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The use of cannabis during pregnancy has emerged as a mounting cause for concern due to its potential adverse consequences on both the mother and her offspring. This review will focus on the dangers associated with prenatal exposure to cannabis, particularly those related to neurodevelopment. It will also discuss the features of maternal and placental functioning that are likely to have long-term effects on the offspring's development. The most pertinent and up-to-date materials can be found through a literature search. The literature emphasizes the substantial hazards associated with prenatal exposure to cannabis. These include impairments in cognitive function and difficulties in behavior in this particular instance. Structural and functional alterations in the brain can be noticed in offspring. The use of cannabis has been associated with an increased likelihood of experiencing pregnancy-related complications, such as giving birth prematurely and having a baby with a low birth weight. Additionally, it has been connected to potential negative effects on mental and emotional well-being. Studies have shown that when a pregnant woman is exposed to cannabis, it can negatively impact the functioning of the placenta and the growth of the fetus. This might potentially contribute to the development of placental insufficiency and restricted growth in the womb. Longitudinal studies reveal that children who were exposed to cannabis in the womb experience additional long-term developmental challenges, such as decreased cognitive abilities, reduced academic performance, and behavioral issues. In order to address the problem of cannabis usage during pregnancy, it is essential to adopt a comprehensive and coordinated strategy. This method should integrate and synchronize public health policy, education, and research initiatives. By implementing these targeted strategies, it is possible to mitigate potential health and welfare concerns for both present and future generations. [ABSTRACT FROM AUTHOR]

Background/Objectives: The utility of shear wave elastography (SWE) as an adjunct to ultrasound biometry and Doppler velocimetry for the examination of placental dysfunction and suboptimal fetal growth is unclear. To date, limited data exist correlating the mechanical properties of placentae with fetal growth. This study aimed to investigate the relationship between placental shear wave velocity (SWV) and ultrasound estimated fetal weight (EFW), and to ascertain if placental SWV is a suitable proxy measure of placental function in the surveillance of small-for-gestational-age (SGA) pregnancies. Methods: This prospective, observational cohort study compared the difference in placental SWV between SGA and appropriate-for-gestational-age (AGA) pregnancies. There were 221 women with singleton pregnancies in the study cohort—136 (61.5%) AGA and 85 (38.5%) SGA. Fetal biometry, Doppler velocimetry, the deepest vertical pocket of amniotic fluid, and mean SWV were measured at 2–4-weekly intervals from recruitment to birth. Results: There was no difference in mean placental SWV in SGA pregnancies compared to AGA pregnancies, nor was there any relationship to EFW. Conclusions: Although other studies have shown some correlation between increased placental stiffness and SGA pregnancies, our investigation did not support this. The mechanical properties of placental tissue in SGA pregnancies do not result in placental SWVs that are apparently different from those of AGA controls. As this study did not differentiate between constitutionally or pathologically small fetuses, further studies in growth-restricted cohorts would be of benefit. [ABSTRACT FROM AUTHOR]

Objectives: T2*‐weighted magnetic resonance imaging (MRI) sequences have been identified as non‐invasive tools with which to study placental oxygenation in vivo. This study aimed to use these to investigate both static and dynamic responses to hyperoxia of the normal placenta across gestation. Methods: We conducted a single‐center prospective study including 52 uncomplicated pregnancies. Two T2*‐weighted sequences (T2* relaxometry) were performed, one before and one after maternal hyperoxia. The distribution of placental T2* values was modeled by fitting a gamma probability density function (T2* ~Γαβ), describing the structure of the histogram using the mean T2* value, the shape parameter (α) and the rate (β). A dynamic acquisition (blood‐oxygen‐level‐dependent (BOLD) MRI) was also performed before and during maternal oxygen supply, until placental oxygen saturation had been achieved. The signal change over time was modeled using a sigmoid function, to determine the intensity of enhancement (ΔBOLD (% with respect to baseline)), a temporal variation coefficient (λ (min–1), controlling the slope of the curve) and the maximum steepness (Vmax (% of placental enhancement/min)). Results: The histogram analysis of the T2* values in normoxia showed a whole‐placenta variation, with a decreasing linear trend in the mean T2* value (Pearson's correlation coefficient (R) = −0.83 (95% CI, −0.9 to −0.71), P < 0.001), along with an increasingly peaked and narrower distribution of T2* values with advancing gestation. After maternal hyperoxia, the mean T2* ratios (mean T2*hyperoxia/mean T2*baseline) were positively correlated with gestational age, while the other histogram parameters remained stable, suggesting a translation of the histogram towards higher values with a similar appearance after maternal hyperoxia. ΔBOLD showed a non‐linear increase across gestation. Conversely, λ showed an inverted trend across gestation, with a weaker correlation (R = −0.33 (95% CI, −0.58 to −0.02), P = 0.04, R2 = 0.1). As a combination of ΔBOLD and λ, the changes in Vmax throughout gestation were influenced mainly by the changes in ΔBOLD and showed a positive non‐linear correlation with gestational age. Conclusions: Our results suggest that the decrease in the T2* placental signal as gestation progresses does not reflect placental dysfunction. The BOLD dynamic signal change is representative of a free‐diffusion model of oxygenation and highlights the increasing differences in oxygen saturation between mother and fetus as gestation progresses (ΔBOLD) and in the placental permeability to oxygen (λ). © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) severely impairs fetal development and offspring health. Odd-chain fatty acid (OCFA) possess beneficial biological activities in regulating insulin resistance, inflammation and oxidative stress. However, the effects of OCFA on improving IUGR through regulating placental function and maternal health remain unclear. Herein, maternal OCFA-rich algal oil supplementation improved variable coefficient of fetal weight and fetal oxidative stress in low protein diet (LPD)-induced IUGR mice model. OCFA-rich algal oil also improved placental dysfunction, placental fatty acid metabolism disorder, maternal insulin resistance, oxidative stress and intestinal injury, suggesting an improved maternal health. OCFA-rich algal oil reshaped the intestinal microbiome of dams, decreasing unclassified Bacteroidales and Parvibacter, and increasing Weissella, which positively impacted insulin resistance and intestinal injury. Overall, OCFA-rich algal oil supplementation during pregnancy ameliorated oxidative stress, insulin resistance and intestinal injury in LPD-induced IUGR pregnant mice, improved placental functions and litter characteristics, and further enhanced fetal antioxidant capacity.

