Repeated Implantation Failure Research Articles

Personalized embryo transfer guided by rsERT improves pregnancy outcomes in patients with repeated implantation failure

IntroductionEmbryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal causes for embryo implantation failure [especially repeated implantation failure (RIF)] when biopsied good-quality euploid embryos are transferred. An RNA-seq-based endometrial receptivity test (rsERT) was previously established to precisely guide successful embryo implantation. In this study, we aimed to evaluate the effect of personalized embryo transfer (pET) via rsERT on the clinical outcomes in patients with RIF.MethodsA total of 155 patients with RIF were included in the present retrospective study and were divided into two groups: 60 patients who underwent rsERT and pET (Group rsERT) and 95 patients who underwent standard frozen embryo transfer (FET) without rsERT (Group FET). Reproductive outcomes were compared for patients who underwent rsERT-guided pET and standard FET.ResultsForty percent (24/60) of the patients who underwent rsERT were receptive, and the remaining 60% (36/60) were non-receptive. The positive human chorionic gonadotropin (β-hCG) rate (56.3% vs. 30.5%, P = 0.003) and clinical pregnancy rate (43.8% vs. 24.2%, P = 0.017) were significantly higher in Group rsERT patients than in FET group patients. Additionally, Group rsERT patients also showed a higher implantation rate (32.1% vs. 22.1%, P = 0.104) and live birth rate (35.4% vs. 21.1%, P = 0.064) when compared with FET patients, although without significance. For subpopulation analysis, the positive β-hCG rate, clinical pregnancy rate, implantation rate, and live birth rate of receptive patients were not statistically significant different from those of non-receptive patients.ConclusionsThe rsERT can significantly improve the pregnancy outcomes of RIF patients, indicating the clinical potential of rsERT-guided pET.

On the issue of repeated implantation failures with assisted reproductive technologies

Embryo implantation is the first key step of a successful pregnancy, but implantation failures in patients undergoing assisted reproductive technology (ART) programs remains quite common. The main known factors of repeated implantation failures (RIF) in patients undergoing ART are unhealthy lifestyle, genetic factor, uterus pathology, endometriosis and adenomyosis, thrombophilia, and also male factor and embryonic factors. RIF factors and ways to overcome them receive much attention from researchers. However, although many possible RIF causes have been identified, much remains unknown regarding the etiology and management of this condition. In clinical practice, studies and interventions are often used without clear scientific rationale or convincing evidence of their effectiveness due to the lack of standardization of diagnostic and treatment methods. An effective strategy for treating RIF risk factors is necessary to increase the chances of successful pregnancy in assisted reproductive technology programs.

Hysteroscopy with Endometrial Vacuum Aspiration in Repeated Implantation Failure: Diagnostic Significance and the Effect on IVF Success

Introduction. This study raises the issue of diagnostic and therapeutic value of hysteroscopy with endometrial vacuum aspiration in patients with recurrent implantation failure (RIF) in IVF programs.The purpose of the study is to determine the structure of uterine pathology in women with RIF according to hysteroscopy with endometrial aspiration biopsy and to study the effect of hysteroscopy with subsequent endometrial vacuum aspiration in patients with a history of repeated implantation failures on clinical pregnancy rate.Materials and methods. In this retrospective cohort study we investigated a sample of 143 patients who passed the program of IVF at the Clinical Institute of Reproductive Medicine (Ekaterinburg, Russia). We studied the frequency of detection of uterine pathology using hysteroscopy and endometrial vacuum aspiration in patients with RIF (n = 36) and in the control group without RIF (n = 89). We analyzed the differences in the chance of clinical pregnancy aſter embryo transfer (s) in the IVF program in patients with RIF aſter hysteroscopy with endometrial vacuum aspiration (n = 30) and in the control group (n = 18).Results. The structure of intrauterine pathology was not statistically different in patients with RIF and without this condition (p > 0.05 for all pathologies). Hysteroscopy with endometrial vacuum aspiration significantly increased the incidence of clinical pregnancies in patients with RIF compared with the control group (23/30 (77.0 %) and 8/18 (44.0 %), p = 0.032).Discussion. The obtained data on the structure of the pathology of the uterus correlate with the results of similar studies. The therapeutic effect of hysteroscopy in infertility remains a matter of controversy.Conclusion. Hysteroscopy with pathomorphological examination of the aspirated endometrium is the same intervention in terms of diagnostic efficiency for patients without identified uterine pathology on ultrasound, regardless of RIF status. Hysteroscopic examination with curative endometrial injury may increase the success rate of embryo transfer implants in patients with RIF.

