Dehydroepiandrosterone (DHEA) role in enhancement and maintenance of implantation (DREAM): randomised double-blind placebo-controlled trial-study protocol.

INTRODUCTION: Dehydroepiandrosterone (DHEA) is an important precursor of androgen and has been studied and researched extensively for improving the various outcome measures of ovarian stimulation in women with advanced age or poor ovarian response. Androgens also play an important role in the enhancement of endometrial and decidual function by regulating both the transcriptome and secretome of the endometrial stromal cells and have a positive effect on various factors like insulin-like growth factor binding protein 1, homeobox genes (HOXA10, HOXA11), secreted phosphoprotein 1, prolactin which are necessary for implantation. It is well-known that the circulating 'precursor pool' of DHEA declines with age more so in poor ovarian reserve patients and exogenous supplementation may be beneficial in such cases. This double-blinded randomised controlled trial (RCT) aims to test the hypothesis whether transient targeted supplementation of DHEA as an adjuvant to progesterone in frozen embryo transfer (FET) cycles, for women with low serum testosterone, helps in improving live birth rate. METHODS AND ANALYSIS: This study is planned as a double-blinded, placebo-controlled randomised trial and the sample size, calculated for the primary outcome measure-live birth rate, is 140. All participants will be having a flexible antagonist protocol for controlled ovarian stimulation and an elective freeze-all policy for the embryos as per the hospital protocol after written informed consent. For FET, the endometrium will be prepared by hormone replacement treatment protocol. During the FET cycle, the intervention group will be receiving DHEA 25 mg two times a day for 15 days from the day of starting progesterone supplementation and the control group will be receiving a placebo. ETHICS AND DISSEMINATION: The approval of the study was granted by the Clinical Trials Registry-India and the Institutional Ethical Committee of CRAFT Hospital and Research Center. All participants will provide written informed consent before being randomised into allocated treatment groups. The results will be disseminated to doctors and patients through conference presentations, peer-reviewed publications, social media and patient information booklets. TRIAL REGISTRATION NUMBERS: CTRI/2020/06/025918; ECR/1044/Inst/KL/2018.

The impact of uterine artery embolization on ovarian reserve: A systematic review and meta-analysis.

INTRODUCTION: Uterine artery embolization (UAE) has been gaining increasing popularity as an effective and minimally invasive treatment for uterine fibroids. However, there has been growing concern over the risk of unintended embolization of the utero-ovarian circulation, leading to reduction of ovarian blood supply with subsequent impairment of ovarian reserve. The purpose of this study was to investigate the impact of UAE on circulating anti-Müllerian hormone (AMH) and other markers of ovarian reserve. MATERIAL AND METHODS: This meta-analysis included all published cohort, cross-sectional and case-control studies, as well as randomized trials that investigated the impact of UAE on circulating AMH. Data sources included MEDLINE, EMBASE, Dynamed Plus, ScienceDirect, TRIP database, ClinicalTrials.gov and the Cochrane Library from January 2000 to June 2019. All identified articles were screened, and articles were selected based on the inclusion and exclusion criteria. AMH and other data were extracted from the eligible articles and entered into RevMan software to calculate the weighted mean difference between pre- and post-embolization values. PROSPERO registration number: CRD42017082615. RESULTS: This review included 3 cohort and 3 case-control studies (n = 353). The duration of follow up after UAE ranged between 3 and 12 months. Overall pooled analysis of all studies showed no significant effect of UAE on serum AMH levels (weighted mean difference -0.58 ng/mL; 95% CI -1.5 to 0.36, I2  = 95%). Subgroup analysis according to age of participants (under and over 40 years) and according to follow-up duration (3, 6 and 12 months) showed no significant change in post-embolization circulating AMH. Pooled analysis of serum follicle-stimulating hormone (FSH) concentrations (4 studies, n = 248) revealed no statistically significant change after UAE (weighted mean difference 4.32; 95% CI -0.53 to 9.17; I2  = 95%). Analysis of 2 studies (n = 62) measuring antral follicle count showed a significant decline at 3-month follow up (weighted mean difference -3.28; 95% CI -5.62 to -0.93; I2  = 94%). CONCLUSIONS: Uterine artery embolization for uterine fibroids does not seem to affect ovarian reserve as measured by serum concentrations of AMH and FSH.

