Wolfgang Würfel

Recurrent miscarriage: current concepts in diagnosis and treatment

Although recurrent miscarriage (RM) affects only 1-3% of couples, it has a major influence on the wellbeing and psychosocial status of patients. Therefore, research into improved diagnosis and development of new treatment strategies is essential. In this review, we summarize current concepts on diagnosis and treatment in RM, drawing upon research reports and international guidelines to provide insights into the pathophysiology of pregnancy disrupted by repeated miscarriage. Anatomical malformations, infectious diseases, endocrine disorders, autoimmune defects as well as acquired and inherited thrombophilia are established risk factors in RM. In addition, our recent findings indicate an impact on miscarriage incidence of glycoproteins such as glycodelin, and nuclear hormone receptors such as the peroxisome proliferator-activated receptors (PPARs). Significantly reduced glycodelin expression is associated with miscarriage, whereas up-regulation of PPARs appears to compensate for either the activated immune response or the disturbed cytotrophoblast differentiation in RM patients. There is also evidence that circulating placental microparticles are increased in a subgroup of RM patients, indicating an acquired procoagulant state even outside pregnancy. Treatment strategies like aspirin and low molecular weight heparin (LMWH) are standard medications in RM, although only a few placebo-controlled trials have proven their benefit in respect to live birth rate. There is emerging evidence that new treatment options, including drugs like TNFalpha inhibitors and granulocyte colony-stimulating factor (G-CSF) might be beneficial in some cases of RM. However, larger clinical trials must be completed to further prove or disprove benefits of these drugs in the treatment of RM patients.

DISORDERS OF IMPLANTATION-ARE THERE DIAGNOSTIC AND THERAPEUTIC OPTIONS?

Recent developments in reproductive medicine address oocyte morphology, sperm analysis and embryo selection. However, in a subgroup of infertile couples, it is the embryo implantation process that is disrupted. Diagnostic tools to identify patients at risk of implantation failure are limited and therapeutic options are far away from being established. In this review we focus on selected possible causes and treatments of failed implantation. Reproductive surgery allows a proper first step diagnosis and therapy of recurrent implantation failure (RIF). Possible anatomical malformations and associated diseases with treatment options are mentioned. Diagnostic procedures in patients often focus on defining gene polymorphisms (like hereditary thrombophilia and p53) and determinants of endometrial receptivity including endometrial gene expression profiles. Although significant differences in gene expression have been identified, the study populations are quite small, some of the data conflicting and clinical significance has yet to be proven. Implantation requires a close interaction between the fetal trophoblast and the maternal endometrium with natural killer cells (NK cells) playing a main part at the feto-maternal interface during early pregnancy. Therefore this review also focuses on NK cell receptor expression and new immunomodulatory treatment options like G-CSF in RIF patients.

Treatment with granulocyte colony-stimulating factor in patients with repetitive implantation failures and/or recurrent spontaneous abortions

Granulocyte colony-stimulating factor (G-CSF) belongs to the family of colony-stimulating factors (CSF). As the name suggests, it was initially identified as being able to target and influence granulopoiesis, but was soon shown to be a ubiquitous growth factor, with synthesis and receptors, such as the related granulocyte macrophage colony-stimulating factor (GM-CSF), which is found in a wide variety of tissue types, including the organs and cell populations involved in reproduction. It must now be assumed that both G-CSF and GM-CSF control, or play a role in controlling, key processes in oocyte and sperm maturation, endometrial receptivity, implantation, and embryo and fetal development, possibly extending to birth. The following article offers an overview of the current findings with regard to animal experimental studies, initial clinical applications in reproductive medicine, and potential risks.

No relationship between biopsy sites near the main testicular vessels or rete testis and successful sperm retrieval using conventional or microdissection biopsies in 220 non-obstructive azoospermic men

In 220 consecutive patients with non-obstructive azoospermia, sperm retrieval was attempted by a combination of conventional and microdissection testicular sperm extraction (TESE). For sperm retrieval, 2-3 conventional biopsies were performed followed by a microdissection TESE in cases of negative conventional biopsies. During the surgery, the vasculature of the testis was assessed using the operative microscope, and the location of positive biopsies was registered in relation to the blood supply. The overall sperm retrieval rate was 58.2%. From the initial conventional biopsies, sperm could be retrieved in 46.8% of the patients. With microdissection TESE, sperm could be retrieved from an additional 11.4% of the patients. The further use of microdissection TESE improved the sperm retrieval rate significantly (P=0.017). No significant accumulation of positive biopsies was found towards the rete testis or the main testicular vessels.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050)

Purpose Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (ÖGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members. Methods Based on the current literature, the committee members developed the statements and recommendations of this guideline in a formalized process which included DELPHI rounds and a formal consensus meeting. Recommendations Recommendations for the diagnosis and treatment of patients with RM were compiled based on the international literature. Specific established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders were taken into consideration.