Performance of preimplantation genetic testing for aneuploidy for patients with unexplained recurrent pregnancy loss and repeated implantation failure

ObjectiveThe primary objective was to investigate whether the utilization of next-generation sequencing (NGS) for preimplantation genetic testing for aneuploidy (PGT-A) could enhance the reproductive outcomes in patients with unexplained recurrent pregnancy loss (uRPL) or unexplained repeated implantation failure (uRIF) undergoing intracytoplasmic sperm injection (ICSI) cycles. Materials and MethodsWe studied the reproductive outcomes of uRPL or uRIF sufferers in Chengdu women and children’s central hospital from July 2020 to Jan 2024 retrospectively. These patients were categorized into two groups based on whether they underwent PGT-A or not. As the patients in the PGT-A group all had ICSI and frozen-thawed embryo transfer (FET), only patients who underwent ICSI and FET were included in the non-PGT-A group for comparison. Demographic characteristics and reproductive outcomes were compared in uRPL or uRIF sufferers. ResultsFor uRPL group, a significant increased ongoing pregnancy rate (63.6% vs 26.1%, p=0.002) and reduced pregnancy loss rate (18.4% vs 73.3%, p<0.001) were found in the PGT-A group in comparison with those in the non-PGT-A group. For uRIF group, no significant difference was noted in the HCG-positive rate, ongoing pregnancy rate, or pregnancy loss rate between the two groups. It is noteworthy that the maternal age in the PGT-A group was significantly higher than that in the non-PGT-A group (p=0.048). ConclusionsNGS-based PGT-A effectively optimized the reproductive outcomes in uRPL sufferers. Although its benefits in uRIF appeared to be limited, there is a potential advantage for those with advanced maternal age. Considering the small sample size, further randomized controlled trials are warranted to validate these findings.

Early embryonic failure caused by a novel mutation in the TUBB8 gene: A case report

BACKGROUND This study aimed to explore the relationship between gene mutations and early embryonic development arrest and to provide more possibilities for the diagnosis and treatment of repeated implantation failure. CASE SUMMARY Here, we collected and described the clinical data of a patient with early embryonic development stagnation after repeated in vitro fertilization attempts for primary infertility at the Department Reproductive Center of Zaozhuang Maternal and Child Healthcare Hospital. We also detected the whole-exon gene of the patient's spouse and parents, and conducted bioinformatics analysis to determine the pathogenesis of the gene. CONCLUSION A novel mutant of the TUBB8 gene [c.602G&gt;T(p.C201F)] was identified, and this mutant provided new data on the genotype-phenotype relationships of related diseases.

Case Report: The combined effect of endometrial receptivity array and laser assisted hatching on embryo implantation in repeated implantation failure case

This case report describes a couple with nine years of primary infertility and three failed in vitro fertilization (IVF) attempts that showed no reproductive abnormality. Negative results were observed following the conventional IVF protocol. The couple then insisted on laser-assisted hatching (LAH) and endometrial receptivity analysis (ERA). The ERA results showed a specific window for embryo implantation, and accordingly, the treatment was carried out, which resulted in seven good-quality oocytes, leading to the formation of four blastocyst-stage embryos. These embryos were then frozen, single embryo transfer (ET) was performed following the ERA results, and the embryos were successfully implanted. The βhCG level was 245 mIU/mL, indicating that the female had successfully conceived. This case highlights the challenges of a thick zona pellucida and recurrent implantation failure (RIF), defining how a personalized method combining both LAH and ERA could lead to successful implantation.