Effect of transfer of a poor quality embryo along with a top quality embryo on the outcome during fresh and frozen in vitro fertilization cycles.

OBJECTIVE: To evaluate the impact of a poor quality embryo (PQE) during double ET (DET) with a top quality embryo (TQE) on IVF outcome. DESIGN: A review of prospectively collected data. SETTING: Tertiary level fertility clinic. PATIENT(S): All patients undergoing blastocyst transfers as part of fresh IVF (n = 939) and frozen ET (n = 1,009) cycles performed between 2010 and 2016. INTERVENTION(S): Single ET (SET) with TQE (group 1) was set as control and compared with outcomes for SET with PQE (group 2), DET with 2 TQEs (group 3), PQE plus TQE (group 4), and 2 PQE (group 5). MAIN OUTCOME MEASURE(S): Live births and multiple births. RESULT(S): The live birth rates for group 4 were statistically similar to group 1 during fresh IVF (26.5% vs. 33.7%; odds ratio [OR], 0.95; 95% confidence interval [CI] 0.53-1.7) and frozen ET (24.2% vs. 32.7%; OR, 0.75; 95% CI 0.48-1.2), although there was a trend for lower success. Conversely, multiple births were higher in group 4 for fresh IVF (19% vs. 4.7%; OR, 2.9; 95% CI 1.3-6.6) and frozen ET (10.3% vs. 2.6%; OR, 2.4; 95% CI 1.2-4.9). The live birth rates for group 2 (12.2% for fresh IVF and 14.6% for frozen ET) and group 5 (21.2% for fresh IVF and 14% for frozen ET) were lower and for group 3 were higher (40.8% for fresh IVF and 40.3% for frozen ET) when compared with group 1. Multiple births were significantly higher with DET. CONCLUSION(S): This study does not support DET with one PQE along with a TQE, when there is only one TQE and one or more PQEs available for fresh IVF or frozen ET.

Efficacy of Dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): A proof of principle double blinded randomized placebo controlled trial.

OBJECTIVE: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates. STUDY DESIGN: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by "intention to treat". Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups. RESULTS: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P=0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P<0.01). The number (median, range) of oocytes retrieved (4, 0-18 versus 4, 0-15 respectively; P=0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups. CONCLUSION: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR.

Assessment of the uterus with three-dimensional ultrasound in women undergoing ART.

BACKGROUND: A detailed assessment of the uterus forms a pivotal part of the ART treatment process. The emergence of three-dimensional ultrasound (3D US) has provided clinicians with a highly powerful tool in this respect. Assessments with 3D US range from the reconstruction of anatomical planes elusive to conventional US, to the objective measurement of anatomical volumes and vascularization parameters. However, despite the ever increasing number of publications emerging in the literature, the question of which aspects of 3D US are of most clinical value remains a topic of debate. OBJECTIVE AND RATIONALE: The objective of this review is to dissect which aspects of the 3D US assessment of the uterus are supported by a strong level of evidence to date, and should therefore be incorporated into current routine clinical practice. SEARCH METHODS: We conducted a systematic search of the PubMed database up to May 2016, using a combination of text words and Medical Subject Headings (MeSH) pertaining to the 3D US assessment of the uterus. All articles published in the English language were screened to ascertain relevance to women of reproductive age; further citations were retrieved through manual reference list searching. OUTCOMES: A multitude of predominantly observational studies were identified, which concerned a vast variety of 3D US uterine assessments. All articles unequivocally praised the non-invasive, cost-effective, highly acceptable and objective nature of 3D US. Studies regarding the value of assessing the endometrial volume and vascularization prior to embryo transfer appeared conflicting and inconsistent. Studies regarding the imaging of uterine pathology and identification of intratubal and intrauterine devices consistently reported high rates of diagnostic accuracy. A recent RCT did not show an improvement in clinical outcomes when comparing 3D versus 2D US during embryo transfer. However, preliminary studies suggested that 3D US is superior in determining the site of implantation, particularly in ambiguous cases such as interstitial and angular pregnancies. Finally, pilot studies have suggested that the further integration of 3D and possibly 4D US with surgical interventions of the uterus may be a promising prospect. WIDER IMPLICATIONS: 3D US may prove to be an invaluable tool in the assessment of the uterus within the context of ART. Currently, the aim should be to highlight the aspects of 3D US that are most evidence-based and valuable for patients, and to incorporate these into routine clinical practice.

