COVID-19 and fertility services in the United Kingdom: a biphasic qualitative study.

Recently, fertility services have started resuming since COVID-19 was declared a pandemic, but there remains significant uncertainty in the way this care will be delivered in the United Kingdom. The objective of our study was to explore the impact of COVID-19 on individuals using fertility services in the United Kingdom. The study was conducted in two phases between May 2020 and July 2020: an online questionnaire involving 1212 participants and subsequent individual semi-structured telephone interviews with 15 participants. Through thematic analysis, we learned from the questionnaire findings that 74% of individuals identified as White British, 21% as Black and Minority Ethnic (BAME) and 2.6% as male. Ninety-six per cent of individuals from the questionnaire explained that COVID-19 had a 'negative impact' on their fertility treatment, namely 'delay in care'. Eighty-two per cent of participants discussed concerns about the 'uncertainty' they felt about fertility services; these included the 'unknown impact of COVID-19 on pregnancy outcomes', the 'unknown impact on general gynaecology services' and the 'unknown impact of COVID-19 on fertility success'. Through semi-structured telephone interviews with 15 participants, we learned about the 'cultural pressures' individuals from BAME backgrounds faced in relation to care. Participants were mindful about the 'pressures on the service' when reopening, and therefore 'advancing maternal age', 'socio-economic background' and 'previous unsuccessful fertility treatment' were the main factors individuals considered important when 'prioritising' fertility care. Our findings can be used by fertility service providers to appreciate the patient perspective when considering the reopening of fertility services nationally and internationally. LAY SUMMARY: The impact of COVID-19 on patients seeking or undergoing fertility treatment is not entirely known. Many patients have had their treatment postponed during the pandemic. As fertility services begin to recommence, it is important to understand how the pandemic has affected this group of patients. In addition, it is vital to appreciate and understand the patient's voice in order to ensure services take into account the patients' concerns as they begin to offer certain fertility treatments. Our study was conducted in two phases and involved an online questionnaire and individual interviews with people. We found that people were worried about services restarting and how care would be prioritised. People also discussed some of the perceived barriers to seeking fertility healthcare. Our findings highlight the importance of understanding the patient's voice when recommencing fertility services.

Effect of deprivation on in vitro fertilisation outcome: a cohort study.

OBJECTIVE: To determine whether socioeconomic deprivation affects IVF outcome independent of the number of cycles undertaken. DESIGN: A retrospective review of prospectively collected data. SETTING: A tertiary level fertility clinic in the North of England. POPULATION: All participants undergoing their first fresh single-embryo transfer, funded by the National Health Service (NHS), between January 2012 and December 2017. METHODS: For each case, identified from the clinic database, we recorded the following: age; body mass index; FSH; number of eggs retrieved; ethnicity; cause of subfertility; stage of embryo transfer; and whether any adjuncts i.e. EmbryoGlue® or Time Lapse Imaging were used. Socio-economic deprivation was assessed using the Index of Multiple Deprivation (IMD) determined by the residential postcode. MAIN OUTCOME MEASURES: Clinical pregnancy (CP) and live birth (LB) rates across IMD quintiles. RESULTS: Three thousand ninety-one women were included. Overall, CP and LB rates were 35.9% and 31.3% respectively. CP rates increased significantly from 31.0% in the most deprived group to 38.8% in the least deprived group (P < 0.01). Similarly, LB rates were significantly lower in the most deprived group compared with the least deprived group (26.8 versus 35.4%, P < 0.01). After adjusting for confounding variables, women in the least deprived group were significantly more likely to have a LB (aRR 1.18, 95% CI 1.00-1.39) than women in the most deprived group. CONCLUSIONS: More socio-economically deprived patients are significantly less likely to achieve a LB than less deprived patients independent of the number of cycles of IVF undertaken. TWEETABLE ABSTRACT: More deprived patients are less likely to have a LB per cycle of IVF than less deprived patients.

Could ethnicity have a different effect on fresh and frozen embryo transfer outcomes: a retrospective study.

