Perda gestacional de repetição e o papel dos progestagênios: evidências atuais / Recurrent pregnancy loss and the role of progestagens: current evidence

Objetivo: Discutir o uso dos progestagênios em mulheres com perda gestacional de repetição (PGR) sem causa aparente, abordando tipos de progestagênios e resultados de ensaios clínicos, revisões sistemáticas e metanálises. Métodos: Trata-se de uma revisão não sistemática de artigos publicados nas bases eletrônicas PubMed, Cochrane e SciELO nos últimos cinco anos, utilizando-se os seguintes descritores: "progesterone", "dydrogesterone", "recurrent pregnancy loss" e "recurrent abortion". Resultados: Duas grandes metanálises encontraram uma redução da taxa de abortamento e aumento da taxa de nascidos vivos com o uso do progestágeno sintético em pacientes com PGR inexplicada, porém essa conclusão foi contestada em uma metanálise mais recente. Entretanto, a progesterona vaginal micronizada poderia aumentar a taxa de nascidos vivos em mulheres com ameaça de aborto e com história de um ou mais abortos anteriores (risco relativo [RR]: 1,08, intervalo de confiança [IC] de 95%: 1,02-1,15). O benefício foi maior no subgrupo de mulheres com três ou mais perdas anteriores. Conclusão: Ainda restam dúvidas sobre o uso de "progesterona" nas pacientes com PGR inexplicada. Sua administração deve ser discutida individualmente com cada mulher, levando-se em conta especialmente a idade materna, o número de abortos prévios e a história de sangramento na gestação em curso, evitando-se tratamentos que trazem custos e não são isentos de efeitos colaterais.(AU)

Objective: To discuss the use of progestins in women with recurrent pregnancy loss (RPL) with no apparent cause, addressing types of progestins, and results of clinical trials, systematic reviews, and meta-analyses. Methods: This is a non-systematic review of articles published in the PubMed, Cochrane, SciELO electronic databases in the last five years, using the following descriptors: "progesterone", "dydrogesterone", "recurrent pregnancy loss", and "recurrent abortion". Results: Two large meta-analyses found a reduction in the rate of miscarriage, and an increase in the rate of live births with the use of synthetic progestin in patients with unexplained RPL, but this conclusion was challenged in a more recent meta-analysis. However, micronized vaginal progesterone could increase the rate of live births in women with a threatened miscarriage and a history of one or more previous miscarriages (RR: 1.08, 95% CI: 1.02-1.15). The benefit was greatest in the subgroup of women with three or more previous losses. Conclusion: There are still doubts about the use of "progesterone" in patients with unexplained RPL. Its administration should be discussed individually with each woman, taking into account especially the maternal age, number of previous abor tions, and history of bleeding during pregnancy, avoiding treatments that bring costs and are not free from side effects.(AU)

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.

Low molecular weight heparin in unexplained recurrent miscarriage

The aim of the study was to investigate whether the use of low molecular weight heparin [LMWH] improve live birth rates when compared with control group in patients with unexplained recurrent miscarriages [URM]. In this prospective observational study 150 women with a history of two or more previous unexplained first trimester pregnancy loss who received LMWH; either enoxaparin [n=50], tinzaparin [n=50] or nothing [n=50] were followed for the pregnancy outcome measures. Only the patients who have used standardized dosage of LMWH [4000 IU/day enoxaparin or 3500 IU/day tinzaparin] were included to the study. The primary end point was the live birth rate and secondary end points were the side effects, late pregnancy complications and neonatal outcome in the study cohorts. Live birth was achieved 85% of the LMWH group and 66% of the control group [p=0.007]. According to the subgroup analysis; live birth rates did not differ significantly between the enoxaparin and tinzaparin group [84% and 86%, respectively]. Maternal and neonatal side effects were not statistically significant among the study participants. Thromboprophylaxis with LMWH resulted in a improved live-birth rate in patient with 2 or more consecutive unexplained recurrent pregnancy loss. Nevertheless these findings need to be confirmed in larger randomized trials

Abortamento de causa aloimune: diagnóstico e tratamento / Alloimmune abortion: diagnosis and treatment

Abortamento espontâneo recorrente (AER) é definido, usualmente, como a perda de três ou mais gestações, até a 20ª semana de gravidez, e afeta aproximadamente 5 % dos casais. Em boa parte dos casos, a causa é desconhecida e muitas hipóteses foram levantadas, dentre elas, a imunológica. Diversos trabalhos vêm tentando mostrar a fisiopatologia da causa aloimune e seu possível diagnóstico e tratamento. Apesar de não haver, até hoje, a liberação por parte de instituições de saúde, como a Food and Drug Administration (FDA) e a Agência Nacional de Vigilância Sanitária (Anvisa), os tratamentos são oferecidos em diversas clínicas ao redor do mundo. Por meio do levantamento dos últimos artigos acerca do assunto, foi possível observar que um método diagnóstico específico que detecte a perda gestacional precoce imune mediada e um método confiável que determine quais mulheres se beneficiariam da manipulação do sistema imune materno são urgentes. Para estabelecer definitivamente ou avaliar a eficácia de qualquer suposto tratamento para o AER, são necessários novos estudos randomizados, com adequado número de amostra.

