The characterization of developmental toxicity in fetal offspring induced by acetaminophen exposure during pregnancy.

OBJECTIVE: Acetaminophen (APAP), an antipyretic and analgesic commonly used during pregnancy, has been recognized as a novel environmental contaminant. Preliminary evidence suggests that prenatal acetaminophen exposure (PAcE) could adversely affect offspring's gonadal and neurologic development, but there is no systematic investigation on the characteristics of APAP's fetal developmental toxicity. METHODS: Pregnant mice were treated with 100 or 400 mg/kg∙d APAP in the second-trimester, or 400 mg/kg∙d APAP in the second- or third-trimester, or different courses (single or multiple) of APAP, based on clinical regimen. The effects of PAcE on pregnancy outcomes, maternal/fetal blood phenotypes, and multi-organ morphological and functional development of fetal mice were analyzed. RESULTS: PAcE increased the incidence of adverse pregnancy outcomes and altered blood phenotypes including aminotransferases, lipids, and sex hormones in dams and fetuses. The expression of key functional genes in fetal organs indicated that PAcE inhibited hippocampal synaptic development, sex hormone synthesis, and osteogenic and chondrogenic development, but enhanced hepatic lipid synthesis and uptake, renal inflammatory hyperplasia, and adrenal steroid hormone synthesis. PAcE also induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage. The sensitivity rankings of fetal organs to PAcE might be hippocampus/bone > kidney > cartilage > liver > gonad > adrenal gland. Notably, PAcE-induced multi-organ developmental toxicity was more considerable under high-dose, second-trimester, and multi-course exposure and in male fetuses. CONCLUSION: This study confirmed PAcE-induced alterations in multi-organ development and function in fetal mice and elucidated its characteristics, which deepens the comprehensive understanding of APAP's developmental toxicity.

One-Carbon Metabolites Supplementation and Nutrient Restriction Alter the Fetal Liver Metabolomic Profile during Early Gestation in Beef Heifers.

Maternal nutrition is pivotal for proper fetal development, with one-carbon metabolites (OCM) playing a key role in fetal epigenetic programming through DNA and histone methylation. The study aimed to investigate the effects of nutrient restriction and OCM supplementation on fetal liver metabolomics in pregnant beef-heifers, focusing on metabolites and pathways associated with amino-acid, vitamin and cofactor, carbohydrate, and energy metabolism at day 63 of gestation. Thirty-one crossbred Angus heifers were artificially inseminated and allocated to four nutritional treatments in a 2 × 2 factorial arrangement of treatments, with the two factors being dietary intake/rate of gain (control-diet [CON]; 0.60 kg/day ADG, vs. restricted-diet [RES]; -0.23 kg/day ADG) and OCM supplementation (supplemented [+OCM] vs. not supplemented [-OCM]). The resulting treatment groups-CON-OCM, CON+OCM, RES-OCM, and RES+OCM were maintained for 63 days post-breeding. Following this period, fetal liver tissues were collected and subjected to metabolomic analysis using UPLC-tandem mass-spectrometry. We identified 288 metabolites, with the majority (n = 54) being significantly influenced by the main effect of gain (P ≤ 0.05). Moreover, RES showed decreased abundances of most metabolites in pathways such as lysine metabolism; leucine, isoleucine and valine metabolism; and tryptophan metabolism, compared to CON. Supplementation with OCM vs. no OCM supplementation, resulted in greater abundance of metabolites (P ≤ 0.05) affecting pathways associated with methionine, cysteine, S-adenosylmethionine and taurine metabolism; guanidino and acetamido metabolism; and nicotinate and nicotinamide metabolism. Notably, OCM supplementation with a moderate rate of gain increased the concentrations of ophthalmate, N-acetylglucosamine, and ascorbic-acid 3-sulfate, which are important for proper fetal development (P ≤ 0.05). Nutrient restriction reduced the majority of liver metabolites, while OCM supplementation increased a smaller number of metabolites. Thus, OCM supplementation may be protective of metabolite concentrations in key developmental pathways, which could potentially enhance fetal development under nutrient-restricted conditions.

Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

Development of an AI-Assisted Embryo Selection System Using Iberian Ribbed Newts for Embryo-Fetal Development Toxicity Testing.

Background: The 3Rs (Reduction, Refinement, Replacement) principle is driving the need for alternative methods in animal testing. Despite advancements in in vitro testing, complex systemic toxicity tests still necessitate in vivo approaches. The aim of this study was to develop a developmental toxicity test protocol using the Iberian ribbed newt (Pleurodeles waltl) as a model organism, integrating AI image analysis for embryo selection to improve test accuracy and reproducibility. Methods: We established a developmental toxicity test protocol based on the zebrafish test. Gonadotropin was administered to induce ovulation, and in vitro fertilization was performed. Embryos were imaged at 5-6 and 6-7 h post-fertilization. AI image analysis was utilized to assess embryo viability. The test chemical was administered 24-48 h post-fertilization, and morphological changes were observed daily until day 8. Additionally, a time-lapse photography system was constructed to monitor embryonic development. Results: Out of 24 cultured embryos, 75% developed normally to the late tail bud stage or initial hatching stage, whereas 25% experienced developmental arrest or death. AI image analysis achieved high accuracy in classifying embryos, with overall accuracies of 92.0% and 92.9% for two learning models. The AI system demonstrated higher precision in the selection of viable embryos compared to visual inspection. Conclusion: The Iberian ribbed newt presents a viable alternative model for developmental toxicity testing, adhering to the 3Rs principles. The integration of AI image analysis substantially enhances the accuracy and reproducibility of embryo selection, providing a reliable method for evaluating developmental toxicity in pharmaceuticals.

Maternal Malnutrition and Elevated Disease Risk in Offspring.

US populations have seen dramatic increases in the prevalence of chronic disease over the past three generations. Rapid increases in type 2 diabetes and obesity have occurred in all the states but have been particularly striking in the Deep South. These increases have contributed to decreases in life expectancy and to painful elevations in health care costs. The causes of worsening population health are complex and incompletely understood. However, there is strong evidence that vulnerability to chronic conditions is determined in early life. Most chronic diseases are developmentally driven. There are specific stressors experienced in early life that influence epigenetic and structural changes during development. These include malnutrition, severe levels of social stress, toxic chemicals, and low oxygen levels. Most US populations have experienced a decrease in the quality of the food they consume as industrial foods have replaced garden-grown foods. Thus, the consumption of too few nutrients before and during pregnancy and during lactation influences the growth of the placenta and fetal organs and their level of resilience when faced with stresses in postnatal life and particularly as adults. Animal studies have shown that the effects of poor nutrition can be passed on to future generations. The most powerful way that the current epidemics of obesity and insulin resistance can be reversed is by providing key nutrients to prospective mothers and those already pregnant.

Development and cross-sectional morphology of the recurrent laryngeal nerves in human fetuses.

The recurrent laryngeal nerve is a bilateral branch of the vagus nerve that is mainly associated with the motor innervation of the intrinsic muscles of the larynx. Despite its bilateral distribution, the right and left recurrent laryngeal nerves display unequal length due to embryological processes related to the development of the aortic arches. This length asymmetry leads to theories about morphological compensations to provide symmetrical functions to the intrinsic muscles of the larynx. In this study we investigated the developmental and cross-sectional morphometrics of the recurrent laryngeal nerves in human fetuses. Fifteen stillbirth fetuses donated to anatomical and medical research were used for investigation. Fetuses had intrauterine age ranging from 30 to 40 weeks estimated by biometry methods. Specialized anatomical dissection of the visceral block of the neck was performed to prepare histological samples of the recurrent laryngeal nerves in its point of contact with the larynx, and morpho-quantitative techniques were applied to evaluate the epineurium and perineural space of the recurrent laryngeal nerves. No statistical difference in the cross-sectional morphology of the epineurium and perineural space between right and left recurrent laryngeal nerves intra-individually was confirmed, however, we found evidence that these structures are under greater development in the left recurrent laryngeal nerve during 30 to 40 weeks of intrauterine life. Our data suggest that the nerves are under morphological development that possibly set the stage for accommodation of larger diameter and myelinization of the left recurrent laryngeal nerve during post-natal life.

