Search Results (24)

A child’s exposure to arsenic (As) can begin in utero through placental transfer to the fetus. There is a growing body of epidemiologic evidence suggesting an association between As exposure and neuropsychological development. Therefore, our objective was to describe the consequences of maternal and/or childhood As exposure on children’s neuropsychological development. We conducted a scoping review with a systematic search of the PubMed, Scopus, EMBASE, Web of Science, and PsycINFO databases. We included studies that assessed the association between maternal and/or childhood As exposure and neuropsychological development in children up to an average of 12 years of age. A total of 77 studies were included, most of which were published between 2020 and 2024 (44.1%), conducted in the United States of America (18.2%) and Bangladesh (16.9%), and involved participants with a median age of 6.6 years. Most studies performed cross-sectional analyses (51.9%) and assessed exposure to elements other than As (64.9%). Childhood was the most frequently studied exposure window (57.2%), and urine was the most commonly used biomarker of exposure (58.4%), followed by blood or serum (32.3%). Cognition was the most frequently evaluated neuropsychological domain (94.8%), followed by psychomotor function (40.3%) and social–emotional function (29.9%). Most studies reported evidence of a negative impact of As exposure on children’s neuropsychological development (73.7%), while some found no changes (27.3%) and a few suggested an improvement (1.3%). An important limitation is that most studies measured total urinary As without speciation into inorganic versus organic forms, which limits the validity of dose–response conclusions based on total arsenic concentrations. This review highlights the potential deleterious neuropsychological effects of maternal and/or childhood As exposure while also identifying areas where the evidence remains inconclusive. Full article

Background: The regionalisation of perinatal care emphasises the importance of transferring high-risk pregnancies “in utero” to minimise risks; yet, neonatal inter-facility transport remains necessary. Neonatal Emergency Transport Services (NETSs) play a crucial role in reducing transportation risks, especially for very preterm infants. Italy’s healthcare system, which is decentralised in nature, leads to variations in NETS organisation and resources across the country, resulting in disparities in access and quality of care. Methods: A questionnaire regarding neonatal transfer practices and NETS activity was sent to the 55 NETSs operating in twenty Italian regions. Demographic data were obtained from the Italian National Statistical Institute (ISTAT). Results: Survey Overview. A 2022 national survey by the Italian Society of Neonatology aimed to assess the status of NETS in Italy, achieving a 100% response rate from the 55 NETS. The 2022 data highlighted the transport of 6494 neonatal, of which 92% were primary transports (transferred to higher-level care) and 553 were back-transports (returning stabilised neonates to lower-level care). Subgroup analysis identified 544 transports of neonates born at 30–34 weeks of gestation and 305 transports of neonates born at under 30 weeks of gestation. This was shown to have regional variability. NETS coverage: 18 regions have full NETS coverage. Sicily offers partial coverage. Sardinia, despite an approved plan, lacks an operational NETS. Operational models: all NETS provide a 24/7 service; 50 NETSs rely on an on-call basis using NICU staff for transport. Only five NETS have dedicated teams exclusively for neonatal transport. This decentralisation results in heterogeneity in service availability, access, and quality. Conclusions: This study highlights that although differences still exist, the NETS in Italy is adequately structured and effective. The presence of NETS operating with limited transport volumes puts a strain on maintaining skilled staff and cost-effective operations. Regional disparities: inequities in NETS access (e.g., in Sicily and Sardinia regions) underline the need to improve regional collaboration. While Italy has made progress in organising NETS, regional discrepancies persist in access and service quality, reflecting the decentralised nature of its healthcare system. Full article

Phenols, parabens, and phthalates (PPPs) are suspected or known endocrine disruptors. They are used in consumer products that pregnant women and their progeny are exposed to daily through the placenta, which could affect offspring health. This review aims to compile data from cohort studies and in vitro and in vivo models to provide a summary regarding placental transfer, fetoplacental development, and the predisposition to adult diseases resulting from maternal exposure to PPPs during the gestational period. In humans, using the concentration of pollutants in maternal urine, and taking the offspring sex into account, positive or negative associations have been observed concerning placental or newborn weight, children’s BMI, blood pressure, gonadal function, or age at puberty. In animal models, without taking sex into account, alterations of placental structure and gene expression linked to hormones or DNA methylation were related to phenol exposure. At the postnatal stage, pollutants affect the bodyweight, the carbohydrate metabolism, the cardiovascular system, gonadal development, the age of puberty, sex/thyroid hormones, and gamete quality, but these effects depend on the age and sex. Future challenges will be to explore the effects of pollutants in mixtures using models and to identify the early signatures of in utero exposure capable of predicting the health trajectory of the offspring. Full article

