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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are believed to be increased compared with normal fertile women, although supporting evidence is limited. Pregnant women with PCOS experience a higher incidence of perinatal morbidity from gestational diabetes, pregnancy-induced hypertension, and preeclampsia. Their babies are at an increased risk of neonatal complications, such as preterm birth and admission at a neonatal intensive care unit. Pre-pregnancy, antenatal, and intrapartum care should be aimed at reducing these risks. The use of insulin sensitizing drugs to decrease hyperinsulinemic insulin resistance has been proposed during pregnancy to reduce the risk of developing preeclampsia or gestational diabetes. Although metformin appears to be safe, there are too few data from prospective, randomized controlled trials to support treatment during pregnancy.

BACKGROUND: Cumulative IVF pregnancy rates are compromised by the large number of couples who drop-out of treatment before achieving pregnancy. The aim of this study was to identify the role of the treatment strategy applied, and potential other factors that influence the decision of couples to discontinue treatment. METHODS: The incidence of drop-out from WIT treatment and factors related to drop-out were studied in a cohort of IVF patients aged 50%. The presence of severe male subfertility (HR 4.80; 95% CI, 1.63-14.13) and the failure to achieve embryo transfer (odds ratio 0.41; 95% CI, 0.24-0.72) were also related to drop-out. CONCLUSIONS: Reducing drop-out rate is crucial to further improve the efficacy and cost-effectiveness of IVF treatment. An important factor determining the risk of drop-out is the burden of the treatment strategy. The application of a mild treatment strategy and managing patient's expectations might reduce drop-out rates.

BACKGROUND Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared with a conventional strategy for IVF. METHODS Four hundred and four patients were randomly assigned to undergo either mild ovarian stimulation/GnRH antagonist co-treatment combined with single embryo transfer, or standard stimulation/GnRH agonist long protocol and the transfer of two embryos. The main outcome measures are total costs of treatment within a 12 months period after randomization, and the relationship between total costs and proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization. RESULTS Despite a significantly increased average number of IVF cycles (2.3 versus 1.7; P < 0.001), lower average total costs over a 12-month period (8333 versus euro10 745; P = 0.006) were observed using the mild strategy. This was mainly due to higher costs of the obstetric and post-natal period for the standard strategy, related to multiple pregnancies. The costs per pregnancy leading to term live birth were euro19 156 in the mild strategy and euro24 038 in the standard. The incremental cost-effectiveness ratio of the standard strategy compared with the mild strategy was euro185 000 per extra pregnancy leading to term live birth. CONCLUSIONS Despite an increased mean number of IVF cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per term live birth. It is unlikely, over a wide range of society's willingness-to-pay, that the standard treatment strategy is cost-effective, compared with the mild strategy.

The objective of this study was to investigate the effect of ovarian stimulation for IVF on endometrial secretion and tissue markers of receptivity in the mid-luteal phase. In 10 oocyte donors, endometrial secretions and biopsies were sampled 5 days after spontaneous ovulation and oocyte retrieval in consecutive cycles. Four subjects received progesterone in the luteal phase of the stimulated cycles. Mid-luteal endometrial maturation in the stimulated cycle was compared with the spontaneous cycle, by histological dating, Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) expression, secretion levels of leukaemia inhibitory factor (LIF), glycodelin A (GdA) and progesterone, and protein profile. No significant differences in histological markers, expression of Ki-67, PR, ER, secretion protein profiles or concentrations of LIF, GdA, or progesterone were observed when comparing natural with stimulated cycles. Progesterone supplementation of stimulated cycles was associated with significantly lower Ki-67 (P = 0.03) and ER (P = 0.04) expression compared with the non-supplemented stimulated cycle. In this pilot study, ovarian stimulation was not demonstrated to alter the studied markers of endometrial maturation in the mid-luteal phase.