RESEARCH QUESTION: Does a woman's ethnicity affect her fresh and frozen embryo transfer outcomes differently? DESIGN: A retrospective cohort study of the first fresh and first frozen embryo transfer per woman carried out at a single tertiary level fertility unit between 2010 and 2016 using data retrieved from an electronic database. Biochemical pregnancy, biochemical pregnancy loss, clinical pregnancy, miscarriage and live birth rates per embryo transfer were compared between 5876 white Caucasian, 1071 South Asian and 114 Black Afro-Caribbean women undergoing their first fresh embryo transfer and for 1418 Caucasian, 273 South Asian and 31 Afro-Caribbean women undergoing their first frozen embryo transfer. Logistic regression was used to adjust for age, number of oocytes retrieved, and number and stage of embryos transferred. RESULTS: South Asian (26% versus 32%, adjusted OR 0.622, 95% CI 0.533 to 0.725) and Black Afro-Caribbean women (21% versus 32%, adjusted OR 0.528, 95% CI 0.332 to 0.839) had a lower live birth rate per fresh embryo transfer compared with white Caucasian women. In contrast, the live birth rates per frozen embryo transfer were not significantly different between South Asian and Caucasian women (26% versus 28%, adjusted OR 0.890, 95% CI 0.661 to 1.200) and between Afro-Caribbean and Caucasian women (29% versus 28%, adjusted OR 0.983, 95% CI 0.447 to 2.162). CONCLUSION: South Asian and Black Afro-Caribbean women have a significantly lower live birth rate than white Caucasian women after fresh embryo transfer, but their frozen embryo transfer live birth rates are not significantly different.

Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. STUDY DESIGN SIZE DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. A (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. The guideline was peer-reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE II criteria and underwent methodological review. This guideline was approved by all members of the GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low (n = 1), low (n = 9) and moderate (n = 4) quality with no EBRs based on high-quality evidence. The guideline provides 14 EBRs, 10 clinical consensus recommendations (CCRs) and 20 clinical practice points on the assessment and management of infertility in PCOS. Key changes in this guideline include emphasizing evidence-based fertility therapy, including cheaper and safer fertility management. LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTERESTS: The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine (ASRM). GDG members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

Cumulative live birth rates and perinatal outcomes with the use of time-lapse imaging incubators for embryo culture: a retrospective cohort study of 1882 ART cycles.

OBJECTIVE: Comparison of live birth rates and the perinatal outcomes after fresh and frozen embryo transfer between time-lapse imaging (TLI) and standard culture (SC) incubators. DESIGN: Retrospective cohort study. SETTING: A single tertiary level IVF unit. POPULATION: Women undergoing IVF between January 2014 and October 2015. METHODS: Comparison was done between 1064 IVF cycles using TLI (TLI cycles) and 818 IVF cycles using SC (SC cycles). MAIN OUTCOME MEASURES: Cumulative live birth rate per oocyte retrieval and perinatal outcomes including birthweight, gestational age, preterm birth (PTB) (<37 weeks), early preterm birth (PTB; <32 weeks), low birthweight (LBW; <2500 g), very LBW (<1500 g) and macrosomia (>4500 g). RESULTS: The fresh embryo transfer live birth rate was noted to be higher for TLI cycles [TLI 36.8 versus SC 33.9%, adjusted odds ratio (aOR) 1.28, 95% CI 1.05-1.57], but the frozen embryo transfer live birth rates were not significantly different. The mean birthweight was higher in the TLI group after both fresh [adjusted mean difference (aMD) 174.78 g, 95% CI 64.80-284.77] and frozen embryo transfers (aMD 175.91 g, 95% CI 16.98-334.84). After a fresh embryo transfer, there was a lower risk of early PTB and very LBW in the TLI group. Among frozen embryo transfers, there was a lower risk of early PTB and LBW in the TLI group. CONCLUSIONS: TLI incubators are associated with improved perinatal outcomes and higher mean birthweight after fresh and frozen embryo transfer. TWEETABLE ABSTRACT: Time-lapse imaging incubators in IVF improve perinatal outcomes after both fresh and frozen embryo transfers.

