Astragalus root increases Treg and Th17 involvement in embryo implantation and pregnancy maintenance by decreasing CTLA-4+ Tregs.

Maintenance of pregnancy is highly dependent on the maternal immune system. High levels of regulatory T cells (Tregs) accumulate in the maternal placenta to suppress immunoreactivity against fetal antigens. We assessed whether Astragalus root (AsR) and AsR-containing Kampo medicines modulate immunoreactivity and thereby increase mouse litter size. AsR-exposed murine splenocytes exhibited significantly increased IL-2 secretion. In AsR-exposed mice, total Tregs were significantly increased, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4)-positive Tregs were decreased in AsR-exposed mice. Tregs express IL-2 receptor subunit alpha and are activated by IL-2. CTLA-4 interacts with B7 expressed in antigen-presenting cells (APCs) with high affinity, and CTLA-4/B7 signaling plays a critical role in inhibiting APC activity, thereby suppressing CD4+ T cell proliferation and activation. The decrease in CTLA-4+ Tregs in AsR-exposed mice is thought to induce an increase in CD4+ T cells, leading to increased IL-2 secretion from CD4+ T cells followed by Treg activation. Th17 cells prevent trophoblast apoptosis, resulting in trophoblast invasion into the decidua. AsR increases Th17 cells, thereby inducing dose-dependent increases in litter size. Although Keishikaogito (KO)- and Ogikenchuto (OK)-exposed mice exhibited increased IL-2 secretion and splenic Tregs, KO also increased CTLA-4+ Tregs. Therefore, KO promoted immunosuppression by increasing CTLA-4+ Tregs, which induced a decrease in Th17 and exerted little effect on litter size. Therefore, an increase in both Tregs and Th17 cells can be considered necessary for embryo implantation and pregnancy maintenance.

Epigenetic role of LINE-1 methylation and key genes in pregnancy maintenance.

Spontaneous abortion is a pregnancy complication characterized by complex and multifactorial etiology. About 5% of childbearing women are globally affected by early pregnancy loss (EPL) and most of them experience recurrence (RPL). Epigenetic mechanisms and controlled inflammation are crucial for pregnancy maintenance and genetic predispositions may increase the risk affecting the maternal-fetal crosstalk. Combined analyses of global methylation, inflammation and inherited predispositions may contribute to define pregnancy loss etiopathogenesis. LINE-1 epigenetic regulation plays crucial roles during embryo implantation, and its hypomethylation has been associated with senescence and several complex diseases. By analysing a group of 230 women who have gone through pregnancy interruption and comparing those experiencing spontaneous EPL (n = 123; RPL, 54.5%) with a group of normal pregnant who underwent to voluntary interruption (VPI, n = 107), the single statistical analysis revealed significant lower (P < 0.00001) LINE-1 methylation and higher (P < 0.0001) mean cytokine levels (CKs: IL6, IL10, IL17A, IL23) in EPL. Genotyping of the following SNPs accounted for different EPL/RPL risk odds ratio: F13A1 rs5985 (OR = 0.24; 0.06-0.90); F13B rs6003 (OR = 0.23; 0.047-1.1); FGA rs6050 (OR = 0.58; 0.33-1.0); CRP rs2808635/rs876538 (OR = 0.15; 0.014-0.81); ABO rs657152 (OR = 0.48; 0.22-1.08); TP53 rs1042522 (OR = 0.54; 0.32-0.92); MTHFR rs1801133/rs1801131 (OR = 2.03; 1.2-3.47) and FGB rs1800790 (OR = 1.97; 1.01-3.87), although Bonferroni correction did not reach significant outputs. Principal Component Analysis (PCA) and logistic regression disclosed further SNPs positive/negative associations (e.g. APOE rs7412/rs429358; FGB rs1800790; CFH rs1061170) differently arranged and sorted in four significant PCs: PC1 (F13A, methylation, CKs); PC3 (CRP, MTHFR, age, methylation); PC4 (F13B, FGA, FGB, APOE, TP53, age, methylation); PC6 (F13A, CFH, ABO, MTHFR, TP53, age), yielding further statistical power to the association models. In detail, positive EPL risk association was with PC1 (OR = 1.81; 1.33-2.45; P < 0.0001) and negative associations with PC3 (OR = 0.489; 0.37-0.66; P < 0.0001); PC4 (OR = 0.72; 0.55-0.94; P = 0.018) and PC6 (OR = 0.61; 0.46-0.81; P = 0.001). Moreover, significant inverse associations were detected between methylation and CKs levels in the whole group (rIL10 = - 0.22; rIL17A = - 0.25; rIL23 = - 0.19; rIL6 = - 0.22), and methylation with age in the whole group, EPL and RPL subgroups (r2TOT = 0.147; r2EPL = 0.136; r2 RPL = 0.248), while VPI controls lost significance (r2VPI = 0.011). This study provides a valuable multilayer approach for investigating epigenetic abnormalities in pregnancy loss suggesting genetic-driven dysregulations and anomalous epigenetic mechanisms potentially mediated by LINE-1 hypomethylation. Women with unexplained EPL might benefit of such investigations, providing new insights for predicting the pregnancy outcome and for treating at risk women with novel targeted epidrugs.