In the last three decades, gene therapy has demonstrated significant progress. Over 700 active investigational new drug (IND) applications have been reported. Research on in utero gene therapy has advanced, but ethical and safety concerns persist. A novel approach under investigation is placental gene therapy, which holds promise for targeting diseases associated with placental dysfunction, such as fetal growth restriction (FGR) and preeclampsia. One of the underlying causes of placental insufficiency in these conditions is reduced placental growth factor-driven angiogenesis and endothelial cell dysfunction during fetal development. Studies have explored the overexpression of growth factor transgenes like IGF-1 to address FGR, yielding promising outcomes in animal models. Furthermore, intra-placental gene transfer, instead of systemic delivery of gene therapy vectors, has the potential to treat and cure these disorders. However, challenges and limitations akin to in utero gene therapy persist, including the risk of in utero infection, potential impairment of the mother’s future fertility, the risk of germline integration, and possible off-target effects of gene transfer in the fetus or the mother. Consequently, additional research and deliberation within the scientific and medical communities are warranted to fully comprehend the potential benefits and risks of placental gene therapy. Full article

In utero colonization or deposition of beneficial microorganisms and their by-products likely occurs through various mechanisms, such as hematogenous spread or ascension from the reproductive tract. With high-throughput sequencing techniques, the identification of microbial components in first-pass neonatal meconium has been achieved. While these components are low-biomass and often not abundant enough to culture, the presence of microbial DNA signatures may promote fetal immune tolerance or epigenetic regulation prior to birth. The aim of this study was to investigate the maternal source of the neonatal first-pass meconium microbiome. Maternal vaginal and anal samples collected from twenty-one maternal–infant dyad pairs were compared via principal component analysis to first-pass neonatal meconium microbial compositions. Results demonstrated the greatest degree of similarity between the maternal gut microbiome in the second and third trimesters and vaginal microbiome samples across pregnancy, suggesting that the maternal gut microbiota may translocate to the fetal gut during pregnancy. This study sheds light on the origin and timing of the potential transfer of maternal microbial species to offspring in utero. Full article

Bifidobacterium infantis are the primary colonizers of the infant gut, yet scientific research addressing the transmission of the genus Bifidobacterium to infants remains incomplete. This review examines microbial reservoirs of infant-type Bifidobacterium that potentially contribute to infant gut colonization. Accordingly, strain inheritance from mother to infant via the fecal-oral route is likely contingent on the bifidobacterial strain and phenotype, whereas transmission via the vaginal microbiota may be restricted to Bifidobacterium breve. Additional reservoirs include breastmilk, horizontal transfer from the environment, and potentially in utero transfer. Given that diet is a strong predictor of Bifidobacterium colonization in early life and the absence of Bifidobacterium is observed regardless of breastfeeding, it is likely that additional factors are responsible for bifidobacterial colonization early in life. Full article

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available. Full article

Activated monocytes/macrophages that produce inflammatory cytokines and nitric oxide are crucial for controlling Trypanosoma cruzi infection. We previously showed that uninfected newborns from T. cruzi infected mothers (M+B- newborns) were sensitized to produce higher levels of inflammatory cytokines than newborns from uninfected mothers (M-B- newborns), suggesting that their monocytes were more activated. Thus, we wondered whether these cells might help limit congenital infection. We investigated this possibility by studying the activation status of M+B- cord blood monocytes and their ability to control T. cruzi in vitro infection. We showed that M+B- monocytes have an upregulated capacity to produce the inflammatory cytokine TNF-α and a better ability to control T. cruzi infection than M-B- monocytes. Our study also showed that T. cruzi-specific Abs transferred from the mother play a dual role by favoring trypomastigote entry into M+B- monocytes and inhibiting intracellular amastigote multiplication. These results support the possibility that some M+B- fetuses may eliminate the parasite transmitted in utero from their mothers, thus being uninfected at birth. Full article

Uterus-related infertility affects 3–5% of all young women, including Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, hysterectomy, or severe Asherman syndrome. For these women with uterus-related infertility, uterus transplantation is now a viable option. We performed the first surgically successful uterus transplant in September 2011. The Donor was a 22-year-old nulliparous woman. After five failed pregnancy attempts (pregnancy losses), ET attempts were discontinued in the first case, and a search for underlying etiology was performed, including static and dynamic imaging studies. Perfusion computed tomography revealed an obstructed blood outflow, particularly in the left anterolateral part of the uterus. In order to correct blood flow obstruction, a revision surgery was planned. By laparotomy, a saphenous vein graft was anastomosed between the left utero-ovarian and left ovarian vein. Perfusion computed tomography performed after the revision surgery confirmed the resolution of venous congestion and a decrease in uterine volume as well. Following surgical intervention, the patient was able to conceive after the first embryo transfer attempt. The baby was delivered with cesarean section at 28 weeks’ gestation due to intrauterine growth restriction and abnormal Doppler ultrasonography findings. Following this case, our team performed the second uterus transplantation in July 2021. The recipient was a 32-year-old female with MRKH syndrome, and the donor was a 37-year-old multiparous braindead woman due to intracranial bleeding. After the transplant surgery, the second patient experienced menstrual bleeding six weeks after the operation. Seven months after the transplant, in the first ET attempt, pregnancy was achieved, and she delivered a healthy baby at 29 weeks of pregnancy. Uterus transplantation from a deceased donor is a feasible option for treating uterus-related infertility. When confronted with recurrent pregnancy losses, vascular revision surgery via arterial or venous supercharging could be an option in order to deal with focal underperfused areas defined by imaging studies. Full article