Anti-Müllerian hormone reflects the severity of polycystic ovary syndrome.

OBJECTIVE: To examine the relationship between anti-Müllerian hormone (AMH) and the severity of the phenotype of patients with polycystic ovary syndrome (PCOS) and whether AMH can act as a diagnostic marker for PCOS? DESIGN: A prospective diagnostic utility study of AMH as a marker of PCOS. PATIENTS: A consecutive series of women presenting to a tertiary infertility clinic (n = 164) plus a second series of women prepared for assisted conception treatments (n = 89) recruited between June 2012 and May 2013. MEASUREMENTS: Polycystic ovary syndrome was diagnosed using the Rotterdam criteria. AMH was measured using the Generation II assay (Beckman Coulter). The diagnostic utility of AMH was established using receiver operator characteristic (ROC) curves. Cut-off values for the individual features of PCOS are proposed. RESULTS: There was a significant difference in serum AMH concentration in women with normal ovaries (13·2 pmol/l), polycystic ovary morphology (PCOM) alone (37·8 pmol/l) and PCOS (53·2 pmol/l). Follicle number, increasing cycle length and evidence of hyperandrogenism were all independently associated with serum AMH concentration (P < 0·01). AMH was significantly affected by the different phenotypic presentations of PCOS with those with all components (PCOM, HA and OA) having the highest mean value [72·7 pmol/l (P < 0·01)]. CONCLUSIONS: Serum AMH has the capacity to act as a diagnostic test for PCOS. Moreover, since its value rises with the more marked phenotypes, different cut-off values need to be used to differentiate those patients with polycystic ovarian morphology (PCOM), hyperandrogenism (HA) and oligoanovulation (OA).

A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomised placebo-controlled trial.

STUDY QUESTION: Does 'metformin' reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for women with polycystic ovary syndrome (PCOS) undergoing a GnRH antagonist assisted conception treatment cycle? SUMMARY ANSWER: A short course of metformin does not reduce the incidence of OHSS for women with PCOS undergoing a GnRH antagonist treatment cycle. WHAT IS KNOWN ALREADY: Metformin does reduce the incidence of OHSS in a GnRH-agonist treatment cycle. STUDY DESIGN, SIZE, DURATION: A randomised placebo-controlled trial (RCT) using metformin or placebo. Randomisation was blinded to both patient and investigator, using a random permuted blocks method with a 50:50 allocation ratio. The study was completed over 5 years (2009-2014) with 153 randomised patients. A sample size calculation based on the incidence of OHSS was completed prospectively suggesting a minimum of 146 recruits was required for the trial with a power of 80% and a type 1 error of 0.05. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients met the Rotterdam criteria for PCOS and were treated with a standard GnRH antagonist IVF/ICSI treatment cycle in a tertiary infertility clinic. The study medication was started prior to stimulation and continued to oocyte retrieval. Of the 153 patients, 77 received metformin and 76 placebo. MAIN RESULTS AND THE ROLE OF CHANCE: There was no reduction in the incidence of moderate-severe OHSS (Placebo (PLA) 12.2%, metformin (MET) = 16%, 95% CI -0.08-0.16, P = 0.66). There was no difference in total gonadotrophin dose (PLA = 1200, MET = 1200, 95% CI -118.67-118.67, P = 0.75), oocytes retrieved (PLA = 15, MET = 14, 95% CI -2.37-4.37, P = 0.66) or fertilisation rate (PLA = 60.7%, MET = 53.3%, 95% CI -0.96-14.94, P = 0.07). However, using metformin resulted in a reduced clinical pregnancy rate (CPR) per cycle started (PLA = 48.7%, MET = 28.6%, 95% CI 0.04-0.35, P = 0.02) and live birth rate (PLA = 51.6%, MET = 27.6%, 95% CI 0.05-0.40, P = 0.02). Furthermore, when ethnicity was taken into account there was a significant reduction in pregnancy outcome for the South Asian population irrespective of metformin or placebo use (CPR per cycle started, White Caucasian = 44.4%, South Asian = 19.4%; 95% CI 0.06-0.39, P = 0.01). LIMITATIONS, REASONS FOR CAUTION: This study was only undertaken on an infertility population with PCOS with a limited duration of study medication use. WIDER IMPLICATIONS OF THE FINDINGS: This is the first adequately powered RCT to assess the impact of metformin on OHSS in a high-risk group (women with PCOS) undergoing a GnRH antagonist cycle. It does not support the empirical prescribing of metformin as an adjunct to a GnRH antagonist treatment cycle. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: EudraCT number 2009-010952-81. TRIAL REGISTRATION DATE: 21 September 2009. DATE OF FIRST PATIENT'S ENROLMENT: 30 October 2009.

Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.

BACKGROUND: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. METHODS: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. RESULTS: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. CONCLUSION: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

The effect of metformin treatment in vivo on acute and long-term energy metabolism and progesterone production in vitro by granulosa cells from women with polycystic ovary syndrome.

STUDY QUESTION: What are the consequences of polycystic ovary syndrome (PCOS) pathology and metformin-pretreatment in vivo in women with PCOS on the metabolism and steroid production of follicular phenotype- and long-term cultured-granulosa cells (GC)? SUMMARY ANSWER: PCOS pathology significantly compromised glucose metabolism and the progesterone synthetic capacity of follicular- and long-term cultured-GCs and the metabolic impact of PCOS on GC function was alleviated by metformin-pretreatment in vivo. WHAT IS KNOWN ALREADY: Granulosa cells from women with PCOS have been shown to have an impaired insulin-stimulated glucose uptake and lactate production in vitro. However, these results were obtained by placing GCs in unphysiological conditions in culture medium containing high glucose and insulin concentrations. Moreover, existing data on insulin-responsive steroid production in vitro by PCOS GCs vary. STUDY DESIGN, SIZE AND DURATION: Case-control experimental research comparing glucose uptake, pyruvate and lactate production and progesterone production in vitro by GCs from three aetiological groups, all undergoing IVF; healthy control women (Control, n = 12), women with PCOS treated with metformin in vivo (Metformin, n = 8) and women with PCOS not exposed to metformin (PCOS, n = 8). The study was conducted over a period of 3 years between 2007 and 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Rotterdam criteria were used for the diagnosis of PCOS; all subjects were matched for age, BMI and baseline FSH. Individual patient cultures were undertaken with cells incubated in a validated, physiological, serum-free culture medium containing doses of 0-6 mM glucose and 0-100 ng/ml insulin for 6 h and 144 h to quantify the impact of treatments on acute and long-term metabolism, respectively, and progesterone production. The metabolite content of spent media was measured using spectrophotometric plate reader assay. The progesterone content of spent media was measured by enzyme-linked immunosorbent assay. Viable GC number was quantified after 144 h of culture by the vital dye Neutral Red uptake assay. MAIN RESULTS AND THE ROLE OF CHANCE: Granulosa cells from women with PCOS pathology revealed reduced pyruvate production and preferential lactate production in addition to their reduced glucose uptake during cultures (P < 0.05). Metformin pretreatment alleviated this metabolic lesion (P < 0.05) and enhanced cell proliferation in vitro (P < 0.05), but cells retained a significantly reduced capacity for progesterone synthesis compared with controls (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Although significant treatment effects were detected in this small cohort, further studies are required to underpin the molecular mechanisms of the effect of metformin on GCs. WIDER IMPLICATIONS OF THE FINDINGS: The individual patient culture strategy combined with multifactorial experimental design strengthens the biological interpretation of the data. Collectively, these results support the notion that there is an inherent impairment in progesterone biosynthetic capacity of the GCs from women with PCOS. The positive, acute metabolic effect and the negative long-term steroidogenic effect on GCs following metformin exposure in vivo may have important implications for follicular development and luteinized GC function when the drug is used in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No competing interests. This work was supported by the UK Medical Research Council Grant Reference number G0800250.

Amino acid turnover by human oocytes is influenced by gamete developmental competence, patient characteristics and gonadotrophin treatment.