Visfatin Affects the Transcriptome of Porcine Luteal Cells during Early Pregnancy.

Visfatin/NAMPT (VIS), the hormone exerting a pleiotropic effect, is also perceived as an important factor in the regulation of reproductive processes and pregnancy maintenance. Previous studies confirmed its involvement in the control of porcine pituitary and ovary function. In this study, we hypothesized that VIS may affect the global transcriptome of luteal cells and thus regulate the functioning of the ovaries. Illumina's NovaSeq 6000 RNA sequencing was performed to investigate the differentially expressed genes (DEGs) and long non-coding RNAs (DELs) as well as the occurrence of differential alternative splicing events (DASs) in the porcine luteal cells exposed to VIS (100 ng/mL) during the implantation period. The obtained results revealed 170 DEGs (99 up- and 71 downregulated) assigned to 45 functional annotations. Moreover, we revealed 40 DELs, of which 3 were known and 37 were described for the first time. We identified 169 DASs events. The obtained results confirmed a significant effect of VIS on the transcriptome and spliceosome of luteal cells, including the genes involved in the processes crucial for successful implantation and pregnancy maintenance as angiogenesis, steroidogenesis, inflammation, cell development, migration, and proliferation.

Pregnancy maintenance and fetal loss assessment in Holstein cows through analyzing pregnancy-associated glycoproteins in milk.

Fetal loss (FL) from the 45th day of gestation until calving can impose a significant economic burden on dairy farmers, resulting in lost profits and increased production costs. Pregnancy-associated glycoprotein (PAG) is commonly used for detecting pregnancy in cows. PAG is secreted by binucleated trophoblast cells of the placenta and regulated by more than 24 genes. The purpose of this study was to determine the PAG threshold for FL and a probability of pregnancy maintenance until calving based on milk PAG levels. Our results reveal that primiparous and multiparous cows that maintained pregnancy until the 40th week exhibited higher PAG sample-negative (SN) values in their milk in the 6th week of gestation than did those that experienced FL later in gestation. Pregnant cows with higher PAG SN values in the 6th week of gestation were more likely to maintain their pregnancies. The area under the receiver operating characteristic curve for predicting the probability of pregnancy maintenance was 0.722 for our prediction model. On the other hand, a milk PAG SN value of <0.192 indicated 95 % confidence that FL would occur between the 7th and 40th weeks of gestation. Milk PAG testing is a noninvasive sampling technique that does not induce additional stress in lactating cows. The study reveals that PAG SN values increase significantly in Holstein cows during the 6th week of gestation. The predictive model developed was effective in forecasting pregnancy outcomes up to the 40th week of gestation or calving. The model's performance is moderately good for field application and could be a useful tool for dairy producers.

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 in vitro-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.

Descripción de las personas gestantes afiliadas a OSEP que solicitan una interrupción del embarazo / Description of pregnant people affiliated to osep who request a pregnancy interruption

En 2021 entró en vigencia en Argentina la Ley N.º 27.610. El objetivo es describir características de afiliadas a OSEP que solicitaron interrupción del embarazo (SIE).Trabajo observacional descriptivo. Se analizaron las variables del 0800 del Ministerio de Salud de la Nación de todas las personas que SIE con OSEP, entre el 24/01 y 31/12/2021. Los datos fueron analizados con SPSS Statistics. Se utilizaron moda, mediana, porcentaje, tasa y el chi2. Se recibieron 427 SIE, se concretaron 330 (77,3%). Solicitaron ive: media 28,59 años. Modo 19 y 33 años. Concretaron ive: modo 22 años. 84,5% se realizó ambulatorio con misoprostol. De las SIE, 50,4% eran solteras, 43,4% trabajaba, 59,1% tenía secundario completo. Se desconoce 32,8%. De las SIE, 52,7% refirió haber estado utilizando MAC (54,2% preservativo; 37,4% anticonceptivos orales; 2,8% métodos "naturales"; 2,2% DIU). La mayor cantidad fue de zonas urbanas del Gran Mendoza. Sin embargo, se observan tasas elevadas en zonas rurales respecto de algunas zonas urbanas y más pobladas. Se observó progresión de SIE a lo largo del año. Un 11% después de SIE decidió continuar con el embarazo. Aparentemente ninguna de las variables tuvo relación con esa decisión. El MAC utilizado fue mayormente preservativo y anticonceptivos orales. Esto podría indicar falta de educación y poco acceso a métodos de larga duración. La problemática de interrupción es transversal. En base a los resultados de este trabajo, las personas sin pareja conviviente, ante un embarazo no planificado serían las que SIE. Ninguna otra variable parece actuar como determinante. Tampoco del paso de la solicitud a la interrupción efectiva o a la continuación del embarazo. Hay que aumentar la accesibilidad a MAC en zonas rurales (AU)

