From numbers to meaning: defining clinical relevance in reproductive medicine research.

Barriers to conducting clinical research in reproductive medicine around the world

Barriers to conducting clinical research in reproductive medicine: Greece

Keeping clinicians in clinical research: the Clinical Research/Reproductive Scientist Training Program

Barriers to conducting clinical research in reproductive medicine: Australia and the United Kingdom

Trends in clinical reproductive medicine research: 10 years of growth

Low participation rates amongst Asian women: implications for research in reproductive medicine

Regulation of assisted reproductive technologies in the United States

How do randomised controlled trials (RCTs) in reproductive medicine report maternal and neonatal outcomes, specifically singleton live birth? Despite the widespread appeal to use singleton live birth as the outcome measure in subfertility trials, 80% of RCTs fail to do so, and fail to report on neonatal and maternal outcomes. The aim of reproductive medicine is to assist subfertile couples in their wish to have children. A decade ago it was proposed to use singleton live birth as the outcome measure. We assessed whether clinical research has followed this recommendation, and how neonatal/maternal outcomes are reported. A review of the published literature from 1 January 1966 to 31 December 2012 was performed using the Cochrane database. We compared the time periods before and after 2004; the year after ESHRE recommended the use of singleton live birth. We searched the Cochrane database for RCTs in reproductive medicine, and recorded the number of studies that used singleton live birth as the outcome measure. We also recorded the reporting neonatal and maternal outcomes. We identified 910 RCTs that reported on fertility treatments, of which 182 RCTs (20%) reported on singleton live birth [before 2004 96/518 (19%); after 2003 86/392 RCTs (22%)]. Singleton live birth was the primary outcome in 68 RCTs (7.4%). Only 44 RCTs (4.8%) reported on neonatal outcome, while 52 RCTs (5.7%) reported on maternal outcome. We only included Cochrane reviews, thus report here only on the higher quality studies. The actual reporting on maternal and neonatal outcome may even be lower when studies of lower quality are included. Although a decade ago singleton live birth was recommended as the outcome measure of reproductive medicine research, this has not been followed; currently most clinical research in reproductive medicine does not report beyond the occurrence of pregnancy. No funding was received for the study. The authors have no conflicts of interest to declare.

The emergence of powerful mass spectrometry-based proteomic techniques has added a new dimension to the field of biomedical research. Application of these high throughput methodologies in pregnancy-related pathology has contributed to the comprehension of the underlying pathophysiologies and the successful identification of relevant protein biomarkers that can potentially change early diagnosis and treatment of several medical conditions related to human pregnancy. Most of the existing research on human reproduction and gestation has focused on follicular fluid, cervical/vaginal fluid, and amniotic fluid. Although proteome technologies in reproductive medicine research are not as yet widely applied, characterization of the proteome of reproductive fluids can be expected to significantly improve maternal healthcare. This article aims to summarize the applications of mass spectrometry based technology on the most important and specific biological fluids related to reproduction and gestation.