STUDY QUESTION: Can amino acid profiling differentiate between human oocytes with differing competence to mature to metaphase II (MII) in vitro? SUMMARY ANSWER: Oocytes which remained arrested at the germinal vesicle (GV) stage after 24 h of in vitro maturation (IVM) displayed differences in the depletion/appearance of amino acids compared with oocytes which progressed to MII and patient age, infertile diagnosis and ovarian stimulation regime significantly affected oocyte amino acid turnover during IVM. WHAT IS KNOWN ALREADY: Amino acid profiling has been proposed as a technique which can distinguish between human pronucleate zygotes and cleavage stage embryos with the potential to develop to the blastocyst stage and implant to produce a pregnancy and those that arrest. Most recently, the amino acid turnover by individual bovine oocytes has been shown to be predictive of oocyte developmental competence as indicated by the gamete's capacity to undergo fertilization and early cleavage divisions in vitro. STUDY DESIGN, SIZE, DURATION: The study was conducted between March 2005 and March 2010. A total of 216 oocytes which were at the GV or metaphase I (MI) stages at the time of ICSI were donated by 67 patients. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The research was conducted in university research laboratories affiliated to a hospital-based infertility clinic. Oocytes were cultured for 24 h and the depletion/appearance of amino acids was measured during the final 6 h of IVM. Amino acid turnover was analysed in relation to oocyte meiotic progression, patient age, disease aetiology and controlled ovarian stimulation regime. MAIN RESULTS AND THE ROLE OF CHANCE: The depletion/appearance of key amino acids was linked to the maturation potential of human oocytes in vitro. Oocytes which arrested at the GV stage (n = 9) depleted significantly more valine and isoleucine than those which progressed to MI (n = 32) or MII (n = 107) (P < 0.05). Glutamate, glutamine, arginine and valine depletion or appearance differed in MII versus degenerating oocytes (n = 20) (P < 0.05). Glutamine, arginine, methionine, phenylalanine, total depletion and total turnover all differed in oocytes from patients aged < 35 years versus patients ≥35 years (P < 0.05). MII oocytes obtained following ovarian stimulation with recombinant FSH depleted more isoleucine (P < 0.05) and more alanine and lysine (P < 0.05) appeared than oocytes from hMG-stimulated cycles. MII oocytes from patients with a polycystic ovary (PCO) morphology (n = 33) depleted more serine (P < 0.05) than oocytes from women with normal ovaries (n = 61). LIMITATIONS, REASONS FOR CAUTION: Immature oocytes collected at the time of ICSI were used as the model for human oocyte maturation. These oocytes have therefore failed to respond to the ovulatory hCG trigger in vivo (they are meiotically incompetent), and have limited capacity to support embryo development in vitro. The lack of cumulus cells and stress of the conditions in vitro may have influenced turnover of amino acids, and owing to the small sample sizes further studies are required to confirm these findings. WIDER IMPLICATIONS OF THE FINDINGS: The findings provide support for the hypothesis that oocyte metabolism reflects oocyte quality. Longitudinal studies are required to link these functional metabolic indices of human oocyte quality with embryo developmental competence. Oocyte amino acid profiling may be a useful tool to quantify the impact of new assisted reproduction technologies (ART) on oocyte quality. STUDY FUNDING/COMPETING INTERESTS: This project was funded by the UK Biology and Biotechnology Research Council (BB/C007395/1) and the Medical Research Council (G 0800250). K.E.H was in receipt of a British Fertility Society/Merck Serono studentship. H.J.L. is a shareholder in Novocellus Ltd, a company which seeks to devise a non-invasive biochemical test of embryo health.

Timing of human chorionic gonadotrophin (hCG) hormone administration in IVF protocols using GnRH antagonists: a randomized controlled trial.

