Acetate to the rescue: Acetyl-CoA facilitates placental development.

While the placenta regulates nutritional exchange between mother and fetus, Yu et al. reveal that human placental development is itself nutrient-sensitive. They elucidate entwined metabolic and epigenetic transitions driving syncytialization and pinpoint a requirement for the metabolite acetyl-CoA, which is sensitive to glucose metabolism.

Nutraceuticals in Pregnancy: A Special Focus on Probiotics.

The placenta is crucial to fetal development and performs vital functions such as nutrient exchange, waste removal and hormone regulation. Abnormal placental development can lead to conditions such as fetal growth restriction, pre-eclampsia and stillbirth, affecting both immediate and long-term fetal health. Placental development is a highly complex process involving interactions between maternal and fetal components, imprinted genes, signaling pathways, mitochondria, fetal sexomes and environmental factors such as diet, supplementation and exercise. Probiotics have been shown to make a significant contribution to prenatal health, placental health and fetal development, with associations with reduced risk of preterm birth and pre-eclampsia, as well as improvements in maternal health through effects on gut microbiota, lipid metabolism, vaginal infections, gestational diabetes, allergic diseases and inflammation. This review summarizes key studies on the influence of dietary supplementation on placental development, with a focus on the role of probiotics in prenatal health and fetal development.

Understanding the intersection between placental development and cancer: Lessons from the tumor suppressor BAP1.

The placenta, a pivotal organ in mammalian reproduction, allows nutrient exchange and hormonal signaling between the mother and the developing fetus. Understanding its molecular intricacies is essential for deciphering normal embryonic development and pathological conditions such as tumorigenesis. Here, we explore the multifaceted role of the tumor suppressor BRCA1-associated protein 1 (BAP1) in cancer and placentation. Initially recognized for its tumor-suppressive properties, BAP1 has emerged as a key regulator at the intersection of tumorigenesis and placental development. BAP1 influences crucial cellular processes such as cell death, proliferation, metabolism, and response to hypoxic conditions. By integrating insights from tumor and developmental biology, we illuminate the complex molecular pathways orchestrated by BAP1. This perspective highlights BAP1's significant impact on both cancer and placental development, and suggests novel therapeutic strategies that could improve outcomes for pregnancy disorders and cancer.

Genomics, the diversification of mammals, and the evolution of placentation.

When and why did variations in placental structure and function evolve? Such questions cannot be addressed without a reliable version of mammalian phylogeny. Twenty-five years ago, the mammalian tree was reshaped by molecular phylogenetics. Soon it was shown, in contrast to prevailing theories, that the common ancestor of placental mammals had invasive placentation. Subsequently, evolution of many other features of extraembryonic membranes was addressed. This endeavour stimulated research to fill gaps in our knowledge of placental morphology. Last year the mammalian tree was again revised based on a large set of genomic data. With that in mind, this review provides an update on placentation in the nineteen orders of placental mammals, incorporating much recent data. The principal features such as shape, interdigitation, the interhaemal barrier and the yolk sac are summarized in synoptic tables. The evolution of placental traits and its timing is then explored by reference to the revised mammalian tree. Examples are the early appearance of epitheliochorial placentation in the common ancestor of artiodactyls, perissodactyls, pangolins and carnivores (with reversion to invasive forms in the latter) and later refinements such as the binucleate trophoblast cells and placentomes of ruminants. In primates, the intervillous space gradually evolved from the more basic labyrinth whereas trophoblast invasion of the decidua was a late development in humans and great apes. Only seldom can we glimpse the "why" of placental evolution. The best examples concern placental hormones, including some striking examples of convergent evolution such as the chorionic gonadotropins of primates and equids. In concluding, I review current ideas about what drives placental evolution and identify significant gaps in our knowledge of placentation, including several relevant to the evolution of placentation in primates.

Impacts of tolylfluanid on implantation and placental development: Disruption of mitochondrial function and implantation-related gene expression in vitro and in vivo.

