Maintenance Of Pregnancy Research Articles

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.

Polycystic ovary syndrome and adverse pregnancy outcomes: potential role of decidual function.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting fertility and mental health among women of reproductive age. In addition to anovulation and hyperandrogenism, patients also experience metabolic issues, such as insulin resistance, obesity, and dyslipidemia, as well as chronic low-grade inflammation throughout the body. Recent studies have shown that even with assisted reproductive technology to treat anovulatory issues, patients with PCOS still have higher rates of adverse pregnancy outcomes and abortion compared to normal pregnancies. These findings suggest that PCOS may impair the endometrium and disrupt the onset and maintenance of healthy pregnancies. Decidualization is a crucial step in the process of healthy pregnancy, during which endometrial stromal cells (ESCs) differentiate into secretory decidual stromal cells (DSCs) regulated by hormones and local metabolism. This article comprehensively reviews the pathological processes of PCOS and the mechanisms involved in its impaired decidualization. In addition, we explore how PCOS increases the incidence of adverse pregnancy outcomes (APO). By gaining a better understanding of the adverse effects of PCOS on pregnancy and its specific mechanisms, we hope to provide a theoretical basis for reducing APO and improving the live birth rate among women with PCOS.

Експресія прогестеронових рецепторів при багатоплідній вагітності

Hormonal disorders, specifically progesterone insufficiency, constitute the primary cause of pregnancy loss. The role of progesterone insufficiency in the genesis of obstetric and gynecological losses is actively discussed worldwide. Progesterone and the quantity of its receptors play a crucial role in the maintenance and prolongation of pregnancy. The placenta, being the main site of progesterone synthesis, represents a significant source of information and serves as an essential diagnostic object. The obtained data during placental research are indispensable for understanding the etiopathogenic changes in pregnancy loss in the case of multiple pregnancies. Purpose - to analyze the immunohistochemical changes in the expression of progesterone receptors in placental structures of parturients with dichorionic diamniotic twins depending on the method of conception. Materials and methods. We conducted a clinical-statistical analysis of the course of pregnancy and childbirth in women with multiple pregnancies induced by assisted reproductive technologies (ART). To determine the expression of progesterone receptors, immunohistochemical research of placentas from women with dichorionic and diamniotic twins resulting from ART was carried out. Results.The study revealed that women with multiple pregnancies induced by ART had a complicated somatic and obstetric-gynecological history, which subsequently negatively influenced the outcomes and course of pregnancy. A complicated pregnancy not only affects the process of childbirth but also the timing of delivery, as premature births in multiple pregnancies occur twice as often as in singleton pregnancies. Immunohistochemical analysis of the placenta showed the highest quantity of progesterone receptors and their expression in the nuclei of decidual cells (50%) of the maternal structure of the placenta in women with dichorionic and diamniotic twins resulting from ART. Conclusions.The obtained data on the expression of progesterone receptors indicate an evident connection between structural interactions of the placenta and endometrium, which is a key component in the advisability of prescribing progesterone therapy for the prevention of obstetric and perinatal losses. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

The Effect of Human Chorionic Gonadotropin and Ketoprofen Applications on Pregnancy Rates in Dairy Cows After Artificial Insemination

The aim of the presented study is to investigate the effect of providing progesterone (P4) support for the formation and maintenance of pregnancy or suppressing the luteolysis mechanism during the maternal acceptance process on pregnancy rates. For this purpose, 96 Holstein cows, aged between 2 and 8 years, were synchronized using the Ovsynch protocol to align their estrous cycles. After artificial insemination, the cows were divided into four groups. The group receiving Human Chorionic Gonadotropn (hCG) on the 6th day after artificial insemination (H; n=20), the group receiving Ketoprofen on the evening of the 15th day and the morning of the 16th day after artificial insemination (K; n=24), the group receiving both hCG on the 6th day and Ketoprofen on the 15th day evening and 16th day morning after artificial insemination (HK; n=25), and the control group (C; n=27) that did not receive any post-insemination treatment were established. Pregnancy checks were conducted on the 30th, 45th, and 60th days through rectal and ultrasonographic (USG) examinations. According to the results of the pregnancy examinations, it was determined that 9 out of 20 cows (45.00%) in Group H, 10 out of 24 cows (41.67%) in Group K, 16 out of 25 cows (64.00%) in Group HK, and 12 out of 27 cows (44.44%) in Group C were pregnant. No statistically significant difference (P>0.05) was observed among the groups. Our results suggest that a multi-purpose treatment may be required to reduce pregnancy loss during the early pregnancy period in cows due to an approximately 20% increased pregnancy rate after administering hCG and Ketoprofen. However, further studies, especially involving more cows, are necessary to optimize and use these combined treatments and potentially increase pregnancy rates.