Heparin for assisted reproduction: summary of a Cochrane review.

It is suggested that heparin given in the peri-implantation period may improve clinical outcomes in women undergoing assisted reproduction techniques (ART). This systematic review evaluates the use of heparin in subfertile women undergoing ART.

Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol.

INTRODUCTION: Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This double-blinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve. METHODS AND ANALYSIS: Sixty women with ovarian antral follicle count ≤10 and serum anti-Mullerian hormone ≤5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75 mg/day or placebo for at least 12 weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300 IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6-8 weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study. ETHICS AND DISSEMINATION: The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups. TRIAL REGISTRATION NUMBER: Protocol V.2.0; EudraCT number: 2011-002425-21; http://www.clinicaltrials.gov; NCT01572025; CTA reference: 03057/0053/001-0002.

Surgical intervention versus expectant management for endometrial polyps in subfertile women.

BACKGROUND: Endometrial polyps, which are benign growths of the endometrium, may be a factor in female subfertility. Possible mechanisms include physical interference with gamete transport, alteration of the endometrial milieu and unresponsiveness to the cyclical global endometrial changes. As such polyps remain mostly asymptomatic, their diagnosis is often incidental during routine investigations prior to embarking on assisted reproductive treatment. Transvaginal sonography, hysterosalpingography and saline infusion sonography are the diagnostic tools most commonly employed. However, hysteroscopy remains the gold standard for diagnosis, as well as for treatment. Due to the possible effect of endometrial polyps on fertility, their removal prior to any subfertility treatment is widely practiced. OBJECTIVES: To determine the effectiveness and safety of removal of endometrial polyps in subfertile women. SEARCH METHODS: Electronic databases were searched, including the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL and trial registers. The reference lists of identified articles were checked. The last search was performed on 30 July 2014. SELECTION CRITERIA: Only randomised controlled trials, reporting pregnancy or live birth rates and complication rates as primary or secondary outcomes, in which polyps were removed surgically prior to treatment of subfertility were eligible for inclusion. The diagnosis of endometrial polyps was required to be made by transvaginal ultrasound, hysterosalpingography, saline infusion, sono-hysterography or hysteroscopy. Any surgical technique of polyp removal was acceptable, with no intervention in the control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles, abstracts and full articles to assess their suitability for inclusion in this review. Quality assessment was attempted independently by two authors with discrepancies being settled by consensus or consultation with a third review author.No data extraction was performed due to the absence of useable data in the one eligible study. If there had been data to include, two review authors would have independently extracted the data from the studies using a data extraction form designed and pilot tested by the authors. Any disagreements would have been resolved by discussion or by a third review author. MAIN RESULTS: Only one randomised controlled trial of endometrial polypectomy was identified for inclusion. However, a single set of data could not be extracted from this study due to internal inconsistencies of the results reported. Attempts to contact the authors to resolve the issue were unsuccessful, by phone, post and e-mail. AUTHORS' CONCLUSIONS: Removal of endometrial polyps in subfertile women is commonly being performed in many countries with an aim to improve the reproductive outcome. We did not identify any analysable randomised trials which would allow us to reach any sound scientific conclusions on the efficacy of endometrial polypectomy in subfertile women. Well designed, methodologically sound, randomised controlled trials are urgently needed.

