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The placenta plays a critical role in fetal development. It serves as a multi-functional organ that protects and nurtures the fetus during pregnancy. However, despite its importance, the intricacies of placental structure and function in normal and diseased states have remained largely unexplored. Thus, in 2014, the National Institute of Child Health and Human Development launched the Human Placenta Project (HPP). As of May 2023, the HPP has awarded over $101 million in research funds, resulting in 41 funded studies and 459 publications. We conducted a comprehensive review of these studies and publications to identify areas of funded research, advances in those areas, limitations of current research, and continued areas of need. This paper will specifically review the funded studies by the HPP, followed by an in-depth discussion on advances and gaps within placental-focused imaging. We highlight the progress within magnetic reasonance imaging and ultrasound, including development of tools for the assessment of placental function and structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Data on placental pathologic features associated with thyreoperoxidase antibodies (TPO Ab) and/or hypothyroidism are limited. The objective of the study was to analyze placental pathologic features of women with TPO Ab positivity., Methods: Prospective case-control observational study of pregnancy outcome among women screened for TPO Ab positivity and/or isolated hypothyroidism (TSH>4mU/L) during the first trimester of pregnancy. Placenta pathologic findings were recorded according to standard classification., Results: The overall rates of TPO Ab positivity and isolated hypothyroidism with negative TPO Ab were 9.6% (86/899) and 2.7% (24/899), respectively. Among TPO Ab positive cases, 77.9% (67/86) and 22.1% (19/86) had TSH ≥2.5mU/L or <2.5mU/L, respectively. Compared to controls, mean first and second trimester uterine artery Doppler pulsatility indices (PI) were higher, placental volume and area were lower among cases with TSH≥2.5mU/L. The rates of fetal growth restriction (FGR)/small for gestational age (SGA) (20/67 versus 8/110, Adjusted Odds Ratio (AdjOR) = 10.8,95%CI = 2.7-44), placental pathological features suggesting decidual vasculopathy (37/67 versus 27/110, AdjOR = 2.7,95%CI = 1.1-6.8) or severe maternal vascular malperfusion (MVM) (22/67 versus 9/110, AdjOR = 5.8,95%CI = 1.6-20.1) were higher among cases with TSH ≥2.5mU/L than in controls. Similar results were obtained comparing overall TPO Ab positive subjects to controls. The increased risk of defective placentation and FGR associated with TPO Ab was independent of simultaneous presence of antinuclear antibodies (ANA) and TSH concentration., Discussion: First trimester TPO Ab positivity was associated with increased rates of abnormal uterine artery Doppler PI and placental features of MVM. This association was independent of TSH concentration and presence of ANA., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., 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 © 2021 Ning and Yang.)

We aimed to compare the pregnancy-associated plasma protein-A (PAPP-A) and the uterine artery pulsatility index (UtA PI) levels of euthyroid pregnant women using levothyroxine vs. a control group of uncomplicated pregnancies and to evaluate the effects of different levothyroxine dosages on pregnancy outcomes. We retrospectively evaluated 206 levothyroxine-using pregnant women by looking at their basic placental function markers and obstetric outcomes. A sample of 449 women whose pregnancies concluded with uncomplicated term deliveries composed of our control group. To examine the relationship between the levothyroxine dosages and the frequency of pregnancy complications, levothyroxine users were divided into different groups according to the 75, 100, and 150 mcg cutoffs. The median PAPP-A MoM levels of levothyroxine users were significantly lower at 0.94 vs. 1.11 ( p  < .001) and the median mean UtA PI was significantly higher than the control group at 2.08 vs . 1.74 ( p  < .0001). The median birth weight was significantly lower for the levothyroxine users' group at 3292 g vs . 3427 g ( p  < .0001). Using 75, 100, and 150 mcg dose cutoffs, PAPP-A MoM, mean UtA PI and obstetric complication frequencies were not significantly different among levothyroxine users. Significant changes in placental function markers have been observed in euthyroid levothyroxine-using pregnant women during the first trimester. However, the frequency of obstetric complications does not appear to be dose dependent.