Understanding the mechanisms by which environmental factors impact reproductive health is crucial for informing public health interventions and policy decisions. By elucidating the pathways through which environmental stressors exert their effects, we can develop targeted strategies to mitigate risks and promote reproductive well-being. In this lecture, we will delve into the latest research findings and emerging trends in the field of environmental reproductive health. By exploring the intricate interplay between environmental exposures and reproductive outcomes, we aim to broaden our understanding of this complex relationship and its implications for human health. Through collaborative efforts across disciplines, we can work towards safeguarding reproductive health for current and future generations.

The use of cannabis during pregnancy has emerged as a mounting cause for concern due to its potential adverse consequences on both the mother and her offspring. This review will focus on the dangers associated with prenatal exposure to cannabis, particularly those related to neurodevelopment. It will also discuss the features of maternal and placental functioning that are likely to have long-term effects on the offspring’s development. The most pertinent and up-to-date materials can be found through a literature search. The literature emphasizes the substantial hazards associated with prenatal exposure to cannabis. These include impairments in cognitive function and difficulties in behavior in this particular instance. Structural and functional alterations in the brain can be noticed in offspring. The use of cannabis has been associated with an increased likelihood of experiencing pregnancy-related complications, such as giving birth prematurely and having a baby with a low birth weight. Additionally, it has been connected to potential negative effects on mental and emotional well-being. Studies have shown that when a pregnant woman is exposed to cannabis, it can negatively impact the functioning of the placenta and the growth of the fetus. This might potentially contribute to the development of placental insufficiency and restricted growth in the womb. Longitudinal studies reveal that children who were exposed to cannabis in the womb experience additional long-term developmental challenges, such as decreased cognitive abilities, reduced academic performance, and behavioral issues. In order to address the problem of cannabis usage during pregnancy, it is essential to adopt a comprehensive and coordinated strategy. This method should integrate and synchronize public health policy, education, and research initiatives. By implementing these targeted strategies, it is possible to mitigate potential health and welfare concerns for both present and future generations.

Mitochondrial fatty acid oxidation (FAO) is lower in placentas with pre-eclampsia. The aim of our study was to compare the placental mRNA expression of FAO enzymes in healthy pregnancies vs. different subgroups of pre-eclampsia according to the severity, time of onset, and the presence of intrauterine growth restriction (IUGR). By using real-time qPCR, we measured the mRNA levels of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), medium-chain acyl-CoA dehydrogenase (MCAD), and carnitine palmitoyltransferases 1A and 2 (CPT1A, CPT2) on the maternal side (anchoring villi in the basal decidua) and on the fetal side (chorionic plate) of the placenta (n = 56). When compared to the controls, LCHAD, MCAD, and CPT2 mRNA had decreased in all pre-eclampsia subgroups globally and on the fetal side. On the maternal side, LCHAD mRNA was also lower in all pre-eclampsia subgroups; however, MCAD and CPT2 mRNA were only reduced in severe and early-onset disease, as well as CPT2 in IUGR (p < 0.05). There were no differences in CPT1A mRNA expression. We conclude that the FAO enzymes mRNA in the placenta was lower in pre-eclampsia, with higher reductions observed in severe, early-onset, and IUGR cases and more striking reductions on the fetal side. [ABSTRACT FROM AUTHOR]