Longitudinal associations between urinary biomarkers of phthalates and replacements with novel in vivo measures of placental health.

STUDY QUESTION: What is the longitudinal association between gestational phthalate exposure and in vivo placental outcomes? SUMMARY ANSWER: Phthalates were adversely associated with placental microvasculature, stiffness, and presence of calcification, with different metabolites associated with different outcomes. WHAT IS KNOWN ALREADY: Phthalate exposure is ubiquitous and implicated as a contributor to adverse pregnancy outcomes, possibly through impacts on the placenta. STUDY DESIGN, SIZE, DURATION: A total of 303 women were recruited in early pregnancy and prospectively followed for up to eight visits across gestation in the Human Placenta and Phthalates study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At each visit, women provided urine samples and underwent placental ultrasounds. Urine was analyzed for 18 metabolites of phthalates and replacements. We took the geometric mean of repeated measurements to reflect pregnancy-averaged phthalate or replacement exposure for each participant (n = 303). Placental microvasculature, stiffness, and microcalcification presence were quantified from ultrasounds at each visit. Higher scores reflected worse placental function for all measures. Generalized linear mixed models were created to estimate the association between pregnancy-averaged exposure biomarker concentrations and repeated outcome measurements for microvasculature and stiffness. Gestational age at the time of calcification detection was modeled using Cox proportional hazards models. MAIN RESULTS AND THE ROLE OF CHANCE: Monocarboxyisononyl phthalate and summed di(2-ethylhexyl) phthalate metabolites were associated with impaired microvasculature development, such that an interquartile range increase in concentration was associated with 0.11 standard deviation increase in the microvasculature ratio, indicating poorer vascularization (95% CI: 0.00, 0.22); 0.11 [95% CI: -0.01, 0.22], respectively. Monoethyl phthalate was associated with increased placental stiffness (0.09 [95% CI: -0.01, 0.19]) while summed di-iso-butyl phthalate metabolites and monobenzyl phthalate were associated with increased hazard of calcification detection (hazard ratios: 1.18 [95% CI: 0.98, 1.42]; 1.13 [95% CI: 0.96, 1.34]). LIMITATIONS, REASONS FOR CAUTION: Outcomes used in this study are novel and further investigation is needed to provide clinical context and relevance. WIDER IMPLICATIONS OF THE FINDINGS: We found evidence of associations between select phthalate biomarkers and various aspects of in vivo placental health, although we did not observe consistency across placental outcomes. These findings could illustrate heterogeneous effects of phthalate exposure on placental function. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES103344), and NIEHS T32ES007018. The authors declare that they have no competing interests to disclose. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services. TRIAL REGISTRATION NUMBER: N/A.

Impact of Bisphenol A exposure on maternal gut microbial homeostasis, placental function, and fetal development during pregnancy.

Pregnancy is extremely vulnerable to external environmental influences. Bisphenol A, an endocrine-disrupting chemical, poses a significant environmental hazard to individuals of all ages and stages, particularly during pregnancy. The placenta is a temporary organ facilitating the connection between the mother and fetus. While it can detoxify certain exogenous substances, it is also vulnerable to the impacts of endocrine disruptors. Likewise, the intestinal flora is highly sensitive to exogenous stresses and environmental pollutants. The regulation of gut microbiota plays a crucial role in ensuring the health of both the mother and the fetus. The gut-placental axis connects the gut, gut microbes, placenta, and fetus. Exploring possible effects on placental function and fetal development involves analyzing changes in gut microbiota composition. Given that bisphenol A may cross the intestine and affect intestinal function, gut microorganisms, and their metabolites, as well as its potential impact on the placenta, resulting in impaired placental function and fetal development, this study aims to establish a link between bisphenol A exposure, intestinal microorganisms, placental function, and fetal development. This paper seeks to analyze the effects of maternal exposure to bisphenol A during pregnancy on the balance of the maternal gut microbiota, placental function, and fetal development, considering the key role of the gut-placental axis. Additionally, this paper proposes potential directions for future research emphasizing the importance of mitigating the adverse outcomes of bisphenol A exposure during pregnancy in both human and animal studies.