Construction of deep learning-based convolutional neural network model for automatic detection of fluid hysteroscopic endometrial micropolyps in infertile women with chronic endometritis

Objective(s)Chronic endometritis (CE) is a localized mucosal inflammatory disorder associated with female infertility of unknown etiology, endometriosis, tubal factors, repeated implantation failure, and recurrent pregnancy loss, along with atypical uterine bleeding and iron deficiency anemia. Diagnosis of CE has traditionally relied on endometrial biopsy and detection of CD138(+) endometrial stromal plasmacytes. To develop a less invasive diagnostic system for CE, we aimed to construct a deep learning-based convolutional neural network (CNN) model for the automatic detection of endometrial micropolyps (EMiP), a fluid hysteroscopy (F-HSC) finding recognized as tiny protrusive lesions that are closely related to this disease. Study designThis is an in silico study using archival images of F-HSC performed at an infertility center in a private clinic. A total of 244 infertile women undergoing F-HSC on the days 6–12 of the menstrual cycle between April 2019 and December 2021 with histopathologically-confirmed CE with the aid of immunohistochemistry for CD138 were utilized. ResultsThe archival F-HSC images of 208 women (78 with EMiP and 130 without EMiP) who met the inclusion criteria were finally subjected to analysis. Following preprocessing of the images, half a set was input into a CNN architecture for training, whereas the remaining images were utilized as the test set to evaluate the performance of the model, which was compared with that of the experienced gynecologists. The sensitivity, specificity, accuracy, precision, and F1-score of the CNN model-aided diagnosis were 93.6 %, 92.3 %, 92.8 %, 88.0 %, and 0.907, respectively. The area under the receiver operating characteristic curves of the CNN model-aided diagnosis (0.930) was at a similar level (p > .05) to the value of conventional diagnosis by three experienced gynecologists (0.927, 0.948, and 0.906). ConclusionThese findings indicate that our deep learning-based CNN is capable of recognizing EMiP in F-HSC images and holds promise for further development of the computer-aided diagnostic system for CE.

Uterine infusion strategies for infertile patients with recurrent implantation failure: a systematic review and network meta-analysis

BackgroundIntra-uterine infusion treatments were reported to be beneficial to embryo implantation and pregnancy outcomes, and considered as potential therapies for infertile patients with recurrent implantation failure (RIF). Nevertheless, their efficiencies were controversial and there lack of consensus on which intrauterine treatment is the most effective.MethodsAll prospective trials (in Chinese or English) were searched in Databases PubMed, Cochrane, Web of Science, and CNKI from July 2013 to July 2023. We included studies that investigated various uterine infusions, including chorionic gonadotropin, granulocyte colony-stimulating factor, monocytes, platelet-rich plasma, etc. during IVF treatment and reported subsequent pregnancy outcomes.ResultsWe finally included 56 researches, including 40 randomized controlled trials, 14 non-randomized controlled trials, and 3 prospective cohort studies. This study included a total of 11 uterine perfusion methods: Placebo, Human Chorionic Gonadotropin (HCG), Granulocyte Colony-Stimulating Factor (G-CSF), platelet-rich plasma (PRP), Peripheral Blood Mononuclear Cell (PBMC), Growth hormone (GH), dexamethasone (DEX), Embryo culture supernatant (ESC), PRP combined with G-CSF (PRP + G-CSF), RPR combined with subcutaneous injection of G-CSF (RPR + G-CSFsc), G-CSF combined with subcutaneous injection of AXaIU (G-CSF + AXaIUsc). Intrauterine infusion of HCG, PBMC, G-CSF, and PRP significantly improves pregnancy outcomes in patients with repeated implantation failure compared with blank controls or placebo, and PRP improved the clinical pregnancy and live birth most. GH and ESC infusion might improve the pregnancy outcomes, but uterine infusion of DEX was shown with high miscarriage. The combination therapy did not show a significant advantage over the mono-therapy.ConclusionsIntrauterine infusion of HCG, PBMC, G-CSF, and PRP are promising strategies for improving pregnancy outcomes for infertile patients with recurrent implantation failure. Among these treatments, PRP may be the best. More researches are required to explore the effect of drug combinations and less commonly used drugs as well.Trial registrationOur study was registered in PROSPERO and the ID was CRD42023467188.

Metabolomic profiling of embryo culture media in patients with repeated implantation failure during assisted reproductive technology cycles.