BACKGROUND: Psychological variables, such as anxiety and depression, may have a negative impact on IVF outcomes, but the evidence remains inconclusive. Previous studies have usually measured a single psychological parameter with clinical pregnancy as the outcome. The objective of the current study was to determine whether pretreatment or procedural psychological variables in women undergoing a first IVF cycle affect the chance of achieving a live birth from that cycle. METHODS: Between February 2002 and February 2004, 391 women with an indication for IVF were recruited at two University Medical Centres in The Netherlands. Pretreatment anxiety and depression were measured with the Hospital Anxiety and Depression Scale. The Daily Record Keeping Chart was used to measure negative and positive affect before treatment and daily during ovarian stimulation. Multiple stepwise forward logistic regression analysis was performed with term live birth as the dependent variable. RESULTS: Regression analysis showed that women who expressed less negative affect at baseline were less likely to achieve live birth (P = 0.03). After one IVF cycle, women who received a standard IVF strategy were more likely to reach live birth delivery than those who received a mild IVF strategy (P = 0.002). A male/female indication for IVF was associated with a higher chance of achieving term live birth than a female only indication (P = 0.03). Age, duration of infertility or type of infertility were not independent predictors of live birth. CONCLUSIONS: The relationship between psychological parameters and IVF success rates is more complex than commonly believed. The expression of negative emotions before starting IVF might not be always detrimental for outcomes.

BACKGROUND: Failure of IVF treatment after a number of cycles can be devastating for couples. Although mild IVF strategies reduce the psychological burden of treatment, failure may cause feelings of regret that a more aggressive approach, including the transfer of two embryos, was not employed. In this study, the impact of treatment failure after two or more cycles on stress was studied, following treatment with a mild versus a standard treatment strategy. METHODS: Randomized controlled two-centre trial (ISRCTN35766970). Women were randomized to undergo mild ovarian stimulation (including GnRH antagonist co-treatment) and single embryo transfer (n 5 197) or standard GnRH agonist long-protocol ovarian stimulation with double embryo transfer (n 5 194). Participants completed the Hospital Anxiety and Depression Scale prior to commencing treatment and 1 week after the outcome of their final treatment cycle was known. Data from women who underwent two or more IVF cycles were subject to analysis (n 5 253). RESULTS: Women who experienced treatment failure after standard IVF treatment presented more symptoms of depression 1 week after treatment termination compared with women who had undergone mild IVF: adjusted mean (+ +95% confidence interval)510.2 (+2.3) versus 5.4 (+1.8), respectively, P 5 0.01. CONCLUSIONS: Failure of IVF treatment after a mild treatment strategy may result in fewer short-term symptoms of depression as compared to failure after a standard treatment strategy. These findings may further encourage the application of mild IVF treatment strategies in clinical practice.

textabstractBackground: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. Methods: A total of 174 IVF patients aged

Mild hyperhomocysteinemia is caused by B vitamin deficiencies. We hypothesize that these biochemical derangements detrimentally affect spermatogenesis. Therefore, the aim of this study was to investigate the folate, cobalamin, pyridoxine, and homocysteine concentrations in blood and seminal plasma and the associations between these biomarkers and semen parameters in men participating in an in vitro fertilization or intracytoplasmic sperm injection program. From 73 men (median age [range]: 37 years [28-53]), blood and semen samples were obtained for the determination of serum and red blood cell (RBC) folate, serum total cobalamin, whole-blood pyridoxal-5'-phosphate, plasma total homocysteine (tHcy), and serum total testosterone. Semen analysis included sperm concentration, motility, and morphology according to World Health Organization criteria. The B vitamins and tHcy concentrations were significantly correlated in blood but not in seminal plasma. The serum and RBC folate concentrations were significantly correlated also with the total folate concentration in seminal plasma (r = .44; P < .001 and r = .39; P < .001, respectively). Likewise, the total cobalamin concentration in serum and seminal plasma was significantly correlated (r = .55; P = .001). Of interest is that the total cobalamin concentration in seminal plasma was significantly correlated with the sperm concentration (r = .42; P < .001). This is in contrast to the absence of significant associations between the other vitamins and tHcy in blood and seminal plasma and any of the semen parameters. These findings suggest that folate and cobalamin are transferred from the blood to the male reproductive organs and emphasize the role of cobalamin in spermatogenesis in human.