The Role of DNMT1 and C/EBPα in the Regulation of CYP11A1 Expression During Syncytialization of Human Placental Trophoblasts.

Progesterone synthesized in the placenta is essential for pregnancy maintenance. CYP11A1 is a key enzyme in progesterone synthesis, and its expression increases greatly during trophoblast syncytialization. However, the underlying mechanism remains elusive. Here, we demonstrated that passive demethylation of CYP11A1 promoter accounted for the upregulation of CYP11A1 expression during syncytialization with the participation of the transcription factor C/EBPα. We found that the methylation rate of a CpG locus in the CYP11A1 promoter was significantly reduced along with decreased DNA methyltransferase 1 (DNMT1) expression and its enrichment at the CYP11A1 promoter during syncytialization. DNMT1 overexpression not only increased the methylation of this CpG locus in the CYP11A1 promoter, but also decreased CYP11A1 expression and progesterone production. In silico analysis disclosed multiple C/EBPα binding sites in both CYP11A1 and DNMT1 promoters. C/EBPα expression and its enrichments at both the DNMT1 and CYP11A1 promoters were significantly increased during syncytialization. Knocking-down C/EBPα expression increased DNMT1 while it decreased CYP11A1 expression during syncytialization. Conclusively, C/EBPα plays a dual role in the regulation of CYP11A1 during syncytialization. C/EBPα not only drives CYP11A1 expression directly, but also indirectly through downregulation of DNMT1, which leads to decreased methylation in the CpG locus of the CYP11A1 promoter, resulting in increased progesterone production during syncytialization.

Epidermal growth factor: Expression in goat endometrial epithelia during early pregnancy and regulation by interferon tau and FOXO1

In ruminants, establishment and maintenance of pregnancy depends upon a well-coordinated interaction between the conceptus and the maternal endometrium. Epidermal growth factor (EGF) is important for embryo implantation and pregnancy establishment. However, the regulatory mechanisms of EGF expression remain unclear. FOXO1, a member of the Forkhead box O (FOXO) subfamily of transcription factors, is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. In this study, we examined the spatiotemporal expression profile of EGF in goat uterus during early pregnancy (Day 0 to Day 50 of pregnancy) and verified that EGF expression was regulated by FOXO1 and interferon tau (IFNT). Our results showed that EGF was highly expressed in the luminal epithelium (LE) and the glandular epithelium (GE) during conceptus adhesion (Day 16 to Day 25 of pregnancy). After implantation, EGF protein signals were continuously detected in the endometrial epithelia and appeared in the conceptus trophectoderm. Furthermore, EGF expression could be up-regulated by IFNT in goat uterus and primary endometrial epithelium cells (EECs). The luciferase assay results showed that FOXO1 could promote EGF transcription by binding to its promoter. And FOXO1 positively regulates EGF expression in goat EECs. These findings contribute to better understanding the role and regulation mechanisms of EGF during ruminant early pregnancy.

The Prl3d1-Cre mouse line selectively induces the expression of Cre recombinase in parietal trophoblast giant cells.

The placenta plays a pivotal role in the maintenance of normal pregnancy, but how it forms, matures, and performs its function remains poorly understood. Here, we describe a novel mouse line (Prl3d1-iCre) that expresses iCre recombinase under the control of the endogenous prl3d1 promoter. Prl3d1 has been proposed as a marker for distinguishing trophoblast giant cells (TGCs) from other trophoblast cells in the placenta. The in vivo efficiency and specificity of the Cre line were analyzed by interbreeding Prl3d1-iCre mice with B6-G/R reporter mice. Through anatomical studies of the placenta and other tissues of Prl3d1-iCre/+; B6-G/R mouse mice, we found that the tdTomato signal was expressed in parietal trophoblast giant cells (P-TGCs). Thus, we report a mouse line with ectopic Cre expression in P-TGCs, which provides a valuable tool for studying human pathological pregnancies caused by implantation failure or abnormal trophoblast secretion due to aberrant gene regulation.