Tolylfluanid is a widely used pesticide and antifouling agent in agricultural and marine industries and is recognized as a potential endocrine disruptor. However, the toxicological effects of tolylfluanid on the placenta development was not elucidated. This study used trophoblastic cell (HTR-8/SVneo cell) and endometrial cell (T HESCs) lines as in vitro model and mouse models as in vivo model to investigate the toxic effects of tolylfluanid on implantation-associated cell and placenta development during early pregnancy. Experimental results indicated that both cell lines exhibited reduced viability upon tolylfluanid exposure. Various in vitro experiments were conducted at <1 mg/L concentration. The results indicate that tolylfluanid can arrest cell cycle and induce apoptosis in endometrial and trophoblastic cells, abnormally regulate Ca2+ homeostasis and MAPK signaling pathways, and disrupt mitochondrial function. In vivo experiments, subchronic tolylfluanid exposure to mouse during puberty and pregnancy period impaired placenta development, resulting in reduced fetal and placental weight, abnormal placental structures, and altered gene expression. Specifically, a decrease in the ratio of labyrinth/junctional zones and changes in placenta gene expression patterns after tolylfluanid exposure were similar to characters of adverse pregnancy outcomes such as preeclampsia and fetal growth restriction (FGR). This study suggests that tolylfluanid exposure may have negative outcomes on female reproduction, and highlights the need for stricter regulation and monitoring of tolylfluanid use to protect women's reproductive health. This is the first study indicating the adverse effects of tolylfluanid on implantation and placental development during pregnancy.

Comparison of nutrient supply from the dam to fetus and placental development in Holstein and Japanese black cows pregnant with similar or different fetus breeds.

A lower nutrient supply from Holstein (HOL) dams to beef fetuses than HOL fetuses has been demonstrated, but the underlying factors remain unclear. We investigated maternal, umbilical vein, and calf blood glucose and amino acid concentrations at calving, along with placental development at term, in HOL dams with similar fetuses (HOL-HOL, n = 12), F1 crosses (HOL × Japanese Black [JB]; HOL-F1, n = 4), JB fetuses (HOL-JB, n = 7), and JB dams with similar fetuses (JB-JB, n = 11). Calf birth weight, total cotyledonary weight, and surface area were greater in HOL-HOL compared to JB-JB or HOL-JB (P < 0.05), whereas those of HOL-F1 were similar. Blood amino acid concentrations in the umbilical veins and calves were similar among HOL-HOL, HOL-F1, and HOL-JB. Calf blood glucose concentrations were lower in HOL-F1 than HOL-HOL (P < 0.05), despite similar maternal blood glucose levels. HOL-JB exhibited higher maternal, umbilical vein, and calf blood glucose concentrations than JB-JB (P < 0.05). Therefore, the glucose supply to the fetus may be inhibited in HOL-F1 due to maternal-fetal breed differences. Higher maternal blood glucose concentrations in HOL-JB may result in elevated fetal glucose exposure, potentially affecting postnatal growth and metabolism.

Allicin in pregnancy diets modulates steroid metabolism in pregnant sows and placental sulphate metabolism promoting placental angiogenesis and foetal development.

The low-birth-weight of piglets is an important factor affecting pig enterprises. The placenta, as a key organ for material exchange between mother and foetus, directly influences the growth and development of the foetus. Allicin exhibits various biological activities, including anti-inflammatory and antioxidant properties. It may also play a crucial role in enhancing sow reproductive performance and placental angiogenesis. In this study, we used 70 lactating Landrace × Yorkshire binary heterozygous sows to explore the effect of allicin on the reproductive performance of sows and placental development. The sows were randomly assigned into the Allicin group (Allicin), which was fed with a diet containing 0.25% allicin, and the negative control group, which was fed with basal feed. The experimental period lasted for 114 d from the date of mating to the end of farrowing. The results showed that the addition of allicin to the gestation diets increased the number of total born piglets, born alive piglets, and high-birth-weight piglets, reduced peripartum oxidative stress, alleviated dysregulation of glucose-lipid metabolism in sows, and increased the levels of antioxidant markers in the placenta. Differential analysis of metabolites in maternal plasma and placenta samples by non-targeted metabolomics revealed that allicin improved cholesterol metabolism, steroid biosynthesis, and increased plasma progesterone levels in sows. Allicin promoted sulphur metabolism, cysteine and methionine metabolism in placental samples and increased the hydrogen sulphide (H2S) content in the placenta. In addition, Quantitative Real-time PCR, Western blot and immunofluorescence results showed that allicin upregulated the expression of angiogenesis-related genes, VEGF-A, FLK 1 and Ang 1, in the placenta, implying that it promoted placental angiogenesis. These results indicate that supplementing the diet of pregnant sows with allicin reduces oxidative stress, alleviates dysregulation of glucose-lipid metabolism during the periparturient period, and promotes placental angiogenesis and foetal development by increasing plasma progesterone level and placental H2S content.