Objective To assess the accuracy of antimullerian hormone (AMH) in predicting cumulative live birth rate (CLBR) within 1 year after treatment initiation in GnRH antagonist treatment cycles for in vitro fertilization (IVF). Design Observational (retrospective) substudy as part of an ongoing prospective cohort study. Setting University medical center. Patient(s) A total of 487 patients scheduled for IVF/intracytoplasmic sperm injection (ICSI). Intervention(s) Patients starting their first IVF/ICSI cycle with 150 or 225 IU recombinant FSH and GnRH antagonist cotreatment were included. Serum samples collected before the first IVF treatment were used to determine AMH. Treatment data after treatment initiation for a maximum of 1 year were recorded. Main Outcome Measure(s) Prediction of CLBR with the use of AMH. Result(s) The model for predicting CLBR within 1 year included age at first treatment, AMH, type of infertility, and previous assisted reproductive technology treatment leading to live birth. The accuracy in discriminating between women who did or did not achieve a live birth was only 59%. AMH had intermediate added value in the prediction of CLBR as demonstrated by the net reclassification improvement (total 29.8). A nomogram based on age and AMH was developed by which a subgroup of patients could be identified with the poorest pregnancy prospects. Conclusion(s) The predictive accuracy of AMH for 1-year CLBR in GnRH antagonist treatment cycles was limited and did not yield much additional value on top of age. Withholding treatment based on predictors such as age and AMH, or a combination, remains problematic. Clinical Trial Registration Number www.clinicaltrials.gov, NCT02309073.

STUDY QUESTION Do the amino acid levels of human uterine fluid vary with age, BMI, phase of menstrual cycle, benign pathology or diet? SUMMARY ANSWER The levels of 18 amino acids in human uterine fluid were shown to be affected only by maternal diet. WHAT IS KNOWN ALREADY Murine, bovine and ovine uterine amino acid content has been reported, but no reliable data on the human exist. Murine studies have demonstrated that the intrauterine periconceptional nutritional environment is affected by maternal diet. STUDY DESIGN, SIZE, DURATION Uterine secretions were aspirated from 56 women aged 18–45 years. The women were recruited preoperatively from gynaecological theatre operating schedules or hysterosalpingo-contrast-sonography (HyCoSy) lists. A proportion of these women had proven fertility; however, the majority were being investigated for subfertility. The BMI, gynaecological history and dietary pattern of these women were also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS Reverse phase high performance liquid chromatography was used to analyse the concentrations of 18 amino acids within the uterine fluid and blood serum. The results were analysed against the women's stage of cycle, age, BMI and diet. MAIN RESULTS AND THE ROLE OF CHANCE The profile of 18 amino acids in uterine fluid was described. In total, human uterine fluid was observed to contain an amino acid concentration of 3.54 mM (interquartile range: 2.27–6.24 mM). The relative concentrations of 18 amino acids were not significantly altered by age, BMI, cycle phase or the presence of specific benign gynaecological pathologies. However, a diet identified by a validated scoring system as being less healthy was associated with higher concentrations of asparagine (P = 0.018), histidine (P = 0.011), serine (P = 0.033), glutamine (P = 0.049), valine (P = 0.025), phenylalanine (P = 0.019), isoleucine (P = 0.025) and leucine (P = 0.043) in the uterine fluid compared with a healthier diet, defined as one with a higher intake of fresh vegetables, fruit, whole-grain products and fish and a low intake of red and processed meat and high fat dairy products. There were no significant correlations between serum amino acid concentrations and those in the uterine fluid. LIMITATIONS, REASONS FOR CAUTION Our results enabled us to detect the effect of diet on the concentrations of amino acids in human uterine fluid; however, the study may not have had sufficient numbers to detect mild effects of BMI or age. WIDER IMPLICATIONS OF THE FINDINGS These findings increase our understanding of the nutritional environment encountered by the preimplantation embryo, and indicate how periconceptional diet may alter this. Given the importance of early embryo environment for programming of development and future health, this information may aid in the development of nutritional interventions aimed at optimizing the preimplantation phase of human embryo development in vivo. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the NIHR, the Medical Research Council (G0701153) and the University of Southampton and was supported by the NIHR BRC in Nutrition and Southampton University NHS Foundation Trust. The authors declare no conflicts of interest.

