Bushen Huoxue Fang improves recurrent miscarriage in mice by down-regulating the JAK2/STAT3 pathway / 南方医科大学学报

OBJECTIVE@#To investigate the efficacy of Bushen Huoxue Fang (BSHXF, a traditional Chinese medicine formula) for improving recurrent spontaneous abortion (RSA) in mice and the role of tyrosine kinase (JAK2) and transcriptional activator (STAT3) signaling pathway in its therapeutic mechanism.@*METHODS@#Female CBA/J mice were caged with male DBA/2 mice to establish RSA mouse models, which were randomly divided into model group, dydrogesterone group and BSHXF group, with the female mice caged with male BALB/c mice as the control group (n=6). From the first day of pregnancy, the mice were subjected to daily intragastric administration of BSHXF, dydrogesterone, or distilled water (in control and model groups) for 12 days. After the treatments, serum levels of antithrombin III (AT-III), activated protein C (APC), tissue plasminogen activator (t-PA), progesterone, human chorionic gonadotropin (HCG), and estradiol (E2) were detected in each group using ELISA. HE staining was used to observe the morphological changes of the endometrium of the mice. Western blotting was performed to determine the expressions of p-JAK2, p-Stat3 and Bcl-2 in the placenta of the mice.@*RESULTS@#Compared with the control mice, the mouse models of RSA showed a significantly increased embryo loss rate with decreased serum levels of AT-III, T-PA, progesterone, APC and HCG, increased placental expressions of p-JAK2, p-STAT3 and Bax, and decreased expression of Bcl-2 (P < 0.05). Treatments with BSHXF and dydrogesterone both increased serum levels of AT-III, t-PA and HCG in the mouse models; Serum APC level was significantly reduced in BSHXF group and serum progesterone level was significantly increased in dydrogesterone group (P < 0.05).@*CONCLUSION@#BSHXF can improve the prethrombotic state and inhibit cell apoptosis by downregulating the JAK2/STAT3 pathway to increase the pregnancy rate in mouse models of RSA.

Effects of aspirin, vitamin D3, and progesterone on pregnancy outcomes in an autoimmune recurrent spontaneous abortion model

High proportions of placental lymphocytes expressing DX5+/CD25+/FOXP3+/CD45+/CD4+ are beneficial to maintain immune tolerance and improve pregnancy outcomes. This study aimed to compare and evaluate the therapeutic effects of aspirin, vitamin D3 (VitD3), and progesterone on the autoimmune recurrent spontaneous abortion (RSA) model. The autoimmune RSA mouse model was constructed, and the embryo loss rate was calculated for each group. Then, primary mouse placental lymphocytes were isolated, and the expression of DX5+/CD25+/FOXP3+/CD45+/CD4+ was detected through flow cytometry. The serum levels of anti-cardiolipin antibody (ACA), β2-GP1, CXCL6, IFN-γ, and IL-6 were measured by ELISA to evaluate the proportion of Th1 and Th2 cells. Autoimmune RSA significantly increased the embryo loss rate, which was improved by aspirin, VitD3, and progesterone treatment, and progesterone treatment had the best effect among the three treatments. The positive expression of DX5+/CD25+/FOXP3+/CD45+/CD4+ in the VitD3 and progesterone groups was significantly higher than that in the autoimmune RSA group, and the expression was highest in the progesterone treatment group. In the plasma of autoimmune RSA mice, the ACA, β2-GP1, CXCL6, and IFN-γ levels were significantly higher and the IL-6 level was lower than the levels in control mice. All these changes could be reversed by aspirin and progesterone treatment. In conclusion, aspirin, VitD3 and progesterone treatment improved pregnancy outcomes in autoimmune RSA mice by regulating the Th1/Th2 balance and cytokines, and progesterone had the best effect of the three treatments.

Anticoagulação e prevenção de morbidade obstétrica em trombofilias hereditárias: mito ou verdade? / Anticoagulation and prevention of obstetric morbidity in hereditary thrombophilia: myth or truth?

Tem sido observado, corriqueiramente, o uso indiscriminado de anticoagulantes durante a gravidez com a finalidade de evitar perdas gestacionais. A eficácia do uso de anticoagulantes na prevenção de perdas, precoces e tardias, tem sido questionada, levando-se em consideração os impactos econômicos, sociais e psicológicos gerados nas famílias a partir da indicação da utilização dessa terapia. Dada a relevância do tema, realizou-se uma revisão da literatura nos bancos de dados PubMed, Cochrane Library e Medline com a finalidade de avaliar evidências científicas do uso e da eficácia de anticoagulação na gravidez. Na literatura revisada, não foi possível sustentar a hipótese de que a anticoagulação é capaz de intervir ativamente no sucesso do curso da gravidez. Conclui-se, portanto, que mais estudos devem ser realizados a fim de determinar intervenções eficazes ao casal, preservar a saúde do concepto e minimizar o impacto econômico, social e psicológico da utilização de anticoagulantes durante a gravidez.(AU)

