularly notable with the higher dose of DEHP. Conclusions: Overall, prenatal EDC exposure altered behavior, hormones, and brain monoamines, with adult E2 treatment further exacerbating some of these effects in female offspring. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA), one of the most widely produced plasticisers, can have a major effect on the growing embryo and the mother during pregnancy; as this is the most vulnerable period, the cutoff established in the legislation does not take this factor into account. Thus, this narrative review aims to highlight the consequences for the foetus and the pregnant woman of maternal and foetal exposure to BPA by analysing epidemiological and experimental studies on humans. Extensive research has examined the effects of BPA on several systems outcomes. Specifically, BPA exposure affects the immune system of the offspring and promotes the development of respiratory diseases, including asthma and wheezing. Moreover, BPA has been negatively associated with children's neurodevelopment, leading to behavioural changes; autism; and reproductive changes, mainly deviations in anogenital distance, sexual hormone levels and sexual maturation, which can result in infertility. Furthermore, in mothers, BPA exposure may be linked to pre-eclampsia and gestational diabetes mellitus and affects birth parameters, leading to a higher risk of preterm delivery, shorter birth lengths and lower birth weights, although the results were not always consistent. These results demonstrate the urgent need for stricter legislation banning the use of BPA during pregnancy to reduce the hazards to the health and development of the foetus and the unborn child. [ABSTRACT FROM AUTHOR]