Vitamin C inactivates c-Jun N-terminal kinase to stabilize heart and neural crest derivatives expressed 1 (Hand1) in regulating placentation and maintenance of pregnancy.

Vitamin C (VC) serves as a pivotal nutrient for anti-oxidation process, metabolic responses, and stem cell differentiation. However, its precise contribution to placenta development and gestation remains obscure. Here, we demonstrated that physiological levels of VC act to stabilize Hand1, a key bHLH transcription factor vital for the development trajectory of trophoblast giant cell (TGC) lineages, thereby promoting the differentiation of trophoblast stem cells into TGC. Specifically, VC administration inactivated c-Jun N-terminal kinase (JNK) signaling, which directly phosphorylates Hand1 at Ser48, triggering the proteasomal degradation of Hand1. Conversely, a loss-of-function mutation at Ser48 on Hand1 not only significantly diminished both intrinsic and VC-induced stabilization of Hand1 but also underscored the indispensability of this residue. Noteworthy, the insufficiency of VC led to severe defects in the differentiation of diverse TGC subtypes and the formation of labyrinth's vascular network in rodent placentas, resulting in failure of maintenance of pregnancy. Importantly, VC deficiency, lentiviral knockdown of JNK or overexpression of Hand1 mutants in trophectoderm substantially affected the differentiation of primary and secondary TGC in E8.5 mouse placentas. Thus, these findings uncover the significance of JNK inactivation and consequential stabilization of Hand1 as a hitherto uncharacterized mechanism controlling VC-mediated placentation and perhaps maintenance of pregnancy.

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.

Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

The role of placental kisspeptin in trophoblast invasion and migration: an assessment in Kiss1r knockout mice, BeWo cell lines and human term placenta.

Context There is mounting evidence implicating kisspeptin signalling in placental development and function. Aims This study aimed to elucidate kisspeptin's role in trophoblast invasion and migration using three experimental models. Methods First, we examined the mouse fetus and placenta in a kisspeptin receptor (Kiss1r) knockout (KO) model. Fetal/placental weights and gene expression (quantitative polymerase chain reaction) were assessed. Second, we determined kisspeptin effects on a human trophoblast (BeWo) cell line in vitro . Third, we examined KISS1 and KISS1R gene expression in human placenta from term and pre-term pregnancies. Key results No difference was found in fetal or placental weight between Kiss1r KO and wildtype mice. However, expression of the trophoblast invasion marker, Mmp2 mRNA, was greater in the placental labyrinth zone of Kiss1r KO mice. BeWo cell models of villus cytotrophoblast and syncytiotrophoblast cells exhibited kisspeptin protein expression, with greater expression in syncytiotrophoblast, consistent with KISS1 mRNA. Kisspeptin treatment inhibited the migratory potential of cytotrophoblast-like cells. Finally, while no difference was seen in KISS1 and KISS1R mRNA between term and pre-term placentas, we saw a difference in the relative expression of each gene pre-term. We also observed a positive correlation between KISS1 expression and maternal body mass index. Conclusions Our results indicate that kisspeptin may inhibit trophoblast invasion. Implications Further investigation is required to clarify specific regulatory mechanisms.

Behind the Curtain of Abnormal Placentation in Pre-Eclampsia: From Molecular Mechanisms to Histological Hallmarks.

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte's fertilization, the embryo's pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients.

Placental Senescence and the Two-Stage Model of Preeclampsia.

In this review, we summarize how an increasingly stressed and aging placenta contributes to the maternal clinical signs of preeclampsia, a potentially lethal pregnancy complication. The pathophysiology of preeclampsia has been conceptualized in the two-stage model. Originally, highlighting the importance of poor placentation for early-onset preeclampsia, the revised two-stage model explains late-onset preeclampsia as well, which is often preceded by normal placentation. We discuss how cellular senescence in the placenta may fit with the framework of the revised two-stage model of preeclampsia pathophysiology and summarize potential cellular and molecular mechanisms, including effects on placental and maternal endothelial function. Cellular senescence may occur in response to inflammatory processes and oxidative, mitochondrial, or endoplasmic reticulum stress and chronic stress induce accelerated, premature placental senescence. In preeclampsia, both circulating and tissue-based senescence markers are present. We suggest that aspirin prophylaxis, commonly recommended from the first trimester onward for women at risk of preeclampsia, may affect placentation and possibly mechanisms of placental senescence, thus attenuating the risk of preeclampsia developing clinically. We propose that biomarkers of placental dysfunction and senescence may contribute to altered preventive strategies, including discontinuation of aspirin at week 24-28 depending on placenta-associated biomarker risk stratification.