Assessment of endometrial and subendometrial blood flow in women undergoing frozen embryo transfer cycles.

This study evaluated whether 3D power Doppler (3DPD) indices from endometrium and subendometrium can identify increases in endometrial volume/vascularity induced by exogenous oestradiol and subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET). Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets were acquired at down-regulation, on days 5, 10 and 15 of oestradiol administration and at the time of FET. Endometrial thickness was measured using the multiplanar method and endometrial volume and blood flow from the endometrium and subendometrium were estimated using virtual organ computer-aided analysis and shell-imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant. 3DPD angiography is not a sufficiently sensitive tool to predict the outcome of FET. We evaluate whether 3D ultrasound using power Doppler (3DPD) indices from endometrium and subendometrium can identify predictable increases in endometrial volume and vascularity induced by serial increments in exogenous oestradiol and the subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET) using hormone replacement therapy to prepare the endometrium. Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets of the uterus were acquired at down-regulation, on days 5, 10, and 15 of oestradiol administration, and at the time of FET. Endometrial thickness was measured. Endometrial volume and blood flow from the endometrium and subendometrium were measured using virtual organ computer-aided analysis (VOCAL) and shell imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all the parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant, suggesting that quantitative 3D power Doppler angiography is not a sufficiently sensitive tool to predict the outcome of FET treatment.

Heparin for assisted reproduction.

BACKGROUND: Heparin as an adjunct in assisted reproduction (peri-implantation heparin) is given at or after egg collection or at embryo transfer during assisted reproduction. Heparin has been advocated to improve embryo implantation and clinical outcomes.  It has been proposed that heparin enhances the intra-uterine environment by improving decidualisation with an associated activation of growth factors and a cytokine expression profile in the endometrium that is favourable to pregnancy. OBJECTIVES: To investigate whether the administration of heparin around the time of implantation (peri-implantation heparin) improves clinical outcomes in subfertile women undergoing assisted reproduction. SEARCH METHODS: A comprehensive and exhaustive search strategy was developed in consultation with the Trials Search Co-ordinator of the Cochrane Menstrual Disorders and Subfertility Group (MDSG). The strategy was used in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). Relevant trials were identified from both electronic databases and other resources (last search 6 May 2013). SELECTION CRITERIA: All randomised controlled trials (RCTs) were included where peri-implantation heparin was given during assisted reproduction. Peri-implantation low molecular weight heparin (LMWH) during IVF/ICSI was given at or after egg collection or at embryo transfer in the included studies. Live birth rate was the primary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of trials and extracted relevant data. The quality of the evidence was evaluated using GRADE methods. MAIN RESULTS: Three RCTs (involving 386 women) were included in the review.Peri-implantation LMWH administration during assisted reproduction was associated with a significant improvement in live birth rate compared with placebo or no LMWH (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.07 to 2.90, three studies, 386 women, I(2) = 51%, very low quality evidence with high heterogeneity). There was also a significant improvement in the clinical pregnancy rate with use of LMWH (OR 1.61, 95% CI 1.03 to 2.53, three studies, 386 women, I(2) = 29%, very low quality evidence with low heterogeneity).However these findings should be interpreted with extreme caution as they were dependent upon the choice of statistical method: they were no longer statistically significant when a random-effects model was used.Adverse events were poorly reported in all included studies, with no comparative data available. However, LMWH did cause adverse effects including bruising, ecchymosis, bleeding, thrombocytopenia and allergic reactions. It appeared that these adverse effects were increased if heparin therapy was used over a longer duration. AUTHORS' CONCLUSIONS: The results of this Cochrane review of three randomised controlled trials with a total of 386 women suggested that peri-implantation LMWH in assisted reproduction treatment (ART) cycles may improve the live birth rate in women undergoing assisted reproduction. However, these results were dependent on small low quality studies with substantial heterogeneity, and were sensitive to the choice of statistical model. There were side effects reported with use of heparin, including bruising and bleeding, and no reliable data on long-term effects. The results do not justify this use of heparin outside well-conducted research trials.These findings need to be further investigated with well-designed, adequately powered, double-blind, randomised, placebo-controlled, multicentre trials. Further investigations could also focus on the effects of the local (uterine) and not systemic application of heparin during ART.