Recurrent spontaneous abortion (RSA) is usually defined as three or more consecutive pregnancy losses prior to the 20th week of gestation, and affects approximately 5 % of the couples. The etiology of recurrent spontaneous abortion is often unclear and may be multifactorial. However, the majority of cases of RSA remain unexplained and some studies have been attempting to associate it with autoimmune and alloimmune antibodies. Although until today there is no release by health institutions such as Food and Drug Administration (FDA) and Agência Nacional de Vigilância Sanitária (Anvisa), these treatments are offered at various clinics around the world. Through the survey of recent articles on this subject, it was possible to see that a specific diagnostic method to detect the early pregnancy loss imune mediated as well as a reliable method to determine which women would benefit from the manipulaton of the maternal immune system are more than necessary. To definitively establish or evaluate the effectiveness of any treatment for RSA, further randomized studies with adequate number of sample are needed.

Abortamento habitual III - Trombofilias e fatores imunológicos / Habitual abortion III - Thrombophilia and imunologic factors

A associação dos anticorpos antifosfolípides, em particular o anticorpo anticardiolipina e o anticoagulante lúpico, com o abortamento habitual, bem como a eficácia do tratamento com a associação de heparina e ácido acetilsalicílico em baixa dose durante a gravidez estão respaldadas em fortes evidências clínicas. A participação e a eficácia do tratamento de outras trombofilias, tais como o fator V de Leiden, resistância à proteína C ativada, mutação do gene da protrombina e deficiência de proteína S, embora sugerida em alguns estudos, ainda não estão claramente estabelecidas. Não existe até o momento indicações de que alterações aloimunes possam ser causa de abortamento habitual. O tratamento empírico dessas alterações com imunoglobulina endovenosa ou transfusão de linfócitos paternos não tem melhorado os resultados obstétricos das mulheres com perdas recorrentes.

The association of antiphopholipid antibodies, specially the anticardiolipin antibody and lupus anticoagulant, with habitual abortion, as well as the efficacy of the treatment with heparin and low-dose aspirin during pregnancy are based in strong clinical evidence. The role and efficacy of the treatment of other thrombophilias, such as factor V Leiden, resistance to activated C protein, mutation of prothrombin gene and deficiency of protein S, althrough suggested in some studies, are not clearly established. There is no evidence, so far, that aloimmune alterations can be cause of habitual abortion. The empirical treatment of these alterations with IV immunoglobulin of paternal leukocyte transfusion have not improved obstetrical results in women with recurrent miscarriage.

Maternal and fetal complications of antiphospholipid syndrome: a case report with long-term follow-up

We report a case of a 26- year old woman having antiphospholipid syndrome in pregnancy with long-term follow up. She presented with recurrent miscarriages, venous thrombosis, avascular necrosis of femoral head, mid-cerebral artery infarction and skin ulcers. Antiphospholipid syndrome is a recognized disorder of pregnancy. Diagnosis requires a high index of suspicion when evaluating women with recurrent pregnancy losses and vascular thrombosis. A low dose aspirin combined with heparin can reduce morbidity and improves the pregnancy outcome

Tratamiento del factor inmunológico en el aborto recurrente y en el retardo de crecimiento intrauterino / Treatment of the immunologic factor in the recurrent abortion and the intrauterine growth retardation

Objetivo: Describir los resultados del tratamiento anti-agregante plaquetario en un grupo de pacientes con auto-anticuerpos y antecedentes de aborto recurrente (AR) y/o retardo de crecimiento intrauterino (RCIU). Material y Método: Catorce pacientes que consultaron por AR y/o RCIU, en cuyo estudio inmunológico se detectaron autoanticuerpos, constituyen el material del presente trabajo. A las pacientes que tenían como antecedentes un RCIU, una vez descartados todos los cuadros clínicos que pudieran ocasionarlo, se les efectuó determinación de autoanticuerpos. Las parejas que consultaban por AR eran sometidas a estudio para descartar un factor uterino, infeccioso, endocrinológico, metabólico, genético, inmunológico y espermático. En algunas pacientes se realizó una laparoscopia para descartar endometriosis. Todas las pacientes fueron tratadas con Acido Acetilsalicílico (AAS) 80 mg. diarios, a partir del momento de la detección de autoanticuerpos. A una sola paciente se le administró además Heparina subcutánea durante dos embarazos. Resultados: De las catorce pacientes en las que se detectaron autoanticuerpos, doce embarazaron, algunas de ellas en más de una oportunidad, sumando un total de 19 embarazos. De ellos, 5 concluyeron en aborto espontáneo y catorce concluyeron en el tercer trimestre con recién nacido vivo. De éstos, cinco presentaron un crecimiento fetal normal, mientras que los nueve restantes desarrollaron RCIU. La vía de terminación fue vaginal en cinco casos y abdominal en los nueve restantes. Conclusiones: El tratamiento del síndrome antifosfolipídico con antiagregantes plaquetarios (AAS o heparina), parecería ofrecer un porvenir reproductivo alentador a las portadoras de dicho síndrome