Placental Epigenome Impacts Fetal Development: Effects of Maternal Nutrients and Gut Microbiota.

Evidence is emerging on the role of maternal diet, gut microbiota, and other lifestyle factors in establishing lifelong health and disease, which are determined by transgenerationally inherited epigenetic modifications. Understanding epigenetic mechanisms may help identify novel biomarkers for gestation-related exposure, burden, or disease risk. Such biomarkers are essential for developing tools for the early detection of risk factors and exposure levels. It is necessary to establish an exposure threshold due to nutrient deficiencies or other environmental factors that can result in clinically relevant epigenetic alterations that modulate disease risks in the fetus. This narrative review summarizes the latest updates on the roles of maternal nutrients (n-3 fatty acids, polyphenols, vitamins) and gut microbiota on the placental epigenome and its impacts on fetal brain development. This review unravels the potential roles of the functional epigenome for targeted intervention to ensure optimal fetal brain development and its performance in later life.

Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

Impact of Microplastics on Pregnancy and Fetal Development: A Systematic Review.

Microplastic (MP) pollution is a growing global concern because of its potential to impair human health, particularly with regard to fetal development. However, the origins of prenatal MP exposure and its effects on fetal development have not been well studied. This study aimed to provide a systematic review of the literature regarding the impact of microplastics on pregnancy and fetal development. PubMed, Embase, ScienceDirect, Web of Science, Scopus, and Google Scholar were searched from 2010 until March 2024. Original publications exploring the impact of microplastics on pregnancy and fetal development were included in the study. After selecting papers, two independent reviewers extracted data regarding study characteristics, microplastics identified, and reproductive impacts. The quality of studies was assessed using the Critical Appraisal Checklists for Studies created by the Joanna Briggs Institute (JBI). Twelve studies, including 234 subjects, were selected from a total of 2,809 citations for the final qualitative analysis. Articles were published between 2021 and 2024, and most were conducted in China. The results of the included studies confirmed the existence of microplastics with varying sizes (2.1 to 100 micrometers) in the placenta and the fetal body. Studies revealed correlations between lifestyle choices and the presence of microplastics in the placenta. They also reported correlations between the level of microplastics and diminished microbiome diversity, reduced birthweights, affected gestational age, and fetal growth and development. Microplastics may be detrimental to a developing fetus during pregnancy. Nonetheless, more thorough research is required to comprehend the impact of microplastic exposure on pregnancy and fetal development.

Inflammation as a Sex-Specific Mediator in the Relationship between Maternal and Offspring Obesity in C57Bl/6J Mice.

Maternal obesity is a well-established risk factor for offspring obesity development. The relationship between maternal and offspring obesity is mediated in part by developmental programming of offspring metabolic circuitry, including hypothalamic signaling. Dysregulated hypothalamic inflammation has also been linked to development of obesity. We utilized an established C57Bl/6J mouse model of high-fat, high-sugar diet induced maternal obesity to evaluate the effect of maternal obesity on systemic and hypothalamic TNF-α, IL-6, and IL-1ß levels in neonatal and adult offspring. The offspring of dams with obesity demonstrated increased adiposity and decreased activity compared to control offspring. Maternal obesity was associated with decreased plasma TNF-α, IL-6 and IL-1ß in adult female offspring and decreased plasma IL-6 in neonatal male offspring. Neonatal female offspring of obese dams had decreased TNF-α gene expression in the hypothalamus compared to control females, while neonatal and adult male offspring of obese dams had decreased IL-6 gene expression in the hypothalamus compared to control males. In summary, our results highlight important sex differences in the inflammatory phenotype of offspring exposed to maternal obesity. Sex-specific immunomodulatory mechanisms should be considered in future efforts to develop therapeutic interventions for obesity prevention and treatment.