Item does not contain fulltext STUDY QUESTION: What is the clinical value of anti-Mullerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? SUMMARY ANSWER: AMH as a single test has substantial accuracy for ovarian response prediction in GnRH antagonist treatment for IVF, with a higher accuracy for predicting a high response than for low response. WHAT IS KNOWN ALREADY: The role of AMH and other patient characteristics in ovarian response prediction has been studied extensively in long GnRH agonist protocols; however, little information is available regarding the clinical value in GnRH antagonists. STUDY DESIGN, SIZE, DURATION: This is an observational (retrospective) substudy as part of an ongoing cohort study. A total of 487 patients scheduled for IVF/ICSI between 2006 and 2011 were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a regular cycle who underwent their first IVF/ICSI cycle with GnRH antagonist treatment while receiving a starting dose of 150 or 225 IU recombinant FSH were included in the study. Patients were divided into three subgroups according to the following ovarian response categories: high (>15 oocytes or cycle cancellation), normal (4-15 oocytes) and low (

Pregnant women with a history of miscarriages experience symptoms of anxiety and depression in a subsequent pregnancy and are in need of support in the period after miscarriage, when trying to get pregnant again and during the first phase of pregnancy. The aim of this study was to investigate whether a Positive Reappraisal Coping Intervention (PRCI) and Daily Record Keeping (DRK) chart, developed for use in assisted conception treatment, are also appropriate for use in pregnant women with a history of miscarriage(s). In this convergent parallel mixed method study, thirteen women visiting an Early Pregnancy Unit and/or Recurrent Miscarriage Clinic in a university medical center in the Netherlands were selected on the basis of the number of miscarriages and age. Exclusion criteria were not speaking the Dutch language, pregnancy after fertility treatment and having a medical cause identified for the miscarriages. Women used the PRCI and DRK for 3 weeks in a subsequent pregnancy. Quantitative data were obtained from the DRK and were analyzed by reporting frequencies and means for each case. Qualitative data were collected by semi-structured interviews and were analyzed by using thematic analysis. The majority of the women were able to use the PRCI and DRK for 3 weeks. Women adapted the way in which they used the PRCI and DRK based on their judgment about the effect, the intensity of the emotions they experienced, or whether they felt the effort to use these instruments to be worthwhile or not.

When considering the chances of establishing a healthy ongoing pregnancy after in vitro fertilization (IVF), the cause of infertility plays a relatively minor role. In recent years, there has been a shift from determining the diagnosis to the individual prognosis for a given patient. A number of prognostic factors were identified, which enabled clinicians to appropriately counsel patients. Patient-determined factors are of crucial importance and some are amenable to intervention such as lifestyle and nutritional advice. However, the attention of clinicians remains on seeking adjuvant therapeutic interventions designed to improve the outcomes of IVF treatment. In this article, the patient-determined factors underlying the individual chance of conceiving and the more commonly prescribed empirical medical therapies prescribed to enhance outcomes are reviewed. It is concluded that greater attention to optimizing the health of the couple before starting IVF treatment may be more beneficial than adjuvant medical therapies during treatment.

Implantation is a complicated process that requires the orchestration of a series of events involving both the embryo and the endometrium. Even with the transfer of high quality embryos, implantation rates remain relatively low. The growing tendency towards transferring fewer embryos provides further incentives to improve implantation rates. In this article, the various clinical strategies employed to increase the chance of implantation are reviewed. Embryo transfer technique is a critical step in assisted reproductive technology cycles. Recent studies have shown significant improvements in clinical pregnancy rates resulting from careful embryo transfer technique, appropriate catheter type and placing for embryo transfer. Increasingly, adjuvant pharmaceutical therapies are also being applied with the aim of improving embryo implantation. However, the evidence for their efficacy and safety is limited. Recent evidence suggests that adoption of milder ovarian stimulation regimens may provide a more effective clinical approach to improving implantation, since beneficial effects have been shown for both endometrial receptivity and embryo quality.

BACKGROUND: In order to assess the frequency of aneuploidy and mosaicism in embryos obtained from IVF patients aged