Objectives: Evidence regarding placental function in pregnancies complicated by confined placental mosaicism (CPM) is conflicting. We aimed to compare placental function between CPM and non‐CPM pregnancies prenatally and at birth. A secondary objective was to evaluate the relationship between placental function and chromosomal subtype of CPM. Methods: This was a retrospective study of pregnancies with CPM and control pregnancies delivered at a tertiary hospital in Denmark between 2014 and 2017. Placental volume and placental transverse relaxation time (T2*) were estimated on magnetic resonance imaging (MRI), fetal weight and uterine artery pulsatility index (UtA‐PI) were estimated on ultrasound and fetoplacental ratio was assessed on MRI and at birth. These estimates of placental function were adjusted for gestational age and compared between groups using the Wilcoxon rank‐sum test. Within the group of CPM pregnancies, measures of placental function were compared between those at high risk (chromosome numbers 2, 3, 7, 13 and 16) and those at low risk (chromosome numbers 5, 18 and 45X). Results: A total of 90 pregnancies were included, of which 12 had CPM and 78 were controls. MRI and ultrasound examinations were performed at a median gestational age of 32.6 weeks (interquartile range, 24.7–35.3 weeks). On MRI assessment, CPM placentae were characterized by a lower placental T2* Z‐score (P = 0.004), a lower fetoplacental ratio (P = 0.03) and a higher UtA‐PI Z‐score (P = 0.03), compared with non‐CPM placentae. At birth, the fetoplacental ratio was significantly lower (P = 0.02) and placental weight Z‐score was higher (P = 0.01) in CPM pregnancies compared with non‐CPM pregnancies. High‐risk CPM pregnancies showed a reduced placental T2* Z‐score (P = 0.003), lower birth‐weight Z‐score (P = 0.041), earlier gestational age at delivery (P = 0.019) and higher UtA‐PI Z‐score (P = 0.028) compared with low‐risk CPM pregnancies. Low‐risk CPM pregnancies did not differ in any of these parameters from non‐CPM pregnancies. Conclusions: CPM pregnancies are characterized by an enlarged and dysfunctional placenta. Placental function was highly related to the chromosomal type of CPM; placental dysfunction was seen predominantly in high‐risk CPM pregnancies in which chromosomes 2, 3, 7, 13 or 16 were involved. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Based on epidemiological observations Barker et al. put forward the hypothesis/concept that an adverse intrauterine environment (involving an insufficient nutrient supply, chronic hypoxia, stress, and toxic substances) is an important risk factor for the development of chronic diseases later in life. The fetus responds to the unfavorable environment with adaptive reactions, which ensure survival in the short run, but at the expense of initiating pathological processes leading to adult diseases. In this review, the major mechanisms (including telomere dysfunction, epigenetic modifications, and cardiovascular–renal–endocrine–metabolic reactions) will be outlined, with a particular emphasis on the role of oxidative stress in the fetal origin of adult diseases. [ABSTRACT FROM AUTHOR]