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes.

Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes.

Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice.

Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific Slc7a5 overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a Slc7a5 transgene, we achieved trophoblast-specific overexpression of Slc7a5 (Slc7a5 OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific Slc7a5 overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). Slc7a5 overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of Slc7a5 activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.

Hyperemesis gravidarum and the risk of offspring morbidity: a longitudinal cohort study.

PURPOSE: Hyperemesis gravidarum has the potential to affect the long-term health of offspring. We examined whether maternal hyperemesis gravidarum was associated with the risk of hospitalization for childhood morbidity. METHODS: We conducted a longitudinal cohort study of 1,189,000 children born in Quebec, Canada, between April 2006 and March 2021. The main exposure measure was maternal hyperemesis gravidarum requiring hospitalization in the first or second trimester. The outcome was any pediatric admission between birth and 16 years of age, with follow-up ending in March 2022. We used Cox regression models adjusted for maternal and socioeconomic factors to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between maternal hyperemesis gravidarum and childhood hospitalization. RESULTS: Among 1,189,000 children, 6904 (0.6%) were exposed to maternal hyperemesis gravidarum. Hospitalization rates at age 16 years were higher for children exposed to hyperemesis gravidarum than unexposed children (47.6 vs 43.9 per 100 children). Relative to no exposure, hyperemesis gravidarum was associated with a 1.21 times greater risk of any hospitalization before 16 years (95% CI 1.17-1.26). Hyperemesis gravidarum was associated with hospitalization for neurologic (HR 1.50, 95% CI 1.32-1.71), developmental (HR 1.51, 95% CI 1.29-1.76), digestive (HR 1.40, 95% CI 1.30-1.52), and allergic disorders (HR 1.39, 95% CI 1.24-1.56). When contrasted with preeclampsia, hyperemesis gravidarum was a stronger risk factor for these outcomes. CONCLUSIONS: Maternal hyperemesis gravidarum is associated with an increased risk of childhood hospitalization, especially for neurologic, developmental, digestive, and atopic disorders. WHAT IS KNOWN: • Hyperemesis gravidarum is associated with neurodevelopmental disorders in offspring. • However, the effect of hyperemesis gravidarum on other childhood morbidity is unclear. WHAT IS NEW: • In this longitudinal cohort study of 1.2 million children, maternal hyperemesis gravidarum was associated with a greater risk of hospitalization before age 16 years. • Exposure to hyperemesis gravidarum was associated with developmental, neurologic, atopic, and digestive morbidity in childhood.

Quantitative study of the ossification centers of the body of sphenoid bone in the human fetus.

The aim of the present study was to examine the growth dynamics of the two ossification centers of the body of sphenoid bone in the human fetus, based on their linear, planar and volumetric parameters. The examinations were carried out on 37 human fetuses of both sexes aged 18-30 weeks of gestation, which had been preserved in 10% neutral formalin solution. Using CT, digital image analysis software, 3D reconstruction and statistical methods, we evaluated the size of the presphenoid and postsphenoid ossification centers. The presphenoid ossification center grew proportionately in sagittal diameter, projection surface area and volume, and logarithmically in transverse diameter. The postsphenoid ossification center increased logarithmically in sagittal diameter, transverse diameter and projection surface area, while its volumetric growth followed proportionately. The numerical findings of the presphenoid and postsphenoid ossification centers may be considered age-specific reference values of potential relevance in monitoring the normal fetal growth and screening for congenital disorders in the fetus. The obtained results may contribute to a better understanding of the growing fetal skeleton, bringing new numerical information regarding its diagnosis and development.

Regulation of placental amino acid transport in health and disease.

Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

Does the use of bisphosphonates during pregnancy affect fetal outcomes? A systematic review.

PURPOSE: This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. METHODS: A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. RESULTS: From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. CONCLUSION: Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.