This study investigated the metabolic status of the spent culture media from embryos of patients with repeated implantation failure (RIF) undergoing in vitro fertilization-intracytoplasmic sperm injection cycles in comparison with the embryos from healthy fertile women. Metabolite levels in spent culture media were assessed and compared between embryos from RIF patients (n=35) and oocyte donors as controls (n=15). Protein levels of insulin-like growth factor 1 (IGF-1) were determined using Western blotting. Concentrations of glucose, pyruvate, and lactate were measured using spectrophotometry. Ionic colorimetric assay kits were utilized to analyze the concentrations of sodium, chloride, calcium, and magnesium ions. High-performance liquid chromatography was employed to measure the concentrations of glutamic acid, aspartic acid, methionine, phenylalanine, and histidine. Glucose consumption and lactate secretion were higher in the control group than in the RIF group. The magnesium concentration was significantly higher in the control group than in the RIF group, but glutamic acid and aspartic acid concentrations were lower in the control group than in the RIF patients (p<0.05). The levels of IGF-1, sodium, calcium, chloride, methionine, histidine, and phenylalanine did not show statistically significant differences between the two groups. The metabolic profile of the culture medium of the embryos in the RIF group differed from that of the control group. These findings suggest potential factors that may affect implantation capacity in RIF patients and provide a new perspective on embryo selection.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1β, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Effect of Chronic Endometritis Treatment on The Outcome of ICSI in Patients with Repeated Implantation Failure

Effect of Chronic Endometritis Treatment on The Outcome of ICSI in Patients with Repeated Implantation Failure

Neu5Gc regulates decidual macrophages leading to abnormal embryo implantation.

Repeated implantation failure (RIF) is one of the most prominent problems in the field of assisted reproduction. Neu5Gc on the surface of decidual macrophages (dMΦ) leads to different activation patterns of dMΦ, which affects embryo implantation and development. Cmah-/- (Neu5Gc-deficient) mice induced to produce anti-Neu5Gc antibodies in vivo were given a special diet rich in Neu5Gc and their fertility was monitored. The long-term diet rich in Neu5Gc induced the decrease of endometrial receptivity of female mice. The pregnancy rate of female mice fed the normal diet was 63.6% (n = 11) and the average number of embryos was 9.571 ± 1.272, while the pregnancy rate of female mice fed the diet rich in Neu5Gc was 36.4% (n = 11) and the average number of embryos in pregnant mice was 5.750 ± 3.304. The intake of Neu5Gc and the production of anti-Neu5Gc antibody led to M1 polarization of endometrial dMΦ and abnormal embryo implantation.

Recurrent Implantation Failure from an Immunological Point of View

Introduction: Repeated implantation failure (RIF) is one of the main challenges in modern infertility treatments. Although assisted reproductive technology (ART) has undergone a lot of progression over the last recent years, some women still experience implantation failure after several embryo transfers (ET). Disruption of the mother's immunologic tolerance towards the fetus is one of the risk factors that increases the possibility of rejection the semi-allogeneic embryo by the mother’s immune system and causes failure of embryo implantation. Studies have shown that immunomodulatory treatment approaches, if used in a timely and appropriate manner, have promising results in improving pregnancy outcomes and live birth rates in this group of women. This review focuses on changes in the immune system and the use of immunomodulatory treatments in women with recurrent implantation failure.&#x0D; Conclusion: It seems that the appropriate use of immunologic tests and proper immunomodulatory treatments can manage IVF failure after repeated embryo transfers.

Intrauterine autologous platelet-rich plasma treatment in women with at least two implantation failures: A retrospective cohort study.

Finding the most effective way to improve implantation rate in women who are receiving assisted reproductive technology treatment is still a challenge. This study aimed to assess the pregnancy outcomes of intrauterine platelet-rich plasma (PRP) therapy in women with a history of at least 2 implantation failures. In this retrospective cohort study, data of 852 women who were candidates for frozen-thawed embryo transfer was extracted from their medical records from April 2017 to September 2021 at Yazd Reproductive Sciences Institute, Yazd, Iran. Of these, 432 received intrauterine PRP treatment 48 hr before transfer (PRP group), and the results of the pregnancy outcomes compared with 420 of the control group who did not receive the treatment before transfer. Pregnancy outcomes, including chemical, clinical, ongoing pregnancy, and live birth rate were statistically significant in the PRP group (p 0.001). However, when categorized according to the implantation history, this significant improvement in all 4 was only seen in women with at least 2 prior implantation failures. In women with a history of only one implantation failure, PRP therapy significantly improved the ongoing pregnancy and live birth rate (19.5%, p = 0.04). Also, in women who received donor eggs and had repeated implantation failure, PRP improved pregnancy outcomes clinically but not statistically (p = 0.15). PRP seems to be effective in improving the pregnancy rate in women with a history of 2 or more implantation failures and also shows an increase in the live birth rate in women with only one implantation failure.