Traditionally, embryo transfer has been performed using tactile senses and judgment to determine when the transfer catheter is in the correct position, this being referred to as ‘clinical touch’. Alternatively, ultrasound imaging can be used to guide placement of the catheter during embryo transfer. Visualization of the catheter during insertion can help the operator to align it with the curvature of the uterus, to ensure the embryos are deposited in a favorable position within the endometrial cavity and to check the position of air bubbles after embryo transfer1 (Figure 1). Frequently, transabdominal ultrasound-guided embryo transfer (TA-UGET) is performed, and this requires the patient to have a full bladder. Less commonly, transvaginal ultrasound (TV-UGET) is performed, which requires the use of a special, extra-long, embryo transfer catheter along with either a special speculum that permits the ultrasound probe to be retained in the vagina while performing the transfer2 or removal of the vaginal speculum after insertion of the outer sheath of the catheter into the cervix, followed by insertion of the ultrasound probe into the vagina to adjust the catheter position under ultrasound guidance before performing the transfer3. Another possibility is evaluation of the cervix and uterus for planning catheter placement in advance; this can be accomplished by measuring the length from the external os to the fundus, either using a uterine sound or by ultrasound (Figure 1). This technique is called uterine-length measurement before embryo transfer (ULMbET). Large trials are required for the proper evaluation of patient-based outcomes in reproductive medicine because they can detect small, yet clinically relevant, differences. Revelli et al.4, in the current issue of the Journal, report a study in which they randomized almost 1700 women to compare the effectiveness of ULMbET by transvaginal ultrasound and TA-UGET, resulting in very similar reproductive outcomes (ongoing pregnancy rate = 32% vs 33% for ULMbET vs TA-UGET, intention-to-treat analysis). While this might not seem interesting at first, ULMbET has some advantages that are unrelated to the reproductive outcome. It simplifies fertility treatment, both improving the experience for the patient and reducing the costs involved: there is no need for the woman to have a full bladder, reducing the discomfort related to the embryo transfer procedure (1% vs 20% of the women complained of moderate to severe discomfort)4; and it eliminates the need for a second well-trained sonographer or physician to be present, reducing costs. Efforts towards making fertility treatment simpler and more affordable should be at the forefront in reproductive medicine research, because financial access is, along with safety, one of the most critical issues in this field. Although in-vitro fertilization (IVF) is effective, several cycles are frequently necessary to achieve a live birth5 and the expense makes it inaccessible to most women. This is particularly true in developing countries, in which even a single treatment might mean catastrophic expenditure for the couple6. Additionally, several couples give up before achieving pregnancy because of the physical and psychological burden, which could be reduced by using a friendlier and less uncomfortable approach7, 8. It is interesting to examine the evidence from the study of Revelli et al.4 alongside that from other randomized controlled trials comparing different ultrasound techniques for assisting embryo transfer9. Considering only studies that reported ongoing pregnancy, we identified 13 studies comparing TA-UGET with ‘clinical touch’10-22, three studies comparing TV-UGET with TA-UGET23-25 and only the present study comparing ULMbET with TA-UGET4, and compared them in a forest plot (Figure 2). As a result, we are confident that TA-UGET improves pregnancy rate compared with ‘clinical touch’ and that similar results might be obtained by using either TV-UGET or ULMbET. Additionally, two smaller RCTs, published only as abstracts and not reporting ongoing pregnancy, compared ULMbET by transvaginal ultrasound with TA-UGET26, 27. These studies also had encouraging results, with ULMbET proving to be at least as effective as TA-UGET: reported pregnancy rates were 10/13 (77%) vs 5/13 (38%)26 and 44/100 (44%) vs 25/100 (25%)27. In summary, assessing the ULMbET and performing embryo transfer with the patient's bladder empty has financial advantages, is less uncomfortable for the woman and provides similar results when compared to TA-UGET. It is likely, therefore, that this technique will be employed by several centers around the world in the near future.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.