In medical practice, the anticoagulants indiscriminate use during pregnancy has been commonly observed to prevent future pregnancy losses. The effectiveness of using anticoagulants in preventing losses, early and late, has been questioned taking into account the economic, social and psychological impacts generated on families from the indication of the use of such drugs. Given the relevance of the topic, a literature review was carried out in the PubMed, Cochrane Library and Medline databases in order to assess scientific evidence on the anticoagulation efficacy use in pregnancy. It was not possible to support the hypothesis that anticoagulation is able to actively intervene in the success of the course of pregnancy. It is concluded, therefore, that more studies should be carried out in order to determine effective interventions for the couple, preserve the health of the fetus and minimize the economic, social and psychological impact of the anticoagulants use during pregnancy.(AU)

Trombofilias: a prevenção direcionada a uma gravidez bem-sucedida / Thrombophilia: prevention targeted to a successful pregnancy

Vários efeitos adversos na gravidez, como pré-eclampsia, deslocamento de placenta, prematuridade e até mesmo perdas fetais recorrentes vêm sendo amplamente associados a estados trombofílicos. Uma vez que o número de trombofilias herdadas tem crescido rapidamente nos últimos anos com a identificação de vários fatores genéticos predispondo ao desenvolvimento de trombose venosa ou arterial, cada vez mais se torna de grande interesse a identificação de mulheres de risco, na tentativa de minimizar os problemas na gravidez e, principalmente, instituir regimes terapêuticos para a prevenção de perdas fetais. Esta revisão aborda os riscos associados à presença de alterações genéticas predispondo à trombose e a importância de um monitoramento adequado.

Many adverse effects during pregnancy, like preeclampsia, placental abruptions, prematurity and recurrent fetal loss have been widely associated with thrombophilic states. The number of inherited thrombophilias has grown rapidly in recent years with the identification of many predisponent genetic factors to the development of venous and/or arterial thrombosis. Therefore, the identification of women of risk becomes of great interest in the attempt to minimize the problems during pregnancy and mainly to institute therapeutical regimens for fetal loss prevention. This review approaches the risk associated to the presence of genetic alterations predisposing to thrombosis, and the importance of an adequate follow up.

Técnicas emergentes en medicina reproductiva: diagnóstico cromosómico del primer corpúsculo polar del ovocito / Emerging techniques in reproductive medicine: chromosomal diagnosis of the oocyte first polar body

El Diagnóstico Genético Preimplantacional (PGD) se ha convertido en una herramienta de rutina para la detección de anormalidades cromosómicas o genéticas, en muchos países del mundo. Se han reportado más de 20.000 ciclosde PGD, desde su desarrollo hace más de 20 años, habiendo nacido más de 4.000 niños hasta el año 2007. En Chile, esta técnica es realizada por la Unidad de Medicina Reproductiva de Clínica Las Condes, y se realiza sólo en la variante previa a la fecundación, en donde se biopsia el primer corpúsculo polar y sólo se insemina a los ovocitos encontrados cromosómicamente sanos. Las indicaciones más comunes para este tratamiento son: 1) evitar el aborto en pacientes con aborto recurrente sin explicación anatómica ni clínica; 2) mejorar las tasas de implantación en mujeres mayores de 37 años con antecedentesde procedimientos anteriores en los que se transfirieron embriones de buena calidad; 3) evitar el nacimiento deniños con enfermedades de origen cromosómico en mujeres mayores de 39 años.

Pre-implantational Genetic Diagnosis has become a common tool in most countries of the world. In almost 20 years since its development, it has been reported more than 20,000 cycles of PGD and till 2007, more than 4,000 children have been born. In Chile, this technique is done by the Unit of Reproductive Medicine of Clínica Las Condes. It is done only in the mode previous to fertilization. In where we study polar bodies and only chromosomically healthy oocytes are inseminated. The most common indications for this treatment are: 1) to avoid abortions in patients with recurrent abortion without anatomical nor clinical explanation; 2) to improve implantation rates in women older than 37 years of age, with previous procedures in which good quality embryos were transferred; 3) to avoid birth of children with diseases of chromosomal origin in women over 39 year of age.