Introduction: Fetuses who fail to reach their genetic growth potential are thought to have sub-optimal placental function. Low placental growth factor (PlGF) levels have been shown to be predictive of placentally mediated conditions, such as pre-eclampsia or fetal growth restriction. We investigated the screening performance of PlGF for the prediction of low birth weight (<10th centile for gestation) and adverse intrapartum and neonatal outcomes in apparently low-risk term pregnancies., Materials and Methods: Maternal PlGF levels were measured fortnightly in a blinded, prospective, observational study from 36 weeks of pregnancy. Women and clinicians were blinded to PlGF results, and pregnancies were managed according to local policies and guidelines. Intrapartum and neonatal outcomes were recorded. PlGF was analysed for association with, and predictive capacity for, low birth weight, caesarean section for intrapartum fetal compromise (CS-IFC) and adverse neonatal outcomes., Results: A total of 438 women were included in the final analysis. Lower PlGF levels were associated with low birth weight, CS-IFC and adverse neonatal outcome. For a false-positive rate of 10 and 20%, respectively, the corresponding sensitivities were 9.7-11.1% and 22.2-26.8%., Conclusion: As a sole predictor for low birth weight, CS-IFC and adverse neonatal outcome, PlGF was poor as a test., (© 2017 S. Karger AG, Basel.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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/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]

A possible mechanism for poor perinatal outcomes in singleton pregnancies conceived following assisted reproductive technologies (ART) and those conceived naturally following a period of infertility (>12 months) is thought to be placental dysfunction. This was investigated by measuring plasma concentrations of biochemical markers: (i) soluble fms-like tyrosine kinase1 (sFlt1); (ii) placental growth factor (PlGF); (iii) leptin; and (iv) plasminogen activator inhibitor 2 (PAI-2), serially at four antenatal time points. Baseline concentrations of each marker after delivery were also measured. The control group was naturally conceived singleton pregnancies with no history of infertility. Non-smoking, age-matched nulliparous women with no significant medical history were recruited to all groups. The ART group had significantly lower mean plasma concentrations of PlGF at all antenatal time points compared to the control group (p < 0.001). The subfertility (SF) group had significantly higher mean serum concentrations of leptin than the other groups at all time points (p < 0.001), even after correction for body mass index. There were no significant differences in sFlt1 and PAI-2 concentrations between the groups. Low plasma PlGF concentrations in the ART group might suggest abnormal placentation and/or abnormal function in ART pregnancies with relevance to pathogenesis of pregnancy complications in these women. [ABSTRACT FROM PUBLISHER]

This study examined the effect of bisphenol A (BPA) on human placental gene expression using primary trophoblast cells as an in vitro model system. Trophoblast cells were isolated from human placentas at term, cultured and then exposed to environmentally relevant concentrations of BPA (0.1–2 μg/ml) for up to 24 h, after which levels of 11β-HSD2 mRNA, protein and activity were determined by standard radiometric conversion assay, western blotting, and qRT-PCR, respectively. The mRNA levels of several other prominent placental hormones/factors were also assessed by qRT-PCR. BPA dramatically increased levels of 11β-HSD2 activity, protein and mRNA in a time- and concentration-dependent manner (>4-fold). BPA also augmented aromatase, glucose transporter-1, CRH, and hCG mRNA levels while reducing the level of leptin mRNA. These findings demonstrate that BPA severely disrupts human placental gene expression in vitro , which suggests that exposure to BPA may contribute to altered placental function and consequent pregnancy complications. [ABSTRACT FROM AUTHOR]

During human pregnancy, the maternal immune system develops and changes, providing protection for the growing placenta and fetus. These protective changes provide mechanisms allowing two genetically different individuals to interact with each other without allograft rejection. In addition to normal pregnancy, some pregnancies may develop under immunologic diseases, during which specific monitoring and medical treatments are essential. The aim of this current review is to provide information regarding the development of human placental function during pregnancy, the immunology of human pregnancy and the role of the placenta in providing the fetal tissue with antibodies (IgG and its subclasses 1-4), which are required for the passive immunization of the newborn. In addition, the available methods for the determination of placental function will be explored. Furthermore, immunologic diseases observed during pregnancy and the possible therapies for these diseases will be assessed. [ABSTRACT FROM AUTHOR]