Effectiveness of Autologous Platelet-Rich Plasma Therapy in Women with Repeated Implantation Failure: A Randomized Clinical Trial.

Platelet-rich plasma (PRP) therapy has been shown to enhance tissue regeneration by expressing several cytokines and growth factors (GFs). This study investigated the effect of intrauterine infusion of PRP as a noninvasive autologous GF on pregnancy outcomes in women with repeated implantation failure. This randomized clinical trial was conducted to compare the pregnancy rates between two groups of women who were candidates for the frozen-thawed embryo transfer with a history of two or more implantation failures. The PRP group (n=33) was treated with hormone replacement therapy+0.5 cc to 1 cc PRP infused into the uterine cavity two days before the embryo transfer. The control group (n=33) was only treated with hormone replacement therapy. The endometrial preparation process was done similarly in both groups. The chemical, clinical, and ongoing pregnancy, and implantation rates were compared between the two groups. Our results showed that the chemical pregnancy rate was not statistically higher in the PRP group in comparison with the control group (36.4 vs. 24.2%). In addition, the clinical pregnancy, ongoing pregnancy, and implantation rates were higher in the PRP group than the control group; however, the difference between the two groups was not statistically significant. Administration of intrauterine PRP before embryo transfer in women with repeated implantation failure (RIF) does not affect assisted reproductive technology (ART) outcomes (registration number: IRCT2016090728950N3).

LncRNA TTTY14 participates in the progression of repeated implantation failure by regulating the miR-6088/SEMA5A axis.

To identify potential biomarkers and the molecular mechanisms associated with repeated implantation failure (RIF), three microarray datasets, GSE71331 (lncRNA + mRNA), GSE111974 (lncRNA + mRNA), and GSE71332 (miRNA), were retrieved from the Gene Expression Omnibus (GEO) database. The differentially expressed mRNAs (DEMs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs) between normal control samples (C group) and RIF samples (RIF group) were identified, and then a module partition analysis was performed based on weighted correlation network analysis (WGCNA). Following enrichment analysis of the genes, the lncRNA-miRNA-mRNA interactions (ceRNA) were examined. The mRNAs in the ceRNA network were evaluated using the GSE58144 dataset. Finally, the key RNAs were verified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Fifty-three DEmiRNAs, 327 DEMs, and 13 DElncRNAs were identified between the C and RIF groups. According to WGCNA, the magenta module was positively correlated with RIF disease status. The lncRNA-mRNA interaction analysis based on genes in the magenta module revealed the intersecting lncRNAs, including peptidylprolyl isomerase E-like pseudogene (PPIEL) and the testis-specific transcript, y-Linked 14 (TTTY14); these lncRNAs are mainly involved in functions, such as plasma membrane organization. The ceRNA network analysis revealed several interactions, such as TTTY14-miR-6088-semaphorin 5A (SEMA5A). Finally, SEMA5A and the zinc finger protein 555 (ZNF555) were identified to be significantly upregulated in the RIF group compared with those in the C group in the GSE58144 dataset. The RT-qPCR results aligned with the above results. Overall, TTTY14, ZNF555, SEMA5A, PPIEL, and miR-6088 could serve as novel biomarkers of RIF.

Endometrial BMP2 Deficiency Impairs ITGB3-Mediated Trophoblast Invasion in Women With Repeated Implantation Failure.