In 2021, Law No. 27610 entered into force in Argentina. The objective is to describe characteristics of people with OSEP who requested termination of pregnancy (PWRTP). Descriptive observational work. The variables of the 0800 of the Ministry of Health of Argentina of all the PWRTP with OSEP, between 01/24 and 12/31/2021, were analyzed. Data were analyzed with SPSS Statistics. Mode, median, percentage, rate and chi2 were used. PWRTP: 427 requests were received, 330 (77.3%) were completed. PWRTP: mean 28.59 years. Mode 19 and 33 years. People who had an abortion: mode 22 years. 84.5% were performed on an outpatient basis with misoprostol. 50.4% of the PWRTP were single, 43.4% worked, 59.1% had completed high school, 32.8% unknown, 52.7% reported having been using contraceptive methods (CM): 54.2% condoms; 37.4% oral contraceptives; 2.8% "natural" methods; 2.2% IUDs. The largest amount was from urban areas of Mendoza. However, high rates are observed in rural areas. A progression of the amount of PWRTP was observed throughout the year. 11% after requesting an abortion decided to continue with the pregnancy. Apparently none of the variables was related to that decision. The CM used were mostly condoms and oral contraceptives. This may indicate a lack of education and poor access to long-acting CM. The problem of interruption is transversal. People without a cohabiting partner, faced with an unplanned pregnancy, are the ones who RTP. No other variable seems to act as a determinant. Nor from the transition from the request to the effective interruption or continuation of the pregnancy. We must increase the accessibility to CM in rural areas (AU)

Expression profile of genes related to pregnancy maintenance in Dromedary Camel during the first trimester.

So far, few signals involved in embryo-maternal dialogue have been identified in pregnant she-camel. Our objective was to investigate expression profiles of genes relevant to uterine extracellular matrix remodeling (ITGB4, SLCO2A1, FOS, and JUN), uterine tissue vascularization, and placental formation (VEGFA, PGF, and PDGFA), embryonic growth and development (IGF1 and PTEN), plus cell death of uterine tissue (BCL2) in early pregnant versus non-pregnant she-camels. Forty genital tracts (20 pregnant and 20 non-pregnant) and blood samples were collected from abattoirs. Total RNA was extracted from uterine tissues and qRT-PCR was conducted for candidate genes. Serum concentrations of progesterone (P4) and estradiol17-ß (E2) were measured. Expression of ITGB4, FOS, and PGF genes increased (P < 0.001) in the right uterine horn of pregnant versus non-pregnant she-camels. Moreover, JUN, SLCO2A1, VEGFA, and PTEN mRNAs were up-regulated (P < 0.001) in various segments of uterine tissues in pregnant groups. The PDGFA transcript was over-expressed (P < 0.001) in both uterine horns of pregnant groups. Additionally, IGF1 was higher (P < 0.001) in the right horn and the uterine body of pregnant groups, and expression of BCL2 was increased (P < 0.001) in the pregnant uterine body. Moreover, serum concentrations of P4 were higher (P < 0.001) and E2 lower (P < 0.05) in pregnant she-camels. Taken together, the fine-tuning of genes related to implantation, matrix formation, vascularization, and placental formation is highly required for successful pregnancy in she-camels.

Tim-3 Coordinates Macrophage-Trophoblast Crosstalk via Angiogenic Growth Factors to Promote Pregnancy Maintenance.