Objective: Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate‐for‐gestational age. The aim of this study was to evaluate the associations between birth‐weight centile and intellectual development in term/near‐term infants across the entire birth‐weight spectrum, in order to provide a basis for better understanding of the long‐term implications of fetal growth restriction and reduced placental function. Methods: This was a population‐based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003–2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016–2019. Regression analyses were conducted to assess the association of birth‐weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501–550, and proportion of children who reached higher secondary school level. Results: Mean school performance score increased gradually with increasing birth‐weight centile, from 533.6 in the 1st–5th birth‐weight‐centile group to 536.8 in the 81st–85th birth‐weight‐centile group. Likewise, the proportion of children at higher secondary school level increased with birth‐weight centile, from 43% to 57%. Compared with the 81st–85th birth‐weight‐centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth‐weight‐centile groups below the 80th centile, after adjusting for confounding factors. Conclusions: Birth‐weight centile is associated positively with school performance at 12 years of age across the entire birth‐weight spectrum, well beyond the conventional and arbitrary cut‐offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short‐ and long‐term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the relevance of biometrical and blood flow assessments for studying fetoplacental physiology during pregnancy, there is no detailed description of any animal model, which is needed to extrapolate results to human pregnancy. Here, we examined biometry and intrauterine blood flow in pregnant guinea pigs from the second trimester until term. We show that fetal and placental biometry, as well as changes in the main vascular beds across pregnancy, compared qualitatively to data from humans. These findings emphasize that the guinea pig is a reliable model to study fetal development and placental function with translational significance for human pregnancy. Background: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. Methods: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. Results: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. Conclusions: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) severely impairs fetal development and offspring health. Odd-chain fatty acid (OCFA) possess beneficial biological activities in regulating insulin resistance, inflammation and oxidative stress. However, the effects of OCFA on improving IUGR through regulating placental function and maternal health remain unclear. Herein, maternal OCFA-rich algal oil supplementation improved variable coefficient of fetal weight and fetal oxidative stress in low protein diet (LPD)-induced IUGR mice model. OCFA-rich algal oil also improved placental dysfunction, placental fatty acid metabolism disorder, maternal insulin resistance, oxidative stress and intestinal injury, suggesting an improved maternal health. OCFA-rich algal oil reshaped the intestinal microbiome of dams, decreasing unclassified Bacteroidales and Parvibacter , and increasing Weissella , which positively impacted insulin resistance and intestinal injury. Overall, OCFA-rich algal oil supplementation during pregnancy ameliorated oxidative stress, insulin resistance and intestinal injury in LPD-induced IUGR pregnant mice, improved placental functions and litter characteristics, and further enhanced fetal antioxidant capacity. [Display omitted] • OCFA supplemented low protein-fed dams improves antioxidant capacity. • OCFA alleviates placental dysfunction and fetal intrauterine growth restriction. • OCFA supplemented low protein-fed dams improves insulin resistance. • OCFA supplemented low protein-fed dams improves intestinal barrier function. [ABSTRACT FROM AUTHOR]

Background:Empirical use of Hydroxychloroquine (HCQ) in patients with positive antinuclear antibody spectrum (ANAs) test result is controversial regarding its impact on improving perinatal outcomes. This study aimed to investigate the effect of HCQ on adverse pregnancy outcomes associated with placental dysfunction in ANAs-positive patients.Methods:The study included pregnant women with positive ANAs test result from 2016 to 2020 in our center, and divided into a weakly positive and a positive group in just ANA positive patients among them. Univariate and multivariate analyses were conducted to determine the effect of HCQ on pregnancy outcomes in each subgroup. Stratified and interactive analyses were performed to assess the value of HCQ in improving pregnancy outcomes.Results:(i) A total of 261 cases were included, accounting for 30.60% of pregnancy complicated with autoimmune abnormalities, and 65.12% of them used HCQ during pregnancy. (ii) The application of HCQ significantly reduced the incidence of early-onset preeclampsia (1.18% vs. 12.09%, p = 0.040) and small-for-gestational-age infants (10.06% vs. 25.84%, p = 0.003) in the ANAs-positive population, increased birth weight (3075.87 ± 603.91 g vs. 2847.53 ± 773.73 g, p = 0.025), and prolonged gestation (38.43 ± 2.31 vs. 36.34 ± 5.45 weeks, p

COVID-19 is an ongoing pandemic and has been extensively studied. However, the effects of COVID-19 during pregnancy, particularly on placental function, have not been verified. In this study, we used blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate whether COVID-19 incidence during pregnancy has any lasting effects with respect to placental oxygenation. This is a case-control study, in which eight cases of singleton pregnancies before 30 weeks gestation with COVID-19 mothers were included. Placental oxygenation was evaluated using BOLD-MRI after 32 weeks of gestation. BOLD-MRI was consecutively performed under normoxia (21% O2), hyperoxia (100% O2), and normoxia for 4 min each. Individual placental time–activity curves were evaluated to calculate the peak score (peakΔR2*) and the time from the start of maternal oxygen administration to the time of peakΔR2* (time to peakΔR2*). Eighteen COVID-19-free normal pregnancies from a previous study were used as the control group. No significant differences were found between the two groups regarding maternal background, number of days of delivery, birth weight, and placental weight. The parameter peakΔR2* was significantly decreased in the COVID-19 group (8 ± 3 vs. 5 ± 1, p <.001); however, there was no significant difference in time to peakΔR2* (458 ± 74 s vs. 471 ± 33 s, p =.644). In this study, BOLD-MRI was used to evaluate placental oxygenation during pregnancy in COVID-19-affected patients. COVID-19 during pregnancy decreased placental oxygenation even post-illness, but had no effect on fetal growth; further investigation of the possible effects of COVID-19 on the fetus and mother is warranted. [ABSTRACT FROM AUTHOR]