This randomized controlled trial investigated whether delaying human chorionic gonadotrophin hormone (hCG) administration within an IVF cycle impacts upon clinical outcomes. Participants included 125 women undergoing IVF/ICSI cycles at Leeds Centre for Reproductive Medicine. Subjects were aged 20-36 years, body mass index (BMI) 20-30 kg/m(2) with a normal FSH level (<8 IU/l). Administration of hCG took place 35-36 h prior to oocyte retrieval when there were ≥3 follicles ≥17 mm in diameter (Group A), delayed by 1 day (Group B) or 2 days (Group C). Outcomes included the number of oocytes retrieved per cycle, fertilization rate and live birth rate. On the day of oocyte retrieval, women in Groups B and C had significantly more mature follicles than Group A, although the number of oocytes retrieved did not differ (median = 12 in each group). Fertilization rates and embryo quality were comparable between groups. Pregnancies and live births per cycle were higher in Groups B and C (A = 30.8%, B = 54.1%, C = 38.7%; A = 17.9%, B = 27.0%, C = 25.8%), but did not reach statistical significance. Delaying hCG administration had no significant negative impact upon morphological quality of embryos, availability of surplus embryos for freezing or pregnancy outcomes. Postponing hCG may enable increased flexibility of cycle scheduling to avoid weekend procedures.

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Mid-luteal progesterone concentrations are associated with live birth rates during ovulation induction.

This retrospective study investigated whether mid-luteal serum progesterone concentrations are associated with live birth rates in women with WHO group II anovulatory infertility undergoing ovulation induction. Data were from women (n=335) stimulated with gonadotrophins using a low-dose step-up protocol, of which women with presumptive ovulation (n=279), defined as a mid-luteal progesterone concentration ⩾7.9ng/ml (⩾25nmol/l; range 7.9-194ng/ml) were included. Of the women with presumptive ovulation, 57 (20.4%) had a live birth and their serum mid-luteal progesterone concentration was significantly (P=0.016) higher than that of the non-live birth group. There were significant associations between the number of large (⩾15mm) and medium-sized follicles (12-14mm) at human chorionic gonadotrophin administration and the mid-luteal progesterone concentration (P<0.001), while the total number of large and medium-sized follicles was not significantly associated with live birth rate. In conclusion, mid-luteal progesterone concentrations above the cut-off values currently used for defining ovulation were positively associated with live birth rates in normogonadotrophic anovulatory women undergoing ovulation induction with gonadotrophins. The mid-luteal progesterone concentration, apart from being a consequence of the number of corpora lutea, may also reflect the quality of the follicle/oocyte/corpus luteum. Measurement of blood concentration of the steroid hormone progesterone in the mid-postovulatory phase of the menstrual cycle is frequently used to determine ovulation. The aim of this study was to investigate whether increasing blood concentrations of progesterone in the mid-postovulatory phase was associated with higher chances of achieving a live birth in a group of 335 women with anovulatory infertility, who had undergone stimulation with gonadotrophin hormones for the purpose of inducing ovulation. Statistical analysis, performed on the 279 women with presumptive ovulation (defined as a mid-postovulatory progesterone concentration ⩾7.9ng/ml serum), showed that the mid-postovulatory progesterone concentration was significantly positively associated with live birth rate. There was also a significant association between follicular development at end of gonadotrophin stimulation and the mid-postovulatory progesterone concentration, but follicular development could not explain live birth rate as mid-postovulatory progesterone concentrations could. In conclusion, increased blood concentrations of progesterone in the mid-postovulatory phase of the menstrual cycle above the threshold values currently used for defining ovulation were associated with increased live birth rates in anovulatory women undergoing ovulation induction with gonadotrophin hormones. The mid-postovulatory progesterone concentration, apart from being a consequence of the quantity of follicular development, may therefore also reflect the quality of the ovarian follicles and eggs.

Prestimulation parameters predicting live birth in anovulatory WHO Group II patients undergoing ovulation induction with gonadotrophins.