Modeling the human placenta: in vitro applications in developmental and reproductive toxicology.

During its temporary tenure, the placenta has extensive and specialized functions that are critical for pre- and post-natal development. The consequences of chemical exposure in utero can have profound effects on the structure and function of pregnancy-associated tissues and the life-long health of the birthing person and their offspring. However, the toxicological importance and critical functions of the placenta to embryonic and fetal development and maturation have been understudied. This narrative will review early placental development in humans and highlight some in vitro models currently in use that are or can be applied to better understand placental processes underlying developmental toxicity due to in utero environmental exposures.

Cited2 is a key regulator of placental development and plasticity.

The biology of trophoblast cell lineage development and placentation is characterized by the involvement of several known transcription factors. Central to the action of a subset of these transcriptional regulators is CBP-p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). CITED2 acts as a coregulator modulating transcription factor activities and affecting placental development and adaptations to physiological stressors. These actions of CITED2 on the trophoblast cell lineage and placentation are conserved across the mouse, rat, and human. Thus, aspects of CITED2 biology in hemochorial placentation can be effectively modeled in the mouse and rat. In this review, we present information on the conserved role of CITED2 in the biology of placentation and discuss the use of CITED2 as a tool to discover new insights into regulatory mechanisms controlling placental development.

N6-methyladenosine dynamics in placental development and trophoblast functions, and its potential role in placental diseases.

N6-methyladenosine (m6A) is the most abundant modification controlling RNA metabolism and cellular functions, but its roles in placental development are still poorly understood. Here, we characterized the synchronization of m6A modifications and placental functions by mapping the m6A methylome in human placentas (n = 3, each trimester), revealing that the dynamic patterns of m6A were associated with gene expression homeostasis and different biological pathways in placental development. Then, we generated trophoblast-specific knockout mice of Wtap, a critical component of methyltransferase complex, and demonstrated that Wtap was essential for trophoblast proliferation, placentation and perinatal growth. Further in vitro experiments which includes cell viability assays and series molecular binding assays demonstrated that WTAP-m6A-IGF2BP3 axis regulated the RNA stability and translation of Anillin (ANLN) and VEGFA, promoting trophoblast proliferation and secretion. Dysregulation of this regulatory axis was observed in placentas from pregnancies with fetal growth restriction (FGR) or preeclampsia, revealing the pathogenic effects of imbalanced m6A modifications. Therefore, our findings provide novel insights into the functions and regulatory mechanisms of m6A modifications in placental development and placental-related gestational diseases.

Isl Identifies the Extraembryonic Mesodermal/Allantois Progenitors and is Required for Placenta Morphogenesis and Vasculature Formation.

The placenta links feto-maternal circulation for exchanges of nutrients, gases, and metabolic wastes between the fetus and mother, being essential for pregnancy process and maintenance. The allantois and mesodermal components of amnion, chorion, and yolk sac are derived from extraembryonic mesoderm (Ex-Mes), however, the mechanisms contributing to distinct components of the placenta and regulation the interactions between allantois and epithelium during chorioallantoic fusion and labyrinth formation remains unclear. Isl1 is expressed in progenitors of the Ex-Mes and allantois the Isl1 mut mouse line is analyzed to investigate contribution of Isl1+ Ex-Mes / allantoic progenitors to cells of the allantois and placenta. This study shows that Isl1 identifies the Ex-Mes progenitors for endothelial and vascular smooth muscle cells, and most of the mesenchymal cells of the placenta and umbilical cord. Deletion of Isl1 causes defects in allantois growth, chorioallantoic fusion, and placenta vessel morphogenesis. RNA-seq and CUT&Tag analyses revealed that Isl1 promotes allantoic endothelial, inhibits mesenchymal cell differentiation, and allantoic signals regulated by Isl1 mediating the inductive interactions between the allantois and chorion critical for chorionic epithelium differentiation, villous formation, and labyrinth angiogenesis. This study above reveals that Isl1 plays roles in regulating multiple genetic and epigenetic pathways of vascular morphogenesis, provides the insight into the mechanisms for placental formation, highlighting the necessity of Isl1 for placenta formation/pregnant maintenance.