T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal-fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal-fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies. The adoptive transfer of Tim-3+Mφs, rather than Tim-3-Mφs, reversed the murine placental dysplasia resulting from Mφ depletion. With the higher production of angiogenic growth factors (AGFs, including PDGF-AA, TGF-α, and VEGF), Tim-3+dMφs were more beneficial in promoting the invasion and tube formation ability of trophoblasts. The blockade of AGFs in Tim-3+Mφs led to the narrowing of the labyrinthine layer of the placenta, compromising maternal-fetal tolerance, and increasing the risk of fetal loss. Meanwhile, the AGFs-treated Tim-3-Mφs could resolve the placental dysplasia and fetal loss resulting from Mφ depletion. These findings emphasized the vital roles of Tim-3 in coordinating Mφs-extravillous trophoblasts interaction via AGFs to promote pregnancy maintenance and in extending the role of checkpoint signaling in placental development. The results obtained in our study also firmly demonstrated that careful consideration of reproductive safety should be taken when selecting immune checkpoint and AGF blockade therapies in real-world clinical care.

Intervenções psicológicas necessárias: a prática como residente no serviço de medicina fetal / Necessary psychological interventions: the practice as a resident in the fetal medicine service / Intervenciones psicológicas necesarias: la práctica como residente en el servicio de medicina fetal

Com os avanços tecnológicos e o aprimoramento da prática médica via ultrassonografia, já é possível detectar possíveis problemas no feto desde a gestação. O objetivo deste estudo foi analisar a prática do psicólogo no contexto de gestações que envolvem riscos fetais. Trata-se de um estudo qualitativo sob formato de relato de experiência como psicólogo residente no Serviço de Medicina Fetal da Maternidade Escola da Universidade Federal do Rio de Janeiro (UFRJ). Os registros, feitos por observação participante e diário de campo, foram analisados em dois eixos temáticos: 1) intervenções psicológicas no trabalho em equipe em consulta de pré-natal, exame de ultrassonografia e procedimento de amniocentese; e 2) intervenções psicológicas em casos de bebês incompatíveis com a vida. Os resultados indicaram que o psicólogo nesse serviço é essencial para atuar de forma multiprofissional na assistência pré-natal para gravidezes de alto risco fetal. Ademais, a preceptoria do residente é relevante para sua formação e treinamento para atuação profissional no campo da psicologia perinatal.(AU)

Face to the technological advances and the improvement of medical practice via ultrasound, it is already possible to detect possible problems in the fetus since pregnancy. The objective of this study was to analyze the psychologist's practice in the context of pregnancies which involve fetal risks. It is a qualitative study based on an experience report as a psychologist trainee at the Fetal Medicine Service of the Maternity School of UFRJ. The records, based on the participant observation and field diary, were analyzed in two thematic axes: 1) psychological interventions in the teamwork in the prenatal attendance, ultrasound examination and amniocentesis procedure; and 2) psychological interventions in cases of babies incompatible to the life. The results indicated that the psychologist in this service is essential to work in a multidisciplinary way at the prenatal care for high fetal risk pregnancies. Furthermore, the resident's preceptorship is relevant to their education and training for professional performance in the field of Perinatal Psychology.(AU)

Con los avances tecnológicos y la mejora de la práctica médica a través de la ecografía, ya se puede detectar posibles problemas en el feto desde el embarazo. El objetivo de este estudio fue analizar la práctica del psicólogo en el contexto de embarazos de riesgos fetal. Es un estudio cualitativo basado en un relato de experiencia como residente de psicología en el Servicio de Medicina Fetal de la Escuela de Maternidad de la Universidade Federal do Rio de Janeiro (UFRJ). Los registros, realizados en la observación participante y el diario de campo, se analizaron en dos ejes temáticos: 1) intervenciones psicológicas en el trabajo en equipo, en la consulta prenatal, ecografía y los procedimientos de amniocentesis; y 2) intervenciones psicológicas en casos de bebés incompatibles con la vida. Los resultados señalaron como fundamental la presencia del psicólogo en este servicio trabajando de forma multidisciplinar en la atención prenatal en el contexto de embarazos de alto riesgo fetal. Además, la tutela del residente es relevante para su educación y formación para el desempeño profesional en el campo de la Psicología Perinatal.(AU)

Violência sexual e aborto legal: possibilidades e desafios da atuação psicológica / Sexual offence and legal abortion: opportunities and challenges from psychological working / Violencia sexual y aborto legal: posibilidades y desafíos de la atención psicológica