The effectiveness of assisted reproductive technologies immunological prediction

The high frequency of infertility is a significant medical and social problem in many countries of the world; assisted reproductive technologies (ART) are actively used to solve it. Given that immune responses play an important role in the development and maintenance of pregnancy, the study of changes in immune parameters is relevant in different trimesters of pregnancy, as well as at the stage of preconception preparation. It is believed that the maternal-fetal relationship is not limited to the development of maternal tolerance to fetal antigens, but is complemented by complex cytokine interactions that control selective immune regulation, control of adhesion and vascularization processes during embryo implantation and pregnancy. The purpose of the review was to analyze the available scientific data on the use of immune parameters to predict the effectiveness of ART. A review of Russian and foreign scientific papers on prevalence, immunopathogenetic mechanisms, and infertility diagnostics was carried out. A multi-criteria search was carried out for inventions, abstracts of patent documents on immunological prediction of the effectiveness of ART. As predictors, immunocompetent cells (CD3+-, CD4+-, CD3-CD16+56+-venous blood lymphocytes, CD95+ macrophages of endometrial biopsy), cytokines, pregnancy glycoproteins, autoantibodies, immunogenetic markers are presented. The study of the quantitative level of cytokines in blood serum, ovarian follicular fluid and endometrium as mediators of intercellular and intertissue interactions is of undoubted scientific and practical interest in terms of establishing their discriminatory levels specific to different trimesters of a normal pregnancy, the threat of miscarriage, and infertility. There was an association with non-occurrence of pregnancy due to in vitro fertilization of an increased content of interleukin (IL)-2 and interferon (IFN)-γ in the follicular fluid, and a soluble receptor IL-2-α, IL-8 and lactoferrin in the blood serum. The immunosuppressive effects of pregnancy-associated α2-glycoprotein, trophoblastic β1-glycoprotein, α-fetoprotein, α2-macroglobulin contribute to the development and maintenance of pregnancy, but their prognostic value is not unambiguous. The study of the content of immunoglobulins G to α2-macroglobulin, lactoferrin, progesterone, estradiol, cardiolipin in the follicular fluid and blood serum makes it possible to predict the result of ART. Conclusion. The study of immune parameters, especially in combination with sex hormones and characteristics of the state of the embryo, in infertile women has diagnostic value and prognostic significance, and can contribute to the timely correction of therapy and the ART program.

“In House” assays for the quantification of Annexin V and its autoantibodies in patients with recurrent pregnancy loss and in vitro fertilisation failures

Several studies have been shown that Annexin V (ANXV) autoantibodies concentrations are associated with both early recurrent pregnancy losses (RPLs) or in vitro fertilization failure (IVFf). We investigated the association between ANXV autoantibodies and ANVX levels in RPL, IVFf and normal group women. The study was conducted on 22 female patients with RPLs, 66 patients with IVFf, and 16 normal samples from women who had given birth. ANXV autoantibodies were measured using an ELISA test developed by fixing a homemade recombinant ANXV protein and examined with labeled human antibodies, while ANXV concentrations were measured by a competitive ELISA using a homemade anti ANXV polyclonal antibody. The results showed a clear relationship between the high levels of ANXV autoantibodies and the recurrent abortion. On the other hand, ANXV measurement in those patients showed decreased concentrations compared to normal samples. Negative correlation between ANXV and its autoantibodies levels was reported in almost all patients’ samples. Our data supports the possibility that ANXV autoantibodies are a risk factor for reproductive failures associated with both RPLs and/or IVFf and the significant role for ANXV in the maintenance of pregnancy.

Applying a novel kinomics approach to study decidualization and the effects of antigestagens using a canine model†.