Placental function is vital to the fetal growth of sows, and resveratrol (RES) can protect cells against oxidative stress, which is one of the major factors impairing placental function. This study aimed to investigate the effect of dietary resveratrol (RES) on placental function and reproductive performance during late pregnancy in a sow model from the aspects of oxidative stress, insulin resistance, and gut microbiota. A total of 26 hybrid pregnant sows (Landrace × Yorkshire) with similar parity were randomly allocated into two groups (n = 13) and fed with a basal diet or a diet containing 200 mg/kg of resveratrol from day 85 of gestation until parturition. The dietary supplementation of RES increased the litter weight at parturition by 12.53% (p = 0.145), with ameliorated insulin resistance (HOMA-IR), increased triglyceride (TG) levels, and decreased interleukin (IL)-1β and IL-6 levels in serum (p < 0.05). Moreover, resveratrol increased the placental vascular density (p < 0.05) with the enhanced expression of nutrient transporter genes (SLC2A1 and SLC2A3) and antioxidant genes, such as superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) but declined the expression of inflammatory genes, such as IL-1β and IL-6 (p < 0.05). The characterization of the fecal microbiota revealed that resveratrol decreased the relative abundance of the Christensensllaceae R-7 group and Ruminococcaceae UCG-008 (p < 0.05), which had a positive linear correlation with the expression of IL-1β and IL-6 (p < 0.05), but had a negative linear correlation with the expression of SOD2, HO-1, SLC2A1, and SCL2A3 genes (p < 0.05). These data demonstrated that dietary supplementation with resveratrol can improve placental function with ameliorated insulin resistance, oxidative stress, and inflammation potentially by regulating Ruminococcaceae UCG-008 and the Christensensllaceae R-7 group in sows.

Based on epidemiological observations Barker et al. put forward the hypothesis/concept that an adverse intrauterine environment (involving an insufficient nutrient supply, chronic hypoxia, stress, and toxic substances) is an important risk factor for the development of chronic diseases later in life. The fetus responds to the unfavorable environment with adaptive reactions, which ensure survival in the short run, but at the expense of initiating pathological processes leading to adult diseases. In this review, the major mechanisms (including telomere dysfunction, epigenetic modifications, and cardiovascular–renal–endocrine–metabolic reactions) will be outlined, with a particular emphasis on the role of oxidative stress in the fetal origin of adult diseases.

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR. [ABSTRACT FROM AUTHOR]

Background: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. Methods: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. Results: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. Conclusions: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy.

Background/Aim. The placenta is essential in pregnancy, facilitating nutrient and gas exchange between mother and fetus. However, the regulatory proteins involved in this process are not fully understood across gestation. This study aimed to identify the top 20 differentially expressed genes (DEGs) in the placenta across different pregnancy stages to elucidate the molecular mechanisms at play. Methods. Differential gene expression analysis was performed on the placental samples from the first, second, and third trimesters using microarray data from Gene Expression Omnibus and Array Express. Analysis was conducted in RStudio using the R programming language. DEGs were identified using a significance score (π-value) based on the method developed by Xiao Y et al. (2014), which combines fold change and p-value. Volcano plots were created to visualize DEGs, and the top 20 were analyzed for functional enrichment using STRING and EnrichR databases, including Gene Ontology and KEGG pathways. Results. In the transition from the first to the second trimester, significant DEGs included genes involved in steroid metabolism such as HSD11B1, HSD3B2, and HSD17B2. These genes are critical in the biosynthesis and metabolism of steroid hormones, essential for sustaining pregnancy and supporting fetal development. Enrichment analysis showed these genes were significantly associated with steroid biosynthesis and steroidogenesis pathways. For the transition from the second to the third trimester, different sets of genes were highlighted, particularly those related to endocrine regulation and pregnancy-specific functions. Key genes included CRH, INHBA, REN, and members of the pregnancy-specific glycoprotein (PSG) family. These genes are involved in hormone regulation, reproductive processes, and maintaining maternal-fetal homeostasis, with significant associations with pathways related to endocrine processes, reproductive health, and vascular function. For example, the involvement of CRH and REN in endocrine regulation suggests their role in modulating maternal and fetal physiology during the later stages of pregnancy. Also, the genes associated with vascular and hemostatic functions were identified, indicating the importance of maintaining proper blood flow and preventing bleeding complications as pregnancy progresses. Notable genes included SDC1 and HBE1, which are crucial for vascular integrity and oxygen transport. Volcano plots illustrated these shifts in gene expression, with the top 20 genes identified by π-value prominently displayed. Conclusions. This study provides an analysis of gene expression changes in the placenta throughout pregnancy, identifying key genes and pathways that regulate placental function and impact fetal development. These findings enhance the understanding of placental biology and may highlight potential targets for ensuring optimal fetal development. [ABSTRACT FROM AUTHOR]

Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. To assess the impact of toxic and essential trace elements in placenta on placental function. Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 μg/kg, respectively. In the adjusted regression, selenium (>147 μg/kg) was inversely associated with placental weight (B: −158; 95 % CI: −246, −71, per doubling), as was lead at low selenium (B: −23.6; 95 % CI: −43.2, −4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: −0.01; 95 % CI: −0.019, −0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: −11; 95 % CI: −20, −0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation. • Manganese was positively, and selenium inversely, related to placental weight. • Placental lead was inversely related to placental weight at low selenium levels. • Cobalt was inversely associated with relative mtDNA copy number in placenta. • All micronutrients, individually and joint, were positively related to mtDNA. [ABSTRACT FROM AUTHOR]

Abstract Background Early antiretroviral therapy (ART) during pregnancy has dramatically reduced the risk of perinatal HIV transmission. However, studies have shown an association between premature delivery and the use of ART during pregnancy (particularly protease inhibitor (PI)-based therapies), which could be explained by placental dysfunction. The objective of this study was to evaluate the association of ART (class, duration of exposure and time of initiation) with placental function by using angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) as biomarkers. Methods Clinical and biological data from 159 pregnant women living with HIV were analyzed. Levels of each biomarker were measured in the first and second trimester of pregnancy. After logarithmic transformation, we compared these using generalized estimating equations according to (a) the type of ART; (b) the duration of exposure to ART; and (c) the time of initiation of ART. Results After adjusting for variables such as ethnicity, maternal age, gestational age, body mass index, parity, smoking status, and sex of the fetus, we found no significant association between the class of ART (PI-based or not) and serum concentrations of PlGF or sFlt-1. Furthermore, no significant association was found between biomarker levels and the duration of ART exposure or the timing of ART initiation (pre- or post-conception). Conclusions This study suggests that first and second trimester angiogenic factor levels are not significantly associated with ART, regardless of the duration or type (with or without PI). These observations seem reassuring when considering the use of ART during early pregnancy.

The dynamic cycling of N-acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental cellular processes. It is controlled by two essential enzymes, O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation serves as a modulator in placental tissue; furthermore, increased levels of protein O-GlcNAcylation have been observed in women with hyperglycemia during pregnancy, which may affect the short-and long-term development of offspring. In this review, we focus on the impact of O-GlcNAcylation on placental functions in hyperglycemia-associated pregnancies. We discuss the following topics: effect of O-GlcNAcylation on placental development and its association with hyperglycemia; maternal-fetal nutrition transport, particularly glucose transport, via the mammalian target of rapamycin and AMP-activated protein kinase pathways; and the two-sided regulatory effect of O-GlcNAcylation on inflammation. As O-GlcNAcylation in the placental tissues of pregnant women with hyperglycemia influences near- and long-term development of offspring, research in this field has significant therapeutic relevance.

The dynamic cycling of N -acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental cellular processes. It is controlled by two essential enzymes, O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation serves as a modulator in placental tissue; furthermore, increased levels of protein O-GlcNAcylation have been observed in women with hyperglycemia during pregnancy, which may affect the short-and long-term development of offspring. In this review, we focus on the impact of O-GlcNAcylation on placental functions in hyperglycemia-associated pregnancies. We discuss the following topics: effect of O-GlcNAcylation on placental development and its association with hyperglycemia; maternal-fetal nutrition transport, particularly glucose transport, via the mammalian target of rapamycin and AMP-activated protein kinase pathways; and the two-sided regulatory effect of O-GlcNAcylation on inflammation. As O-GlcNAcylation in the placental tissues of pregnant women with hyperglycemia influences near- and long-term development of offspring, research in this field has significant therapeutic relevance. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

Extracellular histones support rodent and human embryo development in at least two ways. First, these molecules in uterine secretions protect embryos from inflammation caused by pathogens that gain access to the reproductive tract. Also, histones in uterine secretions likely support penetration of the uterine epithelium by blastocysts during embryo implantation. Extracellular histones seem to preserve amino acid transport system B0,+ in blastocysts by inhibiting its activity. Preservation of system B0,+ is needed because, at the time of invasion of the uterine epithelium by motile trophoblasts, system B0,+ is likely reactivated to help remove tryptophan from the implantation chamber. If tryptophan is not removed, T-cells proliferate and reject the implanting blastocyst. Epigenetic modification of histones could alter their promotion of normal implantation through, say, incomplete tryptophan removal and, thus, allow partial T-cell rejection of the conceptus. Such partial rejection could impair placental development, embryonal/fetal nutrition, and weight gain prior to birth. Small-for-gestational-age offspring are predisposed to developing metabolic syndrome, obesity, and associated complications as adults. Shifting expression of these phenotypes might contribute to transgenerational variation and evolution. The spectrum of possible extracellular histone targets in early development warrant new research, especially since the effects of epigenetic histone modifications might be transgenerational.