A violência sexual e o aborto legal são temas tabus em nossa sociedade. No campo da saúde, a(o) psicóloga(o) atua em fases distintas, seja na avaliação psicológica do pedido pelo aborto legal, que culminará ou não em sua aquiescência; seja no momento posterior à solicitação, no atendimento em enfermarias ou ambulatorial. Partindo de relato de experiência, este artigo tem como objetivo refletir sobre as possibilidades e desafios da atuação psicológica no atendimento em saúde para pessoas em situação de gestação decorrente de violência sexual e que buscam pelo aborto legal. Para tanto, dividimos o artigo em três momentos. No primeiro deles, será possível encontrar dados conceituais, estatísticos e históricos sobre ambos os temas, trazendo recortes nacionais e internacionais. No segundo, trazemos apontamentos sobre o que chamamos de "eixos norteadores", ou seja, dialogamos com aspectos fundamentais para o trabalho nesta seara, sendo eles gênero, família, sexualidade e trauma. Por fim, no terceiro, aprofundamos a reflexão sobre o atendimento psicológico atrelado aos conceitos já discutidos, analisando de forma crítica principalmente um dos pontos mais espinhosos da atuação: a avaliação para aprovação (ou recusa) do pedido pelo aborto. Apoiamo-nos no referencial psicanalítico e defendemos que esta atuação psicológica é primordialmente uma oferta de cuidado, comprometido com as demandas das pessoas atendidas e com a promoção de saúde mental, e consideramos que o papel da psicologia é essencial para o reconhecimento do sofrimento e dos efeitos do abandono socioinstitucional na vida do público atendido.(AU)

Sexual abuse and legal abortion are taboo subjects in our society. On the health area, the psychologist works on different fields, such as psychological evaluation from the request of legal abortion, that will end or not on its approval, and also in a further moment, either the care on wards or ambulatorial treatment. Relying on a case report, this article aims to contemplate the possibilities and challenges from psychological work on healthcare to pregnant women from sexual violence and seek legal abortion. For this purpose, we divide this article in three moments. On the first, it will find definitions, statistics, and historical data about both issues, including national and international information. On the second, we bring notes called 'guiding pillar,' that is, we interact with fundamental aspects from this area, such as gender, family, sexuality, and trauma. On the third one, in-depth discussions we dwell on psychological care tied to the concepts previously addressed, critically analyzing one of the hardest moments of working in this area: the evaluation to approve (or refuse) the request for abortion. We lean over psychoanalytic thoughts and argue that this psychological work is primarily an offer of care, committed to the needs from those who seek us and to promoting good mental health and, also, we consider that psychology is essential to acknowledge the suffering and the effects of social and institutional neglect on the lives of the people seen.(AU)

La violencia sexual y el aborto son temas tabús en nuestra sociedad. En el campo de la salud, el(la) psicólogo(a) actúa en diferentes fases: en la evaluación psicológica de la solicitud del aborto legal, que culminará o no en su obtención, y/o en el momento posterior a la solicitud en la atención en enfermería o ambulatorio. Desde un reporte de experiencia, este artículo pretende reflexionar sobre las posibilidades y los desafíos de la Psicología en la atención en salud para personas en estado de embarazo producto de violencia sexual y que buscan un aborto legal. Para ello, este artículo está dividido en tres momentos. En el primer, presenta datos conceptuales, estadísticos e históricos sobre los dos temas, trayendo recortes nacionales e internacionales. En el segundo, comenta los llamados "ejes temáticos", es decir, se establece un diálogo con aspectos fundamentales para el trabajo en este ámbito, como género, familia, sexualidad y trauma. Por último, en el tercer, profundiza en la reflexión sobre la atención psicológica asociada a los conceptos discutidos, analizando de forma crítica uno de los puntos más espinosos de la actuación: la evaluación para la aprobación (o negativa) de la solicitud de aborto. Se utilizó el referencial psicoanalítico y se argumenta que esta atención psicológica es sobre todo una forma de cuidado, comprometida con las demandas de las personas atendidas y la promoción de la salud mental, y el papel de la Psicología es esencial para reconocer el sufrimiento y los efectos del abandono socioinstitucional en la vida del público atendido.(AU)

Molecular hydrogen has a positive impact on pregnancy maintenance through enhancement of mitochondrial function and immunomodulatory effects on T cells.