Abortamento habitual I: Fatores endócrinos / Habitual abortion I: Endocrine factors

Distúrbios hormonais que podem levar a perdas fetais recorrentes. Vários estudos têm mostrado aumento na incidência de auto-anticorpos e doenças auto-imunes tireoidianas entre as mulheres com perdas fetais de repetição. A perda fetal de repetição associada à SOP parece estar relacionada aos efeitos endometriais da hiperinsulinemia. Entretanto, a eficácia do uso da metformina para prevenção de perdas fetais em mulheres com SOP ainda carece de comprovação. A progesterona é um hormônio chave durante a gravidez e parece ter inúmeras funções, tais como a indução de alterações secretórias no endométrio e imunotolerância seletiva, embrião-específica, absolutamente essenciais para o desenvolvimento embrionário adequado. Avaliações clínicas têm mostrado que os critérios diagnósticos dos defeitos de fase lútea, como a avaliação histológica endometrial, dosagem de progesterona sérica, ultra-sonografia pélvica com doppler das artérias uterinas e ovarianas têm limitada acurácia, com significativa variabilidade inter e intra-observador. Embora dados preliminares sejam promissores em relação ao uso da progesterona na prevenção da perda fetal recorrente, as evidências ainda são insuficientes para o uso rotineiro.

Endocrine dysfunction might contribute to recurrent pregnancy loss (RPL) in some women. Many studies have correlated thyroid auto-antibodies and auto-immune diseases to recurrent abortion. Pregnancy loss in women with polycystic ovarian syndrome seems to be related to endometrial effects of hyperinsulinemia. Nevertheless, routine use of metformin to prevent miscarriage is not warranted. Progesterone is a key hormone in pregnancy maintenance and appears to have many functions such as inducing secretory changes in the endometrium and embryo-specific immunotolerance, which are absolutely essential to adequate early embryonic development. Clinical studies have shown that the diagnostic criteria for luteal comprising endometrial hystological evaluation, plasmatic progesterone measurement or uterine and ovary arteries Doppler velocimetry have limited accuracy and significant inter and intra observer variability. Althoug some studies have revealed a remarkable improvement in pregnancy outcome after progesterone supplementation in women suffering from recurrent miscariage, further research is required for routine use.

Outcomes of cervical cerclage in preventing pregnancy loss

This study was designed to know the outcome of cervical cerclage in preventing pregnancy loss in patients with cervical insufficiency. This is a prospective study. Patients with previous early pregnancy losses were included. Cervical length less than 2.5cm at 12-16 weeks was taken as an indicator of insufficiency. Cerclage was removed at 37 week and patient and neonate were followed till one week postnatal. A total of 32 patients were included in this study. Fifteen patients had emergency cerclage and 85% had elective cerclage. A total of 79% patient delivered at term and 9% had abortion. Among them 72% patients had normal vaginal delivery and others underwent ceasarean section. Maternal pyrexia was more in emergency group. Jaundice was seen in 62% of the neonates and 17% neonates had respiretory problems. Cervical cerclage has a preventive role in singleton pregnancies with short and insufficient cervix

Estudo das alterações placentárias de gestantes com síndrome antifosfolípide: correlações anátomo-clínicas / Placental changes study in pregnant women with antiphospholipid syndrome: anatomic clinic correlation

A sindrome antifosfolípide é caracterizada pela ocorrência de eventos clínicos tromboembólicos associados a persistência laboratorial de anticorpos antifosfolípides. Na gravidez, está associada à perda fetal de repetição atribuída às tromboses placentárias e aumento de morbidades materno-fetais. Este estudo centrado numa amostra de gestantes com síndrome antifosfolípide, submetidas a protocolo terapêutico de anticoagulação, teve como objetivo avaliar as lesões placentárias encontradas nas placentas resultantes dessas gestações e correlacionar com as intercorrências maternas e repercussões perinatais./The antiphospholipid syndrome is characterized by the occurrence of clinical events thromboembolic associated with the persistence laboratorial of antiphospholipid antibodies. In the pregnancy it is associated with the fetal loss attribuited by the placental thromboses and increase of fetal-maternal complications. This study centered in a sample of pregnant women with the antiphospholipid syndrome, submitted to a therapeutic protocol of anticoagulation, it has as an objective to evaluate the in these pregnant women and correlate with the maternal morbidity and pre-birth repercutions...

Tratamiento con enoxaparina adaptado a los programs de fertilidad em mujeres con aborto recurrente y trombofilia / Treatment with enoxaparin adapted to the fertility programs in women with recurrent abortion and thrombophilia