Study question Does Homeostasis Model Assessment for insulin resistance (HOMA-IR) have an influence in reproductive medicine outcomes? Summary answer HOMA-IR is associated with fertility treatment parameters and has a significant influence on reproductive medicine outcomes. What is known already The HOMA model is used to yield an estimate of insulin sensitivity from basal (fasting) plasma insulin and glucose concentrations. Currently, the model has become a widely used clinical tool to evaluate glucose metabolism. Regarding fertility, the relation between polycystic ovary syndrome (PCOS) and insulin resistance (IR) has been studied. Insulin resistance may be potential contributor to impaired treatment outcomes in artificial reproductive technology (ART). Although a few studies have recently been published on the topic the association of HOMA-IR with fertility treatment parameters remains a black box in reproductive medicine research. Study design, size, duration The observational study was designed and conducted at the Kinderwunsch Institut Schenk GmbH (Dobl, Austria). The study included 175 patients (25 men and 150 women), aged 18-45. HOMA-IR was determined for each patient and then correlated with patient’s medical history, fertility treatment parameters and outcomes. Participants/materials, setting, methods HOMA-IR was determined by taking a blood sample during fasting state and measuring plasma values of glucose (mg/dl) and insulin (mU/ml). A HOMA-IR of ≥ 2 was considered as insulin resistance. HOMA-IR was correlated with medical history (polycystic ovarian syndrome (PCOS), endometriosis, Body-Mass-Index (BMI), nicotine abuse) and fertility treatment parameters (sperm quality, number of retrieved oocytes after controlled ovarian stimulation, number of mature and fertilized oocytes, embryo quality and pregnancy rate). Main results and the role of chance An increased HOMA-IR (³2) was observed in 90 patients (51.4%). They suffered from obesity (n = 36; 80%), PCOS (n = 22; 70.97%), ovarian hyperstimulation syndrome (n = 17; 77.27%) and experienced poor embryo quality (n = 249; 91.54%). A significant positive correlation was found between HOMA-IR and PCOS (p < 0.001), obesity (p < 0.001) and number of retrieved oocytes (p < 0.05). The pregnancy rate correlated negatively with the HOMA-IR (p < 0.001). Furthermore, trends of positive correlations of high HOMA-IR in endometriosis, BMI, pathological spermiogram, nicotine abuse and increased number of mature oocytes were determined. The relation between HOMA-IR and the number of retrieved and mature oocytes is consistent with its relation to PCOS. The data show that HOMA-IR is associated with fertility treatment parameters and has a significant influence on ART outcome. Limitations, reasons for caution The number of patients may be seen as a study limitation. Results should be confirmed with a bigger sample size. An interventional study should confirm the role of HOMA-IR in IVF outcomes. Wider implications of the findings These findings may help to better understand the importance of glucose and insulin metabolism in reproduction and suggest that evaluation of HOMA-IR may be a valuable parameter to be considered when collecting patients’ anamnesis prior to starting ART treatment. Trial registration number not applicable

Basic and translational research in reproductive medicine can provide new insights with the application of scanning probe microscopies, such as atomic force microscopy (AFM) and scanning near-field optical microscopy (SNOM). These microscopies, which provide images with spatial resolution well beyond the optical resolution limit, enable users to achieve detailed descriptions of cell topography, inner cellular structure organization, and arrangements of single or cluster membrane proteins. A peculiar characteristic of AFM operating in force spectroscopy mode is its inherent ability to measure the interaction forces between single proteins or cells, and to quantify the mechanical properties (i.e., elasticity, viscoelasticity, and viscosity) of cells and tissues. The knowledge of the cell ultrastructure, the macromolecule organization, the protein dynamics, the investigation of biological interaction forces, and the quantification of biomechanical features can be essential clues for identifying the molecular mechanisms that govern responses in living cells. This review highlights the main findings achieved by the use of AFM and SNOM in assisted reproductive research, such as the description of gamete morphology; the quantification of mechanical properties of gametes; the role of forces in embryo development; the significance of investigating single-molecule interaction forces; the characterization of disorders of the reproductive system; and the visualization of molecular organization. New perspectives of analysis opened up by applying these techniques and the translational impacts on reproductive medicine are discussed.

Barriers to conducting clinical research in reproductive medicine: Latin America

The aim of reproductive medicine is to help couples with an unfulfilled child wish to have a child by offering them the best treatment option. The choice of treatment reflects effectiveness and safety. While effectiveness refers to the extent to which a treatment increases the chance of a couple in having a baby, safety relates to adverse effects associated with such a treatment. In an attempt to integrate effectiveness and safety, healthy singleton live birth (at term) has been suggested as the ideal outcome measure for evaluative research in reproductive medicine. Although intuitively desirable, this proposal overlooks the fact that assessment of effectiveness and safety in this context cannot be measured as a single outcome. In this paper, we explain why effectiveness and safety outcomes in reproductive medicine should be assessed independently, and later synthesized to inform clinical decision-making.