Background: Gestational Zika virus (ZIKV) infection is associated with the development of congenital Zika syndrome (CZS), which includes microcephaly and fetal demise. The magnitude and quality of orthoflavivirus-specific humoral immunity have been previously linked to the development of CZS. However, the role of ZIKV NS1-specific humoral immunity in mothers and children with prenatal ZIKV exposure and CZS remains undefined. In addition, considering that most of the at-risk population lives in dengue virus (DENV)-endemic areas, it is not clear what is the association between pre-existing DENV NS1-specific humoral immunity and CZS. Methods: Here, we studied 328 mothers and children with a clinical diagnosis and seropositivity for ZIKV infection during pregnancy, included during the 2015–2016 ZIKV epidemic in Colombia. We also performed clinical evaluation and pediatric neurological follow-up. The relative levels of circulating NS1-specific IgM and IgG against ZIKV and DENV were evaluated in mothers and children, and the association with the development of microcephaly was analyzed. Results: DENV and ZIKV IgG-NS1 antibodies in pregnant women were placentally transferred, and this passage and its duration in children depended on the maternal levels of the antibodies. We reported that higher concentrations of pre-existing DENV, but not ZIKV IgG-NS1 antibodies, were associated with a reduced risk of CZS-related microcephaly. Also, we observed that the IgM-NS1 response in infants is long-term and has a minor association with poor outcomes. Conclusions: The development of microcephaly in children prenatally exposed to ZIKV is associated with low plasma levels of placentally transferred, pre-existing DENV IgG-NS1 antibodies. These data are compatible with a protective role of anti-NS1 IgG antibodies against ZIKV infection during pregnancy and highlight the promising role of NS1 as an orthoflavivirus vaccine target in high-risk populations. Author summary: The impact of preexisting DENV anti-NS1 antibodies on the outcome of prenatal ZIKV infection in viral cocirculation areas is a critical and unsolved issue. Here, we show that DENV and ZIKV IgG-NS1, but not NS1-IgM, are placentally transferred to infants. The efficiency and lasting of transferred NS1 antibodies depend on the magnitude of circulating NS1-IgG in mothers. A low or absent DENV NS1-IgG was the most critical characteristic of mothers and children with CZS-related microcephaly, supporting a protective role of preexisting DENV NS1 humoral immunity. These findings will be helpful for future vaccine designs, risk population identification, and updated medical guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and communication, along with restricted and repetitive behaviors. Both genetic and environmental factors contribute to ASD, with prenatal exposure to valproic acid (VPA) and nicotine being linked to increased risk. Impaired adult hippocampal neurogenesis, particularly in the ventral region, is thought to play a role in the social deficits observed in ASD. Methods: In this study, we investigated social behavior and adult hippocampal neurogenesis in C57BL/6J mice prenatally exposed to VPA or nicotine, as well as in genetically modified ASD models, including IQSEC2 knockout (KO) and NLGN3-R451C knock-in (KI) mice. Sociability and social novelty preference were evaluated using a three-chamber social interaction test. Adult hippocampal neurogenesis was assessed by BrdU and DCX immunofluorescence to identify newborn and immature neurons. Results: VPA-exposed mice displayed significant deficits in social interaction, while nicotine-exposed mice exhibited mild impairment in social novelty preference. Both IQSEC2 KO and NLGN3-R451C KI mice demonstrated reduced adult neurogenesis, particularly in the ventral hippocampus, a region associated with social behavior and emotion. Across all ASD mouse models, a significant reduction in BrdU+/NeuN+ cells in the ventral hippocampus was observed, while dorsal hippocampal neurogenesis remained relatively unaffected. Similar reductions in DCX-positive cells were identified in VPA, nicotine, and NLGN3-R451C KI mice, indicating impaired proliferation or differentiation of neuronal progenitors. Discussion: These findings suggest that impaired adult neurogenesis in the ventral hippocampus is a common hallmark across ASD mouse models and may underlie social behavior deficits. This study provides insight into region-specific neurogenic alterations linked to ASD pathophysiology and highlights potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal nicotine exposure (PNE) from maternal smoking disrupts regulatory processes vital to fetal development. These changes result in long-term behavioral impairments, including mood and anxiety disorders, that manifest later in life. However, the relationship underlying PNE, and the underpinnings of mood and anxiety molecular and transcriptomic phenotypes remains elusive. Methods: To model nicotine exposure during prenatal development, our study used human cerebral organoids that were chronically exposed to nicotine and collected for molecular analyses. Results: Short-term, nicotine altered molecular markers of neural identity, mood and anxiety disorders and those involved in maintaining the excitatory/inhibitory (E/I) balance in the cortex. RNA sequencing further revealed transcriptomic changes in genes pertaining to embryonic development, neurogenesis, and DNA binding. Long-term, mature organoids demonstrated similar disruptions in E/I balance, decreased expression of neural identity markers, and altered dopamine receptor expression. Discussion: Collectively, our results demonstrate that nicotine-induced alterations occur acutely and persist at later stages of development. These findings validate an in vitro model of PNE to better comprehend the emergence of neuropsychiatric molecular and transcriptomic endophenotypes resulting from gestational nicotine exposure. [ABSTRACT FROM AUTHOR]

• Subchronic in-utero ETI exposure shows no cataract formation in fetal rat eyes. • Optical coherence tomography reveals increased lens thickness in ETI-exposed pups. • Histological analysis indicates increased lens cavity area in ETI-exposed pups. Elexacaftor-tezacaftor-ivacaftor (ETI) is a drug treatment for cystic fibrosis that is debatable for use in pregnant women. Fetal ocular changes following prenatal exposure and while breastfeeding to ETI have been reported. The aim of this study was to assess eye development in rat fetuses following in-utero exposure to ETI. Eyes from Sprague Dawley rats born to dams given clinically relevant ETI or sham treatment from embryonic day 12–19 (E12-E19) were investigated using histology and optical coherence tomography (OCT). Lens thickness was higher in the ETI-exposure group, as measured by OCT (p = 0.0003). Lens cavities were observed in both groups, but the median individual lens cavities area was higher in the ETI-exposed eyes (p < 0.0001), as measured by histology. In-utero exposure to ETI during E12-E19 was associated with subtle changes to lens anatomy, however the mechanism and clinical significance of this observation requires further investigation. [Display omitted] [ABSTRACT FROM AUTHOR]