Objective: It has been suggested that the use of Doppler ultrasound in term pregnancies with normal-sized fetuses is able to identify those at high risk of subclinical placental function impairment. The objective of this study was to evaluate the relationship between cerebroplacental ratio (CPR) measured in early labor and perinatal and delivery outcomes in a cohort of uncomplicated singleton term pregnancies.Methods: This was a prospective multicenter observational study conducted at three tertiary centers between January 2016 and July 2017. Low-risk term pregnancies, defined by the absence of maternal morbidity or pregnancy complication, accompanied by normal ultrasound and clinical screening of fetal growth in the third trimester, with spontaneous onset of labor were included. Umbilical artery (UA) and fetal middle cerebral artery (MCA) Doppler was assessed on admission for early labor. All measurements were performed in between uterine contractions and according to international standards. CPR was computed by dividing MCA pulsatility index by UA pulsatility index and converted into multiples of the median (MoM) in order to adjust for gestational age. Doctors and midwives involved in the clinical management of the women were blinded to the results of the Doppler evaluation. Mode of delivery and perinatal outcome were compared between pregnancies with reduced CPR MoM, defined as CPR MoM within the lowest decile of the study population, and those with normal CPR MoM. Receiver-operating characteristics curve analysis was used to assess the predictive performance of CPR for obstetric intervention due to fetal distress and composite adverse perinatal outcome.Results: Overall, 562 women were included. The rate of obstetric intervention for suspected fetal distress in labor was more than three times higher among cases with reduced CPR MoM compared to those with normal CPR MoM (9/54 (16.7%) vs 28/508 (5.5%); P = 0.004). Furthermore, a significantly higher rate of composite adverse perinatal outcome was found in fetuses with CPR MoM < 10th percentile compared to those with CPR MoM ≥ 10th percentile (6/54 (11.1%) vs 19/508 (3.7%); P = 0.012). CPR had low sensitivity and low positive predictive value for prediction of obstetric intervention due to fetal distress (24.3% and 18.0%, respectively) and composite adverse perinatal outcome (24.0% and 11.1%, respectively).Conclusions: Data on a wide cohort of low-risk term pregnancies in early labor showed that, while reduced CPR is associated with a higher risk of obstetric intervention due to fetal distress and composite adverse perinatal outcome, it is a poor predictor of adverse perinatal outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Defining the mechanisms underlying the programming of early life growth is fundamental for improving adult health and wellbeing. While the association between maternal diet, offspring growth and adult disease risk is well-established, the effect of father's diet on offspring development is largely unknown. Therefore, we fed male mice an imbalanced low protein diet (LPD) to determine the impact on post-fertilisation development and fetal growth. We observed that in preimplantation embryos derived from LPD fed males, expression of multiple genes within the central metabolic AMPK pathway was reduced. In late gestation, paternal LPD programmed increased fetal weight, however, placental weight was reduced, resulting in an elevated fetal:placental weight ratio. Analysis of gene expression patterns revealed increased levels of transporters for calcium, amino acids and glucose within LPD placentas. Furthermore, placental expression of the epigenetic regulators Dnmt1 and Dnmt3L were increased also, coinciding with altered patterns of maternal and paternal imprinted genes. More strikingly, we observed fetal skeletal development was perturbed in response to paternal LPD. Here, while offspring of LPD fed males possessed larger skeletons, their bones comprised lower volumes of high mineral density in combination with reduced maturity of bone apatite. These data offer new insight in the underlying programming mechanisms linking poor paternal diet at the time of conception with the development and growth of his offspring. [ABSTRACT FROM AUTHOR]

Placental Growth Factor (PlGF) is a very important angiogenic protein secreted by the placenta, necessary for the proper functioning of the endothelial cells during pregnancy. In normal pregnancies, PlGF plasma circulating levels increase up to the 32nd week of pregnancy, and then decrease until the end of pregnancy. Low PlGF plasma levels are a marker of preeclampsia and of placental function deficiency. The aim of our study was to evaluate whether a deficiency of placenta function, diagnosed through the PlGF assay, could be a cause of preterm delivery without known causes. The PlGF levels were measured in plasma samples collected by 250 pregnant women (20-35 weeks of pregnancy). In our study, PlGF levels were significantly lower than cut off values in all women with preterm delivery without known causes. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014) · Cagliari (Italy) · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