Maternal decidual cells are crucial for the maintenance of canine pregnancy as they are the only cells expressing the nuclear progesterone (P4) receptor (PGR) in the placenta. Interfering with P4/PGR signaling adversely affects decidual cells and terminates pregnancy. Although immortalized dog uterine stromal (DUS) cells can be decidualized in vitro using cAMP, the involvement of cAMP-dependent kinases in canine decidualization had not been investigated. Therefore, the present project investigated changes in the kinome of DUS cells following in vitro decidualization, using the serine/threonine kinase (STK) PamChip assay (PamGene). Decidualization led to a predicted activation of 85 STKs in DUS cells, including protein kinase (PK) A, PKC, extracellular signal-regulated kinase (ERK)1/2 and other mitogen-activated protein kinases (MAPKs), calcium/calmodulin-dependent protein kinases (CAMKs), and Akt1/2. In addition, blocking PGR with type 2 antigestagens (aglepristone or mifepristone) decreased the activity of virtually all kinases modulated by decidualization. The underlying transcriptional effects were inferred from comparison with available transcriptomic data on antigestagen-mediated effects in DUS cells. In targeted studies, interfering with PKA or MAPK kinase (MEK)1/2 resulted in downregulation of important decidualization markers (e.g., insulin-like growth factor 1 (IGF1), prostaglandin E2 synthase (PTGES), prolactin receptor (PRLR), PGR, and prostaglandin-endoperoxide synthase 2 (PTGS2/COX2)). Conversely, blocking of PKC decreased the mRNA availability of IGF1, PGR, and PTGS2, but not of PTGES and PRLR. Moreover, suppressing PKA decreased the phosphorylation of the transcription factors cJUN and CREB, whereas blocking of PKC affected only cJUN. This first kinomics analysis to target decidualization showed an increased activity of a wide range of STKs, which could be hindered by disrupting P4/PGR signaling. Decidualization appears to be regulated in a kinase-dependent manner, with PKA and PKC evoking different effects.

Seasonal variation in air pollutant levels and its effects on the sex ratio at birth on Fukue island, Japan

BackgroundIn general, a slightly higher number of boys are born than girls, and the sex ratio at birth (number of male births/number of female births) is reported to be 1.03–1.07 in many countries. However, pregnant women exposed to high levels of atmospheric particulate matter have a reduced sex ratio at birth. Exposure to air pollutants can also lead to premature birth, suggesting that inflammation within the body may affect pregnancy maintenance and fetal development. On the other hand, the effects of air pollutants carried from afar by monsoons on the sex ratio at birth in downstream areas have not been evaluated. We focused on the Goto Islands, where various air pollutants flow from the Eurasian continent. The objective of this study was to clarify the effects of the atmospheric level of each pollutant on the sex ratio at birth on the Goto Islands.MethodsWe extracted observation data of particulate matter 2.5, sulfur dioxide, oxidants, nonmethane hydrocarbons, and methane from the National Institute for Environmental Studies database. In addition, the monthly sex ratio at birth was calculated using birth data from the National Statistics Center. To evaluate the effect of substance exposure just before fertilization on the sex ratio at birth, we analyzed the relationship between the observed pollutant level and the sex ratio at birth 9 months later. A stepwise generalized linear model was used to analyze the effects of air pollutant levels on the sex ratio at birth.ResultsThe observed values for all pollutants were significantly different between seasons, including the particulate matter 2.5 (p < 0.0001), sulfur dioxide (p = 0.0026), oxidant (p < 0.0001), nonmethane hydrocarbon (p < 0.0001), and methane (p < 0.0001) values. In the target population in the target period, the total number of births was 1835, and the sex ratio at birth was 0.967. Univariate analysis showed that the values of particulate matter 2.5 (p = 0.0157) and oxidants (p = 0.0047) correlated negatively with the sex ratio at birth. In addition, the results of multivariate analysis using the stepwise method in the model equation indicated that every 1 ppm increase in the observed OX value resulted in a 0.311 decrease in the sex ratio at birth (p = 0.0034).ConclusionsWe evaluated the relationship between seasonal variations in air pollutant levels and the sex ratio at birth 9 months later on the Goto Islands. We found that an increase in oxidant levels just before and after conception may be a risk factor for a lower sex ratio at birth. Due to the previously reported vulnerability of male fetuses, females who become pregnant when air pollutant concentrations are high may be more likely to have a female baby. It is necessary to evaluate the effects of oxidants on various aspects of pregnancy and childbirth.

Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives.

Reproductive disorders are considered a global health problem influenced by physiological, genetic, environmental, and lifestyle factors. The increased exposure to bisphenols, a chemical used in large quantities for the production of polycarbonate plastics, has raised concerns regarding health risks in humans, particularly their endocrine-disrupting effects on female reproductive health. To provide a basis for future research on environmental interference and reproductive health, we reviewed relevant studies on the exposure patterns and levels of bisphenols in environmental matrices and humans (including susceptible populations such as pregnant women and children). In addition, we focused on in vivo, in vitro, and epidemiological studies evaluating the effects of bisphenols on the female reproductive system (the uterus, ovaries, fallopian tubes, and vagina). The results indicate that bisphenols cause structural and functional damage to the female reproductive system by interfering with hormones; activating receptors; inducing oxidative stress, DNA damage, and carcinogenesis; and triggering epigenetic changes, with the damaging effects being intergenerational. Epidemiological studies support the association between bisphenols and diseases such as cancer of the female reproductive system, reproductive dysfunction, and miscarriage, which may negatively affect the establishment and maintenance of pregnancy. Altogether, this review provides a reference for assessing the adverse effects of bisphenols on female reproductive health.

Effects of long-acting injectable progesterone supplementation at early dioestrus on pregnancy maintenance in beef and dairy recipient cattle.

We tested in the present study the hypothesis that supplementation with long-acting P4 (iP4) at different times of the initial dioestrus improves pregnancy rates in dairy and beef recipients submitted to fixed-time embryo transfer (FTET). Recipients from commercial farms had their oestrous cycle synchronized with an E2/P4-based protocol in three experiments (Exp. 1 to 3). In Exp. 1, dairy heifers (n = 76) and cows (n = 104) were randomly assigned to two experimental groups: the control group (n = 89) and the iP4D4 group (n = 91). For Exps. 2 and 3, suckled beef recipients were used. In Exp. 2, recipients were assigned to two experimental groups: Control group (n = 147) and iP4D7 group (n = 144); whereas in Exp. 3, recipients were randomly assigned to three experimental groups: Control group (n = 85), iP4-D4 group (n = 86) and iP4D7 group (n = 81). Recipients in the iP4D4 and iP4-D7 groups received an i.m. administration of 150 mg iP4, on D4 or D7 (D0 was the day of expected oestrus). On D7, all recipients were evaluated by transrectal ultrasonography and those that had a CL received a fresh or vitrified invitro-produced embryo. In Exp. 2 and 3, the CL area was also determined by ultrasonography at the time of FTET. The pregnancy diagnosis was performed at 30 days in Exp. 1, 57 days in Exp. 2, and between 40 and 72 days of pregnancy in Exp. 3. In Exp. 1, the pregnancy rate did not differ (p > .1) between the Control group (38.2% [34/89]) and iP4D4 group (49.5% [45/91]); yet, a parity effect indicated a greater (p < .05) pregnancy rate in heifers (57.9% [44/76]) than cows (30.8% [32/104]). In Exp. 2, the pregnancy rate was greater (p < .05) in the iP4D7 group (45.0% [65/144]) than in the Control group (34.0% [50/147]). Also, a greater (p = .08) pregnancy rate was observed for recipients with a small CL (≤2.75 cm2 ) that were treated with iP4 on the day of FTET than the control recipients (46.4% [32/69] vs. 32.6% [28/86]). In Exp. 3, no significant effects (p > .1) of the treatment group or CL size were detected on pregnancy rates at days 30 and 60. In conclusion, the beneficial effects of iP4 supplementation at early dioestrus on pregnancy maintenance may vary according to the experimental conditions, but its use at the time of FTET can be used as an alternative to enhance the fertility of beef recipients in challenging conditions in commercial herds.