Manganese porphyrin-based treatment improves fetal-placental development and protects against oxidative damage and NLRP3 inflammasome activation in a rat maternal hypothyroidism model.

Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1ß, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.

The effects of leptin on human cytotrophoblast invasion are gestational age and dose-dependent.

Introduction: Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized. Leptin is overexpressed in the placentas from preeclamptic (PE) pregnancies. PE can result from the impaired invasion of fetal placental cells, cytotrophoblasts (CTBs), into the maternal decidua. We hypothesized that elevated leptin levels would impair human CTB invasion. Methods: The effects of leptin on the invasion of human CTBs were evaluated in three cell models, HTR-8/SVneo cells, primary CTBs, and placental villous explants using invasion assays. Further, leptin receptor expression was characterized in all three cell models using RT-PCR. Further phosphokinase assays were performed in HTR-8/SVneo cells to determine signaling pathways involved in CTB invasion in response to differential leptin doses. Results: We found that, prior to 8 weeks gestation, leptin promoted CTB invasion in the explant model. After 11 weeks gestation in explants, primary CTBs and in HTR-8/SVneo cells, leptin promoted invasion at moderate but not at high concentrations. Further, leptin receptor characterization revealed that leptin receptor expression did not vary over gestation, however, STAT, PI3K and MAPK pathways showed different signaling in response to varied leptin doses. Discussion: These data suggest that the excess placental leptin observed in PE may cause impaired CTB invasion as a second-trimester defect. Leptin's differential effect on trophoblast invasion may explain the role of hyperleptinemia in preeclampsia pathogenesis.

Epigenetic signatures of trophoblast lineage and their biological functions.

Trophoblasts play a crucial role in embryo implantation and in interacting with the maternal uterus. The trophoblast lineage develops into a substantial part of the placenta, a temporary extra-embryonic organ, capable of undergoing distinctive epigenetic events during development. The critical role of trophoblast-specific epigenetic signatures in regulating placental development has become known, significantly advancing our understanding of trophoblast identity and lineage development. Scientific efforts are revealing how trophoblast-specific epigenetic signatures mediate stage-specific gene regulatory programming during the development of the trophoblast lineage. These epigenetic signatures have a significant impact on blastocyst formation, placental development, as well as the growth and survival of embryos and fetuses. In evolution, DNA hypomethylation in the trophoblast lineage is conserved, and there is a significant disparity in the control of epigenetic dynamics and the landscape of genomic imprinting. Scientists have used murine and human multipotent trophoblast cells as in vitro models to recapitulate the essential epigenetic processes of placental development. Here, we review the epigenetic signatures of the trophoblast lineage and their biological functions to enhance our understanding of placental evolution, development, and function.

Placenta-Related Parameters at Delivery in Relation to Folic Acid Supplementation in Different Pregnancies.

Folic acid plays an important role in the synthesis, repair, and methylation of deoxyribonucleic acid (DNA). Currently, most studies have focused on the effects of periconceptional folic acid (FA) supplementation on fetal development, and there is still a lack of population-based research exploring the association between FA use during pregnancy and placental development. This study aimed to investigate the impacts of FA supplementation in different pregnancies on placenta-related parameters at delivery. The study included 2708 pregnant women recruited from Ma'anshan City, Anhui Province, China, between May 2013 and September 2014. Information on FA use from one month before conception to delivery was collected. Placental length, width, and thickness were measured. Multivariable logistic regression analysis was used to assess the effects of FA supplementation in different pregnancies on placenta-related parameters. Based on multiple regression analysis, propensity score weighting was adopted to enhance comparability between different FA supplementation groups. Compared with FA non-users, FA supplementation before conception was associated with increased placental width (0.241 cm, 95%CI: 0.052-0.429, p = 0.013) and increased placental surface area (6.398 cm2, 95%CI: 1.407-11.389, p = 0.012), and FA use in early/middle pregnancy was, respectively, related with increased placental thickness (0.061 cm, 95%CI: 0.004-0.117, p = 0.036; 0.066 cm, 95%CI: 0.004-0.129, p = 0.038). FA use before conception could increase placental width and area, and FA use in early/middle pregnancy could increase placental thickness. To confirm the findings, further investigations are needed.