AIMS: Molecular hydrogen (H2) has attracted growing interest because of its implications in various diseases. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain elusive. No knowledge has been available on the role of H2 in the etiology of pregnancy disorders or its direct influence on human immune cells. Since maternal immunity, T cells in particular, plays a critical role in pregnancy maintenance. We investigated the effects of H2 on T cells and its relation to preterm birth (PTB). MAIN METHODS: Exhaled H2 concentrations in pregnant women were measured and correlated with cytokine concentrations in maternal and umbilical cord blood. H2 was added to T cells collected from healthy donors, and differentiation and proliferation were examined. Energy metabolism was also examined. H2 was administered to mice and cytokine expression was compared. KEY FINDINGS: Our prospective observational study revealed that maternal production of H2 is significantly lower in pregnant women with PTB, suggesting its potential as a biomarker for predicting PTB. We found that H2 has clear associations with several maternal cytokines, and acts as an immunomodulator by exerting mitochondrial function in human T cells. Moreover, in vivo administration of H2 to pregnant mice regulated inflammatory responses and reduced PTB caused by T cell activation, which further supports the notion that H2 may contribute to prolonged gestation through its immunomodulatory effect. SIGNIFICANCE: Measuring maternal H2-production could be a potential clinical tool in the management of PTB, and H2 may have positive impact on pregnancy maintenance.

Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132.

T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (Mφs) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3+ decidual Mφs (dMφs) in response to trophoblasts. The reduced abundance of Tim-3 on Mφs was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3+Mφs, but not Tim-3-Mφs, relieved murine embryo absorption induced by Mφ depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3+ and Tim-3-dMφs were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) Mφs. However, with higher CD132 expression, Tim-3+dMφs subset induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dMφ function and maintaining normal pregnancy, and suggested that Tim-3 on Mφs is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3-Mφs could rescue the fetal resorption induced by Mφ depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.

Pregnancy maintenance following sequential induced prostaglandin pulses in beef cows.

The relationship between the maternal endocrine environment and late embryonic mortality (> 28 d of gestation) in cattle is poorly defined. A definitive rise and alterations in secretion patterns of prostaglandin F2α (PGF2α) concentration without luteal regression is a trademark of this period. The objective was to evaluate whether consecutively induced PGF2α pulses would alter steroid hormone production and luteal blood perfusion potentially influencing pregnancy success. Pregnant beef cows (n = 12) were selected to receive either an oxytocin injection (OT, n = 8) or saline injection (CON, n = 4) on d 30 and 31 of gestation to stimulate sequential prostaglandin releases 24 h apart. Blood samples were collected every 30 min for 1 h before and continuing for 4 h post oxytocin administration. Luteal blood perfusion was measured via Doppler ultrasound at the beginning and end of the OT challenge. Concentrations of prostaglandin F2α metabolite (PGFM) were quantified to show effectiveness of the treatment while concentrations of progesterone, estradiol and pregnancy-associated glycoproteins (PAG) were measured to examine the effect of PGF2α release. Control animals exhibited no changes in any quantified hormone and an expected numerical increase in circulating PAG concentrations. Peak concentrations of PGFM in OT cows were observed 2 h post OT administration and concentrations returned to basal levels by the end of the sampling period. Peak concentrations of PGFM were decreased on d 31 compared to d 30. Following OT administration, progesterone and estradiol concentrations did not change in response to PGF2α release but were decreased on d 31 compared to d 30. There were no changes in luteal blood perfusion in response to PGF release on d 30 or d 31. Repeated PGF2α release may alter steroid hormone production; however, it does not negatively affect pregnancy status during the transition between early and late embryonic development.

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

Antibody microarray analysis of amniotic fluid proteomes in women with cervical insufficiency and short cervix, and their association with pregnancy latency length.

INTRODUCTION: This study aimed to investigate amniotic fluid (AF) proteins that were differentially expressed between patients with cervical insufficiency (CI) and asymptomatic short cervix (SCX, ≤ 25 mm), and whether these proteins could be predictive of spontaneous preterm birth (SPTB) in these patients. METHOD: This was a retrospective cohort study of 129 singleton pregnant women with CI (n = 80) or SCX (n = 49) at 17 to 26 weeks who underwent amniocentesis. An antibody microarray was used to perform comparative proteomic profiling of AF from matched CI (n = 20) and SCX (n = 20) pregnancies. In the total cohort, an ELISA validation study was performed for 15 candidate proteins of interest. Subgroup analyses of patients with CI and SCX were conducted to evaluate the association between the 15 proteins and SPTB at < 32 weeks of gestation. RESULTS: Eighty-six proteins showed intergroup differences. ELISA validation confirmed significantly higher levels of AF EN-RAGE, IL-8, lipocalin-2, MMP-9, S100A8/A9, thrombospondin-2, and TNFR2 in patients with CI than in those with SCX. Multivariable analysis showed that increased AF levels of EN-RAGE, S100A8/A9, and uPA were independently associated with SPTB at < 32 weeks in patients with CI; whereas in patients with SCX, high AF levels of APRIL, EN-RAGE, LBP, and TNFR2 were independently associated with SPTB at < 32 weeks. CONCLUSIONS: Multiple AF proteins show altered expression in patients with CI compared with SCX controls. Moreover, several novel mediators involved in inflammation were identified as potential biomarkers for predicting SPTB after the diagnosis of CI and SCX. These results provide new insights into target-specific molecules for targeted therapies to prevent SPTB in patients with CI/SCX.