Efficacy of dehydroepiandrosterone to improve ovarian response in women with diminished ovarian reserve: a meta-analysis.

Women with diminished ovarian reserve often respond poorly to controlled ovarian stimulation resulting in retrieval of fewer oocytes and reduced pregnancy rates. It has been proposed that pre-IVF Dehydroepiandrosterone (DHEA) adjuvant therapy may improve ovarian response and pregnancy rates in women with diminished ovarian reserve. This meta-analysis aims to investigate efficacy of DHEA as an adjuvant to improve ovarian response and IVF outcome in women with diminished ovarian reserve. Electronic databases were searched under the following terms: (DHEA) and (diminished ovarian reserve) and/or (poor response). Studies were included if they reported at least one of the following outcomes; clinical pregnancy rate, number of oocytes retrieved, miscarriage rate. We identified 22 publications determining effects of DHEA in clinical trials. Only 3 controlled studies were eligible for meta-analysis. There was no significant difference in the clinical pregnancy rate and miscarriage rates between women pre-treated with DHEA compared to those without DHEA pre-treatment (RR 1.87, 95% CI 0.96-3.64; and RR 0.59, 95% CI 0.21-1.65, respectively). The number of oocytes retrieved (WMD -1.88, 95% CI -2.08, 1.67; P < 0.001) was significantly lower in the DHEA group. In conclusion, based on the limited available evidence from a total of approximately 200 IVF cycles, there are insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation in IVF cycle. Well-designed, randomised controlled trials as well as more exact knowledge about DHEA mechanisms of action are needed to support use of DHEA in standard practice for poor-responders.

Aspirin and heparin as adjuvants during IVF do not improve live birth rates in unexplained implantation failure.

This study tested the hypothesis that using aspirin and/or heparin as adjuvants in IVF improves the treatment outcome. This retrospective cohort-control study recruited 234 consecutive subjects aged ≤ 44 years who had previously had one or more unsuccessful IVF cycle. All underwent IVF using conventional protocols. The study group received aspirin and/or heparin post embryo transfer until the day of pregnancy test or until 12 weeks of pregnancy. The control group did not receive adjuvant treatment. The outcome measures were live birth, clinical pregnancy and miscarriage rates. The outcomes were compared by chi-squared test and relative-risk analysis. Analysis was performed in 206 subjects. There was no statistically significant difference in the live birth rate (35.0%, 36/103 versus 47.6%, 49/103), clinical pregnancy rate (40.8%, 42/103 versus 53.4%, 55/103) and miscarriage rate (14.3%, 6/42 versus 10.9%, 6/55) between the study group and the control group. The data in this study show that low-dose aspirin and/or heparin as adjuvant therapies during IVF do not improve live birth rates in an unselected group of subfertile women who have previously had one or more unexplained implantation failure following IVF.

Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women.

