The PRCI study: design of a randomized clinical trial to evaluate a coping intervention for medical waiting periods used by women undergoing a fertility treatment

Background: Many medical situations necessitate a stressful period of waiting for potentially threatening test results. The medical waiting period is often associated with negative anticipatory anxiety and rumination about the outcome of treatment. Few evidence-based self-help coping interventions are available to assist individuals manage these periods. Theory and research suggest that positive reappraisal coping strategies may be particularly useful for this type of unpredictable and uncontrollable stressful context. The objective of this study is to investigate the effects of a Positive Reappraisal Coping Intervention (PRCI) on psychological well-being of women waiting for the outcome of their fertility treatment cycle. Methods/Design: In a three-armed randomized controlled trial, the effectiveness of the PRCI will be tested. Consecutive patients undergoing in vitro fertilisation in a Dutch university hospital and meeting selection criteria will be invited to participate. Those who agree will be randomized to one of three experimental groups (N=372). The PRCI Intervention group will receive the intervention that comprises an explanatory leaflet and the 10 statements designed to promote positive reappraisal coping, to be read at least once in the morning, once in the evening. To capture the general impact of PRCI on psychological wellbeing patients will complete questionnaires before the waiting period (pre-intervention), on day ten of the 14-day waiting period (intervention) and six weeks after the start of the waiting period (post-intervention). To capture the specific effects of the PRCI during the waiting period, patients will also be asked to monitor daily their emotions and reactions during the 14-day waiting period. The primary outcome is general anxiety, measured by the Hospital Anxiety and Depression Scale. Secondary outcomes are positive and negative emotions during the waiting period, depression, quality of life, coping and treatment outcome. During recruitment for the RCT it was decided to add a fourth non-randomized group, a PRCI Control group that received the PRCI and completed the questionnaires but did not complete daily monitoring. Discussion: Positive reappraisal is one of the few ways of coping that has been shown to be associated with increased wellbeing during unpredictable and uncontrollable situations like medical waiting periods. A simple evidence based self-help intervention could facilitate coping during this common medical situation. This RCT study will evaluate the value of a self-help coping intervention designed for medical waiting periods in women undergoing fertility treatment. Trial registration: The study is registered at the Clinical Tials.gov (NCT01701011)

Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos

Background The aetiology of recurrent miscarriage (RM) remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs) of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women. Methodology/Principal Findings Monolayers of decidualized H-EnSCs were generated from endometrial biopsies of 6 women with RM and 6 fertile controls. Cell-free migration zones were created and the effect of the presence of a high-quality (day 5 blastocyst, n = 13), a low-quality (day 5 blastocyst with three pronuclei or underdeveloped embryo, n = 12) or AC-1M88 trophoblast cell line spheroid on H-ESC migratory activity was analyzed after 18 hours. In the absence of a spheroid or embryo, migration of H-EnSCs from fertile or RM women was similar. In the presence of a low-quality embryo in the zone, the migration of H-EnSCs of control women was inhibited compared to the basal migration in the absence of an embryo (P<0.05) and compared to the migration in the presence of high-quality embryo (p<0.01). Interestingly, the migratory response H-EnSCs of women with RM did not differ between high- and low-quality embryos. Furthermore, in the presence of a spheroid their migration was enhanced compared to the H-EnSCs of controls (p<0.001). Conclusions H-EnSCs of fertile women discriminate between high- and low-quality embryos whereas H-EnSCs of women with RM fail to do so. H-EnSCs of RM women have a higher migratory response to trophoblast spheroids. Future studies will focus on the mechanisms by which low-quality embryos inhibit the migration of H-EnSCs and how this is deregulated in women with RM

A population-based survey on family intentions and fertility awareness in women and men in the United Kingdom and Denmark

Background: Across several European countries family formation is increasingly postponed. The aims of the study were to investigate the desire for family building and fertility awareness in the UK and Denmark.Methods: A population-based internet survey was used among women (n?=?1,000) and men (n?=?237) from the UK (40%) and Denmark (60%). Data covered socio-demographics, family formation, and awareness of female age-related fertility. Data analysis used descriptive statistics and logistic regression analysis for studying associations between low fertility awareness and desired family formation.Results: The majority of all participants desired two or three children. Two-thirds of the childless participants desired a first child at 30+ years, and one-fifth of the women and one-third of the men desired a last child at age 40. Overall, 83% of women and 73% of men were aware that female fertility starts to decline around 25–30 years. Men had significantly lower fertility awareness. Women who underestimated the impact of age on female fertility were significantly more likely to have a desire or attempted their first child at a higher age.Conclusion: Even though the majority were aware of the age-related decrease in female fertility, most desired having children at an age when female fertility has declined. Women who were not sufficiently aware of the impact of advanced age were significantly more likely to have their first child at a higher age. There is a need for developing educational programs for women and men in order to increase the population’s knowledge of fertility and risk factors for infertility

Decidual Macrophages Are Significantly Increased in Spontaneous Miscarriages and Over-Express FasL

Decidual macrophages (DM) are the second most abundant population in the fetal-maternal interface. Their role has been so far identified as being local immuno-modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL-expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact

Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment

Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site

Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period

Some women are at risk of forming blood clots in a deep vein during pregnancy, after a caesarean birth, or during the first few weeks after childbirth. If part of the clot breaks off and lodges in a blood vessel in the lungs, it can be life-threatening. Preventive treatments include blood-thinning drugs to prevent clots, support stockings, and exercise soon after the birth to keep circulation moving. However, some drugs might cause problems such as increased blood loss after the birth. Drugs used include heparin, low molecular weight heparin and aspirin. We included 16 randomised controlled studies in the review but only 13 trials with 1774 women contributed data for the outcomes of interest. We did not find enough evidence from the trials to be sure about the effects of these different preventive treatments.This means there is not enough evidence to show which are the best ways to prevent deep vein thrombosis (DVT) during or following pregnancy, or after a caesarean birth