Gravidez heterotópica espontânea: implicações de um diagnóstico tardio / Spontaneous heterotopic pregnancy: implications of a late diagnosis

A gestação heterotópica é uma entidade rara, principalmente se resultante de concepção natural. O diagnóstico é ultrassonográfico, porém a gestação intrauterina concomitante contribui para a dificuldade propedêutica. Neste relato de caso, a detecção foi tardia, a ultrassonografia não identificou a gestação heterotópica e apenas durante a avaliação intraoperatória, por meio de uma cirurgia de emergência devido a choque hemorrágico, houve o reconhecimento. A suspeita de uma gestação heterotópica deve ser sempre aventada quando sinais clínicos típicos (sangramento, dor abdominal) estão presentes, mesmo na ausência de fatores de risco ou imagens anômalas na ecografia. Assim, uma intervenção precoce menos invasiva pode ser realizada, reduzindo a morbimortalidade materna e do feto intrauterino. Este relato de caso destaca uma situação incomum dentro dessa patologia rara: diagnóstico tardio, apenas no segundo trimestre de gestação, sem evidência prévia ultrassonográfica, certificada apenas durante o intraoperatório. O manejo cirúrgico preciso permitiu a manutenção da gravidez intrauterina.(AU)

Heterotopic pregnancy is a rare entity, especially if it is resulted from natural conception. The diagnosis is ultrasonographic, but the concomitant intrauterine pregnancy contributes to the propaedeutic difficulty. In this case report, the detection was late, the ultrasonography did not identify heterotopic pregnancy and, only during intraoperative evaluation through emergency surgery, exploratory laparotomy, there was recognition. The suspicion of a heterotopic pregnancy should always be raised when typical clinical signs (bleeding, abdominal pain) are present, even in absentia of risk factors or anomalous images on ultrasound. Thus, a less invasive early intervention can be performed, reducing maternal and intrauterine fetus morbimortality. This case report highlights an unusual situation within this rare pathology: late diagnosis, only in the second trimester of pregnancy, without previous ultrasound evidence, certified only during the intraoperative period. Precise surgical management allowed the maintenance of intrauterine pregnancy.(AU)

Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes.

PURPOSE: Single-nucleotide polymorphisms (SNPs) in the p53 pathways have shown to play a role in endometrial receptivity and implantation in infertile women undergoing in vitro fertilization (IVF). The present study aimed to assess the influence of these gene variants over pregnancy success through a receptivity model in recipients of egg donation treatments, when factors such as age and quality of the oocytes are standardized. METHODS: A nested case-control study was performed on 234 female patients undergoing their first fresh IVF treatment as recipients of donor oocytes. Genotyping of TP53 Arg72Pro (rs1042522), LIF (rs929271), MDM4 (rs1563828), and USP7 (rs1529916) SNPs in the recipients allowed comparison of allele and genotype frequencies and their association with the IVF treatment outcome. RESULTS: Grouped by genotypes, patients showed differences in IVF outcomes after the embryo transfer. Arg72Pro (rs1042522) gene variant was associated to changes in implantation and clinical pregnancy rates. The polymorphisms USP7 (rs1529916) and MDM4 (rs1563828) were associated to differential ongoing pregnancy rates and variable miscarriage events, respectively. CONCLUSIONS: This study highlights the association between gene polymorphisms related to P53 function and their influence over IVF reproductive outcomes. Arg72Pro variant may influence early events, as lower implantation rates were found in homozygous for Pro72 allele. By contrast, MDM4 (rs1563828) and USP7 (rs1529916) gene variants were associated with the later maintenance of pregnancy.

Endocannabinoid System in Pregnancy Maintenance and Labor: A Mini-Review.

The endocannabinoid system (ECS) is a cell-signaling system present in multiple organ systems and is an integral part of sustaining the microenvironment necessary for early pregnancy success and maintenance. It plays a significant role in embryo development, transport and implantation as well as placentation. The current theory behind the initiation of term labor is that it is a complex, multifactorial process involving sex steroid hormones, prostaglandin production and interplay at the maternal-fetal interface resulting in increased expression of receptors and gap junctions that promote uterine activation. There is increasing evidence that, in addition to early pregnancy events, the ECS plays a regulatory role in pregnancy maintenance and the timing of labor. This review presents an overview of the ECS in pregnancy that focuses on late gestation and parturition.