OBJECTIVE: To estimate the probability of live birth, adverse treatment outcome, and extremes of ovarian response at different antral follicle count (AFC) cutoff levels in a large prospective cohort of women undergoing IVF treatment. DESIGN: Prospective study. SETTING: University-based assisted conception unit. PATIENT(S): A total of 1,012 consecutive subjects of all ages undergoing their first cycle of assisted reproductive techniques. INTERVENTION(S): Transvaginal three-dimensional ultrasound assessment and venipuncture in the early follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Live birth rate, poor ovarian response, and ovarian hyperstimulation syndrome (OHSS). RESULT(S): Analysis was performed in 1,012 subjects. Both age (r = 0.88) and AFC (r = 0.92) thresholds show significant linear relationship with the probability of live birth, but AFC demonstrates a stronger correlation. At AFC quartiles of 3-10, 11-15, 16-22, and ≥23, the mean live birth rates were 23%, 34%, 39%, and 44%, respectively. No live birth was observed in women with AFC <4. Antral follicle count was predictive of ovarian response, with a 67% likelihood of poor ovarian response for AFC ≤4. Although the risk of moderate or severe OHSS is 2.2% with AFC of ≤24, the risk increases to 8.6% at AFC of ≥24. The risk of OHSS increases further to 11% if there are signs and symptoms of polycystic ovary syndrome. CONCLUSION(S): Although age and AFC are significantly correlated with live birth, AFC demonstrates a stronger correlation. Antral follicle count thresholds are useful to predict live birth rates and risks of poor ovarian response and OHSS during IVF treatment.

Doppler imaging in the diagnosis of ovarian disease.

INTRODUCTION: Pelvic ultrasonography remains the non-invasive imaging modality of choice for detecting and characterising adnexal masses. The use of Doppler ultrasound has improved the differential diagnosis of ovarian disease and helped to widen the understanding of the aetiology and possible pathophysiology of the various underlying conditions with an aim of improved diagnosis and management. AREAS COVERED: This review describes the basis of different Doppler techniques and their application in ovarian disease. The present evidence is critically analysed in an attempt to define the current role of Doppler ultrasound of the ovaries. The technique holds promise in certain ovarian diseases but remains controversial in others. EXPERT OPINION: Doppler ultrasound has a role in both the clinical and research settings. Clinically, it can be used to differentiate benign and malignant disease and help confirm diagnoses suggested on grey-scale imaging giving the user more confidence. Its use here, however, is generally restricted to a subjective impression of colour flow rather than a quantitative analysis of vascularity or blood flow velocity. These measures are more relevant in the research setting where quantitative Doppler is being used to clarify the possible underlying aetiology of various ovarian diseases such as polycystic ovarian syndrome and benign cysts. Doppler ultrasound has also been used in various models to evaluate the response to ovarian stimulation and the effect of surgery on the ovary.

Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial.

BACKGROUND: Women with ovaries of polycystic morphology (PCO), without any other features of polycystic ovary syndrome (PCOS), respond similarly to women with PCOS when stimulated with exogenous gonadotrophins, and both groups share various endocrinological disturbances underlying their pathology. In women with PCOS, metformin co-treatment during IVF has been shown to increase pregnancy rates and reduce the risk of ovarian hyperstimulation syndrome (OHSS). The aim of this study was to investigate whether metformin co-treatment before and during IVF can also increase the live birth rate (LBR) and lower severe OHSS rates for women with PCO, but no other manifestations of PCOS. METHODS: This study was a double-blind, multi-centre, randomized, placebo-controlled trial. The study population included 134 women with ovulatory PCO (and no evidence of clinical or biochemical hyperandrogenism) undergoing IVF treatment at three tertiary referral IVF units. The primary outcome was LBR. RESULTS: In total, 134 women were randomized, 69 to metformin and 65 to placebo. There were no statistically significant differences between the two groups in baseline characteristics. With regard to IVF outcome, no significant improvements were found in the metformin group when compared with the placebo group. In particular, there was no difference between the groups in rates of live birth [metformin n = 27 (39.1%), placebo n = 30 (46.2), (95% confidence interval 0.38, 1.49, odds ratio = 0.75)], clinical pregnancy [metformin n = 29 (42.0%), placebo n = 33 (50.8%)] or severe OHSS [metformin n = 6 (8.7%), placebo n = 5 (7.7%)]. CONCLUSIONS: There appears to be no benefit in metformin co-treatment before and during IVF in women with PCO without any other features of PCOS. Clinical Trials.gov: NCT01046032.