#286 : Circus Recurrent Pregnancy Loss by Modulating SETD1B/H3K4me2/me3 LoopK40 Regulates Cell Survival and Participates in

Background and Aims: The epigenetic mechanisms involved in the etiology of unexplained recurrent pregnancy loss (uRPL) is largely unknown. This study aims to investigate the molecular mechanisms of circRNAs modulating decidua function by regulating methylation modification of histones and whereby participating in uRPL. Method: RNA sequencings on decidua of uRPL couples and endometrial stromal cells (ESCs) after overexpressed with circSTK40 were performed to confirm the regulatory relationship between circSTK40 and SETD1B. Functional experiments including TUNEL, autophagy double-label system, the tests of glucose intake, lactic acid production were performed to determine the effects of circSTK40 and SETD1B on ESCs. Mechanism studies were conducted using RNA pulldown, RNA binding protein immunoprecipitation, chromatin immunoprecipitation et al. Results: The expression levels of circSTK40 and SETD1B were significantly downregulated in the decidua of uRPL patients, and a positive regulatory relationship was observed between them. Both circSTK40 and SETD1B promoted cell survival and participated in the maintenance of pregnancy by regulating apoptosis, autophagy and glycolysis of decidualized ESCs. After the knockdown of SETD1B, the protective effect of circSTK40 could be eliminated, resulting in elevated apoptosis, reduced autophagy level and increased cellular glycolysis, leading to pregnancy loss. Regarding mechanism studies, circSTK40 is directly bound to SETD1B and histone H3 to promote their interaction and increase the methylation level of H3K4. H3K4me2 and H3K4me3 reversely bound to the promoter region of SETD1B and enhanced its transcription, resulting in upregulation of SETD1B, and consequently formed a SETD1B/H3K4me2/3 regulatory loop. Conclusion: CircSTK40 influences cell survival by modulating the SETD1B/H3K4me2/me3 regulatory loop. Downregulation of circSTK40 and SETD1B in decidua may contribute to uRPL via promoting cell apoptosis. Our findings indicate a novel epigenetic mechanism for uRPL pathogenesis involving circSTK40 activity and histone methylation modification.

Evaluation of Molecular Interactions and Cellular Dynamics at the Maternal-Fetal Interface During Placental Morphogenesis.

Molecular events at the maternal-fetal interface establish successful pregnancies. Identifying and characterizing the heterogeneous cell population and their cross-talk at the cellular and molecular levels are essential to expand our knowledge on the progression and maintenance of pregnancy. In this chapter, we briefly discuss the organization of maternal-fetal interface in mice/rats and humans. We illustrate methods for studying the cell composition using flow cytometry, immunocytochemical and biochemical studies, intercellular interaction using co-culture system and spheroid assay, and function of trophoblast cells using ELISA, RNA sequencing, mass spectrometry (MS) to analyze the proteome, invasion assay, and scratch wound assay.

Why Does Your Uterus Become Malignant? The Impact of the Microbiome on Endometrial Carcinogenesis.

The aim of this review was to describe the uterine microbiome composition that has been analyzed so far and describe potential pathways in the carcinogenesis of the endometrium. The microbiome in the uterine environment is involved in apoptosis and proliferation during the menstruation cycle, pregnancy maintenance, and immune system support. However, bacteria in the uterus could stimulate inflammation, which when chronic results in malignancy. An altered gut microbiota initiates an inflammatory response through microorganism-associated molecular patterns, which leads to intensified steroidogenesis in the ovaries and cancers. Moreover, intestinal bacteria secreting the enzyme β-glucuronidase may increase the level of circulating estrogen and, as a result, be influential in gynecological cancers. Both the uterine and the gut microbiota play a pivotal role in immune modulation, which is why there is a demand for further investigation from both the diagnostic and the therapeutic perspectives.