• Little is known about the impact of COVID-19 during pregnancy on newborn immunity at birth. • Whether the altered newborn immunity from prenatal COVID-19 exposure is linked to increased neurodevelopmental disorders is largely unknown. • Our cohort study suggests that in utero exposure to COVID-19 may be associated with changes in neonatal immune marker levels, observable at birth. • Among newborns with in utero exposure to COVID-19, higher levels of neonatal IL-22 was associated with lower risk of a later diagnosis of an NDD. Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID+] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID+ mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID+ mothers had significantly higher levels of IL-22 (estimate [est.] = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (est. = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID+ mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (hazard ratio [HR] = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns of COVID + mothers may be linked to an increased risk of a subsequent diagnosis of an NDD. [ABSTRACT FROM AUTHOR]

• Microglia-containing cerebral organoids to study immune challenges during neurodevelopment. • Microglia influence the organoid structure and its expression of ciliated and mesenchymal genes. • Cerebral organoids show distinct responses to inflammatory stimuli. • IFN-γ organoid exposure induces significant changes, partly influenced by microglia. • IFN-γ alters the cerebral organoid expression of genes associated with autism. Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes. [ABSTRACT FROM AUTHOR]

• Maternal CRP (<10 mg/L) is regionally associated with cortical morphology. • High maternal CRP above 10 mg/L predicts cortical measures predominantly in females. • Associations were mostly non-linear, sex-dependent, and specific to each cohort/age. Maternal immune activation (MIA) during pregnancy is implicated in offspring psychiatric disorders. However, it is unknown to what extent MIA affects neurodevelopment, particularly cerebrocortical anatomy, in the general population, and whether effects differ by sex. The current study used vertex-wise statistics to examine the association between maternal prenatal CRP, an archetypal systemic inflammatory marker, and offspring cortical thickness, surface area, and volume, in 2635 mother–child dyads (5.4–26.5 years) from three population-based cohorts, and one clinical cohort enriched for presence of inflammation markers. Maternal CRP within a normal physiological range (<10 mg/L) exhibited sex-specific quadratic associations with cortical morphological measures in 2 regions in males and 1 region in females at childhood. Elevated (>10 mg/L) CRP was associated with regional cortical morphology in females and in a pooled sample of sexes. Overall, MIA is associated with cortical development in a regional and sex-specific manner in studies spanning childhood to adulthood. [ABSTRACT FROM AUTHOR]

Drought induced by climate change poses a serious threat to human health. The gut microbiome also plays a critical role in human health. However, no studies have explored the effect of drought on the human gut microbiome. Therefore, our study aimed to investigate the relationship between drought and gut microbiome. Our study included 59 mothers and 38 neonates in our study. 16S rRNA V3-V4 sequencing was used to profile the gut microbiome. The Standardized Precipitation Evapotranspiration Index (SPEI) was used to represent drought characteristics. KEGG pathway level 3 was employed for functional analysis. Generalized linear models were used to explore the effect of drought on the gut microbiome. Mothers and neonates were divided into the LSPEI (Lower SPEI) group or HSPEI (Higher SPEI) group by calculating the average levels of prenatal SPEI levels. The maternal and neonatal gut microbiome exhibited similar diversities in terms of alpha and beta diversity between the LSPEI and HSPEI groups. However, notable differences were observed in their composition. We found that in the neonatal gut microbiome, Sediminibacterium and Thermovirga were positively associated with SPEI after controlling for PM2.5 in linear regression models. Additionally, SPEI was significantly associated with phenylpropanoid biosynthesis and cyanoamino acid metabolism in neonates. This study identified that prenatal SPEI levels were correlated with specific maternal and neonatal gut microbial taxa, as well as neonatal gut microbial functional pathways. Future studies should further investigate the mechanisms by which drought exposure influences maternal and neonatal gut microbial diversities, composition, and functional pathways. [ABSTRACT FROM AUTHOR]