Las trombofilias adquiridas y hereditarias se asocian con pérdidas embrio-fetales recurrentes. La terapéutica antitrombótica puede reestablecer el balance hemostático y mejorar la fase temprana de la placentación y el pronóstico gestacional. Nosotros evaluamos la eficacia del tratamiento con enoxaparina adaptado a los programas de fertilidad, para prevenir las pérdidas embrio-fetales en 35 mujeres con antecedente de aborto recurrente temprano y trombofilia. Previo al diagnóstico de trombofilia ellas tuvieron un total de 105 embarazos, de los cuales 89 (85%) terminaron en aborto temprano. Luego del diagnóstico de trombofilia, los 35 embarazos subsiguientes fueron tratados con enoxaparina. En 5 casos fue necesario emplear técnicas de reproducción asistida para lograr el embarazo debido a infertilidad de pareja. Diecisiete mujeres con antecedente de al menos un aborto preclínico recibieron enoxaparina (20 mg./día/sc.) previo a la concepción, adaptado al programa de fertilidad. Al lograr el embarazo continuaron con esquema gestacional. Dieciocho mujeres con antecedente únicamente de abortos clínicos ingresaron de novo al esquema gestacional (enoxaparina 20 mg. cada 12 hs/sc) al obtener un test de embarazo positivo Durante la gestación la dosis de heparina se ajustó mediante estudio de Anti Xa, manteniendo un rango entre 0.3 a 0.6 u/ml. Con tratamiento antitrombótico 30/35 (85%) de los embarazos terminaron con nacido vivo, comparado con 16/105 (15%) de los embarazos previos no tratados (p<0.001). Estos resultados sugieren que el tratamiento con enoxaparina adaptado a los programas de fertilidad podría ser efectivo en prevenir los abortos tempranos en mujeres con trombofilia

Cerclaje electivo y resultado perinatal / Elective cerclage and perinatal results

La incompetencia cervical es la causa estructural más frecuente de aborto de II trimestre y parto inmaduro. Su diagnóstico y tratamiento es controvertido. Presentamos nuestra experiencia reciente, indicaciones y manejo de esta patología. Entre 1993 y 1998, se realizaron 31 cerclajes electivos de tipo McDonald en 29 pacientes que tuvieron su parto en el Hospital Clínico de la Universidad Católica, 52 por ciento de las pacientes tenía antecedentes de abortos y 31 por ciento de partos prematuros. Se hizo diagnóstico de incompetencia cervical por historia de abortos de II trimestre en 13 pacientes y por test de dilatadores Hegar en 6. La edad promedio de cerclaje fue 13 semanas y de retiro 36 semanas. El cerclaje se retiró antes de las 24 semanas en 3 pacientes por: feto anencéfalo, trabajo de aborto y RPM. Un 48 por ciento tuvo al menos un cultivo durante su embarazo, el 60 por ciento resultó positivo. Hubo 73 por ciento de parto vaginal y el peso promedio de los RN fue de 2860 g. No hubo apgares bajos. El cerclaje es una alternativa efectiva y segura de tratamiento para la incompetencia cervical, se hace énfasis en el examen ultrasonográfico y en los cultivos seriados cervicovaginales

La aloinmunoterapia en aborto habitual. una controversia abierta

Se presenta una revisión crítica de los resultados del Meta-análisis del Estudio Colaborativo Internacional sobre Inmunoterapia en Aborto habitual y se discuten los principales puntos de controversia, a la luz del VI Congreso Internacional de Inmunología de laReproducción, en Washington, julio de 1995

Paternal leucocyte immunotherapy for recurrent pregnancy loss.

The defective recognition of foetal alloantigens by the maternal immune system is associated with recurrent pregnancy failure and may be prevented by boosting the maternal immune response with paternal or third party leucocyte immunization. The mechanism by which this process achieves success is not known. Clinical trials on recurrent spontaneous abortion have shown an up to 70% successful pregnancy rate after immunotherapy but the importance of this is unclear because there have been success rates of between 29% and 76% even in the control population. These variations could be due to small sample sizes and heterogeneity in the populations studied as well as co-intervention by the placebo. This article reviews the state-of-the-art for immunotherapy and discusses its mechanism of action in the prevention of recurrent foetal loss.

Circlagem do colo uterino por via transabdominal: relato de dois casos / Transabdominal cervicouterine circlage: report of 2 cases

Os autores relatam dois casos de circlagem do colo uterino por via transabdominal, pela técnica de Benson e Durfee. Em ambos a cirurgia teve êxito e as pacientes deram a luz, com 37 e 40 semanas de gestaçäo, respectivamente, e a recém-nascidos saudáveis. A técnica é recomendada, atendidos determinados pré-requisitos técnicos

Cerclaje en pacientes con aborto habitual / Cerclaje in patients with habitual abortion

Se exponen los resultados en 65 pacientes con aborto habitual, sometidas a cerclaje, comparando una serie del período 1982-83 con otra del 1984-85. Los embarazos con niño vivo suben de 16% a casi 94%. Los buenos resultados, serían la consecuencia de la indicación oportuna del cerclaje. De los pocos abortos que ocurrieron, cuatro en total, tres fueron producto de cerclajes en cuello dilatado y membranas prominentes, lo que nos induce a revisar esta indicación y a intentar, en estos casos, tratamiento médico, con reposo, tocólisis y antibióticos