Identification of Intercellular Crosstalk between Decidual Cells and Niche Cells in Mice.

Decidualization is a crucial step for human reproduction, which is a prerequisite for embryo implantation, placentation and pregnancy maintenance. Despite rapid advances over recent years, the molecular mechanism underlying decidualization remains poorly understood. Here, we used the mouse as an animal model and generated a single-cell transcriptomic atlas of a mouse uterus during decidualization. By analyzing the undecidualized inter-implantation site of the uterus as a control, we were able to identify global gene expression changes associated with decidualization in each cell type. Additionally, we identified intercellular crosstalk between decidual cells and niche cells, including immune cells, endothelial cells and trophoblast cells. Our data provide a valuable resource for deciphering the molecular mechanism underlying decidualization.

Saúde da mulher: manutenção da gravidez em gestantes / Women's health: maintenance of pregnancy in pregnant women / Salud de la mujer: mantenimiento del embarazo em mujeres embarazadas

Objetivo: revisar e analisar, através da literatura, as principais alterações fisiológicas e patológicas da gestação, bem como as recomendações para preveni-las. Método: trata-se de um estudo de análise bibliográfica, descritivo, tipo revisão de literatura, com buscas realizadas durante o período de 01 a 17 de abril de 2020 nas bibliotecas virtuais Scientific Electronic Library Online (SciELO) e Biblioteca Virtual em Saúde (BVS). Selecionaram-se 19 artigos, os dados foram processados no software IRAMUTEQ® e analisados descritivamente pelo método de Reinert. Resultados: organizaram-se sete classes, destas emergiram quatro categorias: Classe 1, 4 e 7 - Alterações fisiológicas no peso e a avaliação nutricional na gestação; Classes 2 e 3 ­ Processo Educativo sobre a pirâmide nutricional para um desfecho saudável da gestação; Classe 6 ­ A importância das alterações hematológicas durante a gestação; Classe 5 ­ Benefícios da vitamina D na saúde da gestante ao longo do ciclo gravídico e puerperal. Conclusão: Identificou-se, que é fundamental o conhecimento das mudanças fisiológicas e patológicas para que seja ofertado as condições assistenciais necessárias, com intuito de prevenir complicações.(AU)

Objective: to review and analyze, through the literature, the main physiological and pathological changes in pregnancy, as well as the recommendations to prevent them. Method: this is a descriptive, literature review-type study of bibliographic analysis, with searches carried out during the period from April 1st to 17th, 2020 in the Scientific Electronic Library Online (SciELO) and Virtual Health Library (VHL) virtual libraries. Nineteen articles were selected, the data were processed in the IRAMUTEQ® software and descriptively analyzed using the Reinert method. Results: seven classes were organized, from which four categories emerged: Class 1, 4 and 7 - Physiological changes in weight and nutritional assessment during pregnancy; Classes 2 and 3 ­ Educational Process on the nutritional pyramid for a healthy pregnancy outcome; Class 6 ­ The importance of hematological changes during pregnancy; Class 5 ­ Benefits of vitamin D on the health of pregnant women throughout the pregnancy and puerperal cycle. Conclusion: It was identified that it is essential to know the physiological and pathological changes so that the necessary care conditions can be offered, in order to prevent complications.(AU)

Objetivo: revisar y analizar, a través de la literatura, los principales cambios fisiológicos y patológicos del embarazo, así como las recomendaciones para prevenirlos. Método: se trata de un análisis bibliográfico, estudio descriptivo, tipo revisión de la literatura, con búsquedas realizadas durante el período del 1 al 17 de abril de 2020 en las bibliotecas virtuales de la Biblioteca Científica Electrónica en Línea (SciELO) y la Biblioteca Virtual en Salud (BVS). Se seleccionaron 19 artículos, los datos se procesaron en el software IRAMUTEQ® y se analizaron descriptivamente mediante el método Reinert. Resultados: se organizaron siete clases, de las cuales surgieron cuatro categorías: Clase 1, 4 y 7 - Cambios fisiológicos en el peso y valoración nutricional durante el embarazo; Clases 2 y 3 - Proceso educativo sobre la pirámide nutricional para un resultado de embarazo saludable; Clase 6: la importancia de los cambios hematológicos durante el embarazo; Clase 5 - Beneficios de la vitamina D sobre la salud de la gestante durante todo el embarazo y ciclo puerperal. Conclusión: Se identificó que es fundamental conocer los cambios fisiológicos y patológicos para que se puedan brindar las condiciones de atención necesarias, a fin de prevenir complicaciones.(AU)