Repeated implantation failure (RIF) leads to a waste of high-quality embryos and remains a challenge in assisted reproductive technology. During early human placentation, the invasion of trophoblast cells into the decidua is an essential step for the establishment of maternal-fetal interactions and subsequent successful pregnancy. Bone morphogenetic protein 2 (BMP2) has been reported to regulate endometrial receptivity and promote trophoblast invasion. However, whether there is dysregulation of endometrial BMP2 expression in patients with RIF remains unknown. Additionally, the molecular mechanisms underlying the effects of BMP2 on human trophoblast invasion and early placentation remain to be further elucidated. Midluteal phase endometrial samples were biopsied from patients with RIF and from routine control in vitro fertilization followed by quantitative polymerase chain reaction and immunoblotting analyses. Human trophoblast organoids, primary human trophoblast cells, and an immortalized trophoblast cell line (HTR8/SVneo) were used as study models. We found that BMP2 was aberrantly low in midluteal phase endometrial tissues from patients with RIF. Recombinant human BMP2 treatment upregulated integrin β3 (ITGB3) in a SMAD2/3-SMAD4 signaling-dependent manner in both HTR8/SVneo cells and primary trophoblast cells. siRNA-mediated integrin β3 downregulation reduced both basal and BMP2-upregulated trophoblast invasion and vascular mimicry in HTR8/SVneo cells. Importantly, shRNA-mediated ITGB3 knockdown significantly decreased the formation ability of human trophoblast organoids. Our results demonstrate endometrial BMP2 deficiency in patients with RIF. ITGB3 mediates both basal and BMP2-promoted human trophoblast invasion and is essential for early placentation. These findings broaden our knowledge regarding the regulation of early placentation and provide candidate diagnostic and therapeutic targets for RIF clinical management.

Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss.

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system.

Research progress on the STAT signaling pathway in pregnancy and pregnancy-associated disorders.

Signal transducer and activator of transcription (STAT) proteins, pivotal regulators of signaling cascades, undergo activation in response to the stimulation of cytokines and growth factors, and participate in biological processes, including inflammation, immune responses, cell proliferation, and differentiation. During the process of pregnancy, STAT signaling is involved in regulating embryonic implantation, endometrial decidualization, and establishing and maintaining maternal-fetal immune tolerance. Increasing evidence suggests that aberrant STAT signaling contributes to the occurrence and development of pregnancy disorders, including repeated implantation failure (RIF), preeclampsia (PE), recurrent spontaneous abortion (RSA), preterm birth (PTB) and gestational diabetes mellitus (GDM). Elucidating the molecular mechanisms of the STAT signaling pathway holds promise for further understanding the establishment and maintenance of normal pregnancy, and thereby providing potent targets and strategic avenues for the prevention and management of ailments associated with pregnancy. In this review, we summarized the roles of the STAT signaling pathway and its related regulatory function in embryonic implantation, endometrial decidualization, and maternal-fetal immune tolerance. In conclusion, in-depth research on the mechanism of the STAT signaling pathway not only enhances our understanding of normal pregnancy processes but also offers STAT-based therapeutic approaches to protect women from the burden of pregnancy-related disorders.

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

Abstract This review aimed to summarize the major progress in maternal-fetal medicine achieved by Chinese scientists in recent years. PubMed was systematically searched from January 2020 to November 2023. Publications that reported the progress in embryo implantation, placentation, and parturition made by Chinese scientists in the last 3 years were selected. The milestone events during gestation, embryo implantation, endometrial decidualization, placentation, and parturition are pivotal to a successful pregnancy. Embryo implantation requires intricate interactions between implantation-competent blastocysts and receptive endometrium. To adapt to pregnancy, endometrial stromal cells transform into specialized decidual cells, which occur spontaneously under the influence of ovarian hormones in humans but require the presence of embryos in mice. With embryonic development, the placenta forms to support fetal growth until parturition. The maternal-fetal interface is composed of diverse cell types, including endometrial decidual cells, placental trophoblast cells, endothelial cells, and various immune cells, a sophisticated interplay among which contributes to the maintenance of pregnancy. Near term, the uterus transitions from quiescence to contractility, in preparation for delivery. Disruptions to these events lead to pregnancy-related disorders such as repeated implantation failure, recurrent pregnancy loss, preeclampsia, fetal growth restriction, preterm birth, and infertility. In recent years, Chinese scientists have made prominent achievements in basic research on the aforementioned pregnancy events. Chinese scientists have made remarkable contributions to reproductive biology and maternal-fetal medicine research in recent years, highlighting future research directions in this field.