Background: Empirical use of Hydroxychloroquine (HCQ) in patients with positive antinuclear antibody spectrum (ANAs) test result is controversial regarding its impact on improving perinatal outcomes. This study aimed to investigate the effect of HCQ on adverse pregnancy outcomes associated with placental dysfunction in ANAs-positive patients., Methods: The study included pregnant women with positive ANAs test result from 2016 to 2020 in our center, and divided into a weakly positive and a positive group in just ANA positive patients among them. Univariate and multivariate analyses were conducted to determine the effect of HCQ on pregnancy outcomes in each subgroup. Stratified and interactive analyses were performed to assess the value of HCQ in improving pregnancy outcomes., Results: (i) A total of 261 cases were included, accounting for 30.60% of pregnancy complicated with autoimmune abnormalities, and 65.12% of them used HCQ during pregnancy. (ii) The application of HCQ significantly reduced the incidence of early-onset preeclampsia (1.18% vs. 12.09%, p  = 0.040) and small-for-gestational-age infants (10.06% vs. 25.84%, p  = 0.003) in the ANAs-positive population, increased birth weight (3075.87 ± 603.91 g vs. 2847.53 ± 773.73 g, p  = 0.025), and prolonged gestation (38.43 ± 2.31 vs. 36.34 ± 5.45 weeks, p  < 0.001). (iii) A total of 185 just ANA-positive patients were stratified according to titers. Among them, the rate of HCQ usage was significantly higher than that in the weakly positive group (81.03% vs. 58.27%, p  = 0.003). (vi) Stratified univariate analysis showed that HCQ usage in the ANA-positive group could reduce the incidence of preeclampsia (2.13% vs. 27.27%, p  = 0.019) and prolong gestation (38.29 ± 2.54 vs. 34.48 ± 7.68 weeks, p  = 0.006). In the ANA-weakly positive group, HCQ significantly reduced the incidence of preeclampsia (6.76% vs. 28.30%, p  = 0.002), early-onset preeclampsia (1.35% vs. 13.21%, p  = 0.027), and small-for-gestational-age infants (7.89% vs. 35.19%, p  < 0.001). Multivariate regression analysis showed that HCQ significantly reduced the incidence of preeclampsia in both groups. Intergroup interaction analysis showed no significant difference in the value of HCQ in reducing the incidence of preeclampsia between the two groups., Conclusion: ANAs positivity is an important abnormal autoimmunity type in pregnancy. HCQ can be considered as a choice for improving adverse pregnancy outcomes related to placental dysfunction, such as preeclampsia, in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ye, Liu, Zhao, Ma and Wang.)

BACKGROUND: Connexins comprise a family of ~20 proteins that form intercellular membrane channels (gap junction channels) providing a direct route for metabolites and signalling molecules to pass between cells. This review provides a critical analysis of the evidence for essential roles of individual connexins in female reproductive function, highlighting implications for women's reproductive health. METHODS: No systematic review has been carried out. Published literature from the past 35 years was surveyed for research related to connexin involvement in development and function of the female reproductive system. Because of the demonstrated utility of genetic manipulation for elucidating connexin functions in various organs, much of the cited information comes from research with genetically modified mice. In some cases, a distinction is drawn between connexin functions clearly related to the formation of gap junction channels and those possibly linked to nonchannel roles. RESULTS AND CONCLUSIONS: Based on work with mice, several connexins are known to be required for female reproductive functions. Loss of connexin43 (CX43) causes an oocyte deficiency, and follicles lacking or expressing less CX43 in granulosa cells exhibit reduced growth, impairing fertility. CX43 is also expressed in human cumulus cells and, in the context of IVF, has been correlated with pregnancy outcome, suggesting that this connexin may be a determinant of oocyte and embryo quality in women. Loss of CX37, which exclusively connects oocytes with granulosa cells in the mouse, caused oocytes to cease growing without acquiring meiotic competence. Blocking of CX26 channels in the uterine epithelium disrupted implantation whereas loss or reduction of CX43 expression in the uterine stroma impaired decidualization and vascularization in mouse and human. Several connexins are important in placentation and, in the human, CX43 is a key regulator of the fusogenic pathway from the cytotrophoblast to the syncytiotrophoblast, ensuring placental growth. CX40, which characterizes the extravillous trophoblast (EVT), supports proliferation of the proximal EVTs while preventing them from differentiating into the invasive pathway. Furthermore, women with recurrent early pregnancy loss as well as those with endometriosis exhibit reduced levels of CX43 in their decidua. The antimalaria drug mefloquine, which blocks gap junction function, is responsible for increased risk of early pregnancy loss and stillbirth, probably due to inhibition of intercellular communication in the decidua or between trophoblast layers followed by an impairment of placental growth. Gap junctions also play a critical role in regulating uterine blood flow, contributing to the adaptive response to pregnancy. Given that reproductive impairment can result from connexin mutations in mice, it is advised that women suffering from somatic disease symptoms associated with connexin gene mutations be additionally tested for impacts on reproductive function. Better knowledge of these essential connexin functions in human female reproductive organs is important for safeguarding women's reproductive health. [ABSTRACT FROM AUTHOR]