Regulatory T-cell phenotypes in prenatal psychological distress

BackgroundExperiencing symptoms of psychological distress during pregnancy is common and has been linked to dysregulated immune functioning. In this context, immunoregulatory function is especially relevant because of its crucial role in establishment and maintenance of healthy pregnancy. However, little research has examined associations between women’s prenatal psychological distress and immunoregulatory biomarkers. We investigated how symptoms of depression, anxiety, and stress relate to circulating levels of regulatory T-cells (Tregs). Materials and methodsPregnant Latina women were assessed at around 12 weeks of pregnancy (N = 82). These assessments included blood draws and self-report questionnaires assessing symptoms of depression, state anxiety, pregnancy-related anxiety, and perceived stress. Flow cytometry on PBMCs was used to quantify circulating Tregs, defined as CD3+CD4+CD25hiCD127loFoxP3+, and subpopulations positive for one of the following intra- or extracellular markers, CD45RA, CTLA-4, Helios, PD-1, TIM-3, and TIGIT. We collected 82 samples at 12 weeks. Multivariable linear regressions tested for associations between symptoms of psychological distress and Treg concentrations, adjusted for gestational age. ResultsState anxiety symptoms at 12 weeks were negatively associated with parent Treg cell levels (b = −4.02, p = 0.023) and subpopulations Helios+ (b = −3.29, p = 0.019) and TIM3+ (b = −3.17, p = 0.008). Perceived stress was negatively associated with the PD-1+ subpopulation at 12 weeks (b = −4.02, p = 0.023). Depression was not related to Tregs or the subpopulations. ConclusionOur observation that symptoms of anxiety and stress are related to tolerogenic immunology suggests a possible biomechanism explaining correlations of maternal mood disorders with adverse outcomes for mothers and offspring.

Morphological and molecular features of decidual endometrial cells in miscarriage

Decidualization is a dynamic, multistep process that results in the differentiation of elongated endometrial stromal cells into round, epithelioid-like decidual cells in response to increasing progesterone levels. Throughout pregnancy, decidual stromal cells play an important role by creating a tolerant microenvironment, the decidua, to suppress the maternal immune response and prevent rejection of the allogeneic fetus. Decidualization is considered significant not only in the establishment and maintenance of pregnancy, prevention of early losses, and modulation of the immune response but also in the control of the onset of labor, regulation of trophoblast invasion, and embryo selection. Decidual cells have immunomodulatory properties in relation to cells of innate and adaptive immunity. Pregnancy maintenance requires selective elimination of proinflammatory senescent decidual cells by activated uterine natural killer cells. Data on various populations of decidualizing endometrial stromal cells revealed subtypes with different functional characteristics, namely, predecidual, decidual, transitional, and senescent subpopulations. An increase in the number of the latter with a proinflammatory phenotype leads to miscarriages. This paper analyzes the literature data on decidualization and its role in the genesis of miscarriage and highlights the contribution of decidual stromal cells to the microenvironment and their direct or indirect influence on the recruitment, distribution, and function of immune cells, extracellular matrix remodeling, and placenta formation.

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage

Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of FOLR2+ macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.

The effect of genetic defects on pregnancy loss in Swedish dairy cattle

The effect of carrier status of 10 lethal recessive genetic defects on pregnancy maintenance in Swedish dairy cattle was examined. The genetic defects were Ayrshire Haplotype 1, Ayrshire Haplotype 2, BTA12, BTA23, and Brown Swiss Haplotype 2 in Red Dairy Cattle (RDC), and Holstein Haplotype 1, 3, 4, 6, and 7 (HH1-HH7) in Holstein. Effects of carrier status of BTA12 and HH3 on conception rate (CR), interval from first to last service (FLS), and milk production were also examined. Data were obtained for 1,429 herds in the Swedish milk recording system, while information on carrier status of genetic defects was obtained from the Nordic Cattle Genetic Evaluation. In total, data on 158,795 inseminations in 28,432 RDC and 22,018 Holstein females were available. Data permitted separate analyses of BTA12 and HH3, but carrier frequencies of other defects were too low to enable further analysis. Pregnancy loss was defined as failure to maintain pregnancy, where pregnancy status was confirmed with manual and chemical pregnancy diagnosis, insemination, calving, sales and culling data. Odds ratios (OR) and probabilities of pregnancy loss and CR were estimated using generalized linear mixed models, while pregnancy loss, CR, FLS, milk, protein, and fat yields were analyzed using linear mixed models. Pregnancy losses were reported on average within the first month post-AI. At-risk matings were more prone to suffer pregnancy loss in BTA12 (OR = 1.79) and HH3 carriers (OR = 1.77) than not-at-risk matings. At-risk matings also had lower CR (OR = 0.62 and 0.63 for BTA12 and HH3, respectively) than not-at-risk matings. Carrier females of BTA12 had longer FLS and higher milk production than noncarriers. Conception rate and pregnancy maintenance could be improved by avoiding at-risk matings. This finding could help reduce pregnancy loss due to genetic defects in the breeding program for improved fertility.