BACKGROUND: The objective of this study was to identify baseline predictors of live birth in anovulatory patients undergoing ovulation induction, and based on these predictors, develop nomograms for estimation of the probability of live birth in a single cycle. METHODS: Univariate and multivariate logistic regression were used for retrospective analysis of clinical, sonographic and endocrinological parameters collected prior to the start of ovarian stimulation in a cohort of anovulatory World Health Organization (WHO) Group II patients (n = 335), who were resistant to clomiphene citrate (CC) and therefore stimulated with gonadotrophins using a low-dose step-up protocol. RESULTS: The univariate analysis identified age [OR = 0.91 (95% CI: 0.84-0.98), P = 0.015], duration of infertility [OR = 0.71 (95% CI: 0.56-0.91), P = 0.007], serum follicle stimulating hormone (FSH) concentration at the start of stimulation [OR = 0.83 (95% CI: 0.69-0.99), P = 0.034] and menstrual cycle pattern (P = 0.022) as significant predictors of live birth. Baseline concentrations of luteinizing hormone, androgens, glucose and insulin, as well as body mass index, were not predictors of live birth. In the multivariate analysis, duration of infertility, FSH and menstrual cycle pattern were independent predictors, and nomograms were designed with these three parameters for individual prediction of the probability of live birth. CONCLUSIONS: The chances of live birth in women with WHO Group II anovulatory infertility resistant to CC undergoing ovulation induction with gonadotrophins is highly influenced by the menstrual cycle pattern. Increases in duration of infertility and concentration of FSH (within the normal range) before the start of stimulation have negative influences on the likelihood of achieving a live birth.

Health-related quality of life in PCOS and related infertility: how can we assess this?

In recent years there has been an increasing demand for the design, development and use of questionnaires that can assess patients' experiences of health and illness or their health-related quality of life (HRQoL). The application of these questionnaires in research and clinical practice provides information from the patient's perspective on the ways in which symptoms and treatments can affect their daily well-being and functioning. The aim of this paper is to report on the ways in which information on the HRQoL of women with polycystic ovary syndrome (PCOS) can be collected. With particular reference to PCOS-associated infertility, this paper will discuss the types of questionnaires that are currently available. It will discuss the benefits and limitations of the disease-specific PCOS questionnaire, and the other generic and condition-specific tools that have been used in the existing PCOS literature. Recommendations for future researchers interested in measuring HRQoL outcomes in women with PCOS-associated infertility are also made.

Plasma homocysteine concentrations and the single nucleotide polymorphisms in the methionine synthase gene (MTR 2756A>G): Associations with the polycystic ovary syndrome An observational study.

BACKGROUND: Elevated plasma homocysteine (Hcy) is a recognized risk factor for cardiovascular disease (CVD) and other defects. Biochemical and genetic studies have characterized molecular determinants contributing to alter Hcy metabolism. The vitamin B12 dependent enzyme methionine synthase (MTR) regulates de novo production of methionine from homocysteine. Defects in the activity of this enzyme may possibly predispose to higher plasma Hcy concentrations. STUDY DESIGN: We examined the associations between plasma Hcy concentrations and a single nucleotide polymorphism (SNP) in the MTR gene (MTR 2756A>G), and plasma folate concentrations, in 71 women (Caucasian and South Asian) attending a fertility clinic. We also determined the ethnic variations in the frequencies of the 3 genotypes of the MTR 2756 A>G gene. RESULTS: The frequency of the variant G allele was similar in the Caucasians and the South Asians (OR: 1.83; 95% CI: 0.79-4.23, p=0.2). The frequency was also similar in the PCOS and non-PCOS groups (OR: 0.88; 95% CI: 0.39-1.99). Plasma Hcy levels were significantly higher in women with PCOS compared with non-PCOS controls (p=0.05) and in Caucasian women with PCOS compared with Caucasian controls (p=0.04) in the presence of the MTR 2756 AA genotype (wild type). After adjusting for age, BMI, waist circumference and ethnicity, the significant predictors of plasma Hcy concentrations were plasma LDL, whole blood folate concentrations and a clinical diagnosis of PCOS. CONCLUSIONS: The important predictors of plasma Hcy concentration in women of reproductive age are whole blood folate concentrations, a background of PCOS and plasma LDL concentrations. The SNP 2756 A>G in the MTR gene does not appear to influence the plasma Hcy levels.