The developmental origins of health and disease (DOHaD) indicate that fetal tissues and organs in critical and sensitive periods of development are susceptible to structural and functional changes due to the adverse environment in utero. Maternal immune activation (MIA) is one of the phenomena in DOHaD. Exposure to maternal immune activation is a risk factor for neurodevelopmental disorders, psychosis, cardiovascular diseases, metabolic diseases, and human immune disorders. It has been associated with increased levels of proinflammatory cytokines transferred from mother to fetus in the prenatal period. Abnormal immunity induced by MIA includes immune overreaction or immune response failure in offspring. Immune overreaction is a hypersensitivity response of the immune system to pathogens or allergic factor. Immune response failure could not properly fight off various pathogens. The clinical features in offspring depend on the gestation period, inflammatory magnitude, inflammatory type of MIA in the prenatal period, and exposure to prenatal inflammatory stimulation, which might induce epigenetic modifications in the immune system. An analysis of epigenetic modifications caused by adverse intrauterine environments might allow clinicians to predict the onset of diseases and disorders before or after birth. Full article

Background: To assess changes in the number and profile of in utero transfer requests during the first lockdown. Methods: An observational, retrospective, cohort study. All pregnant women, from the Paris area (France), for whom a request for in utero transfer to the transfer unit was made during the first lockdown in France (from 17 March to 10 May 2020) or during a mirror period (years 2016 to 2019) were included. We compared the numbers and proportions of various indications for in utero transfer, the rates of in utero transfer acceptance and the proportion of outborn deliveries. Results: 206 transfer requests were made during the lockdown versus 227, 236, 204 and 228 in 2016, 2017, 2018 and 2019, respectively. The relative proportion of requests for threatened preterm births and for fetal growth restriction decreased from 45% in the mirror period to 37% and from 8 to 3%, respectively. The transfer acceptance rates and outborn deliveries did not differ between time periods. Conclusions: Although a reduction in in utero transfer requests was observed for certain indications, the first lockdown was not associated with a decrease in acceptance rates nor in an increase in outborn births of pregnancies with a high risk of prematurity in the Paris area. Full article

Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation. Full article

Germ cell quality is a key prerequisite for successful fertilization and early embryo development. The quality is determined by the fine regulation of transcriptomic and proteomic profiles, which are prone to alteration by assisted reproduction technology (ART)-introduced in vitro methods. Gaining evidence shows the ART can influence preset epigenetic modifications within cultured oocytes or early embryos and affect their developmental competency. The aim of this review is to describe ART-determined epigenetic changes related to the oogenesis, early embryogenesis, and further in utero development. We confront the latest epigenetic, related epitranscriptomic, and translational regulation findings with the processes of meiotic maturation, fertilization, and early embryogenesis that impact the developmental competency and embryo quality. Post-ART embryo transfer, in utero implantation, and development (placentation, fetal development) are influenced by environmental and lifestyle factors. The review is emphasizing their epigenetic and ART contribution to fetal development. An epigenetic parallel among mouse, porcine, and bovine animal models and human ART is drawn to illustrate possible future mechanisms of infertility management as well as increase the awareness of the underlying mechanisms governing oocyte and embryo developmental complexity under ART conditions. Full article

Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders. Full article

Premature infants are born prior to a critical window of rapid placental nutrient transfer and fetal growth—particularly brain development—that occurs during the third trimester of pregnancy. Subsequently, a large proportion of preterm neonates experience extrauterine growth failure and associated neurodevelopmental impairments. Human milk (maternal or donor breast milk) is the recommended source of enteral nutrition for preterm infants, but requires additional fortification of macronutrient, micronutrient, and energy content to meet the nutritional demands of the preterm infant in attempts at replicating in utero nutrient accretion and growth rates. Traditional standardized fortification practices that add a fixed amount of multicomponent fortifier based on assumed breast milk composition do not take into account the considerable variations in breast milk content or individual neonatal metabolism. Emerging methods of individualized fortification—including targeted and adjusted fortification—show promise in improving postnatal growth and neurodevelopmental outcomes in preterm infants. Full article