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study.

OBJECTIVE: To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN: Retrospective cohort analysis. SETTING: Fifteen academic reproductive centers. PATIENT(S): A total of 3,871 infertile women. INTERVENTION(S): Blood sampling for AMH level. MAIN OUTCOME MEASURE(S): Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S): Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S): Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

Do ovarian reserve tests predict miscarriage in women undergoing assisted reproduction treatment?

OBJECTIVE: To evaluate the role of ovarian reserve tests for the prediction of miscarriage among pregnancies resulting from assisted reproduction treatment. STUDY DESIGN: Cohort study in a large IVF centre. Three hundred and fourteen women aged <43 years with basal FSH <12 IU/L who conceived following their first cycle of IVF/ICSI were included. Sixty-seven participants experienced miscarriage while the remaining 247 had ongoing pregnancies. Intervention included transvaginal scan and venepuncture on day 3 of the menstrual cycle immediately prior to treatment. Ovarian reserve parameters assessed were antral follicle count (AFC), FSH, basal oestradiol and oestradiol response. The main outcome measure was miscarriage rate (pregnancy loss at <12 weeks). RESULTS: While the baseline clinical characteristics including age and duration of subfertility were comparable, BMI was significantly higher in women who experienced miscarriage compared to those having ongoing pregnancies. Among the ovarian reserve markers studied, only the AFC was significantly different between the miscarriage and pregnant groups. Logistic regression analysis revealed that only these two markers (BMI and AFC) were the significant predictors of clinical miscarriage. However, the discriminative ability of both BMI and AFC for the prediction of miscarriage was low as indicated by AUCs of 0.617 and 0.588 respectively on ROC curve analysis. CONCLUSION: While AFC and BMI are significantly predictive of first trimester miscarriage, the ability of these markers individually or in combination to discriminate women who experience miscarriage from those who continue the pregnancy beyond 12 weeks of gestation is poor.

A novel technique for the semi-automated measurement of embryo volume: an intraobserver reliability study.

The aim was to assess intraobserver reliability of a new semi-automated technique of embryo volumetry. Power calculations suggested 46 subjects with viable, singleton pregnancies were required for reliability analysis. Crown rump length (CRL) of each embryo was analyzed using 2-D and a 3-D dataset acquired using transvaginal ultrasound. Virtual organ computer-aided analysis (VOCAL) was used to calculate volume of gestation sac (GSV) and yolk sac (YSV) and SonoAVC (sonography-based automated volume count) was used to quantify fluid volume (FV). Embryo volume was calculated by subtracting FV and YSV from GSV. Each dataset was measured twice. Reliability was assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs). Fifty-two datasets were analyzed. Median embryo volume was 1.8 cm(3) (0.1 to 8.1 cm(3)); median gestational age 7 + 4 weeks; median CRL 13 mm (2 to 29 mm). Mean difference of embryo volume measurements was 0.1cm(3) (limits of agreement [LOA] -0.3 to 0.4 cm(3)); multiples of mean (MoM) 0.38; mean difference of CRL measurements 0.3 mm (LOA -1.4 to 2.0 mm), MoM = 0.26. ICC for embryo volume was 0.999 (95%CI 0.998 to 0.999), confirming excellent intraobserver agreement. ICC for CRL was 0.996 (95%CI 0.991 to 0.998). Regression analysis showed good correlation between embryo volume and CRL (R(2) = 0.60). The new semi-automated 3-D technique provides reliable measures of embryo volume. Further work is required to assess the validity of this technique.

The cohort of antral follicles measuring 2-6 mm reflects the quantitative status of ovarian reserve as assessed by serum levels of anti-Müllerian hormone and response to controlled ovarian stimulation.

OBJECTIVE: To evaluate the relationship between serum anti-Müllerian hormone (AMH) and antral follicle size, and to ascertain which cohort of antral follicles is most predictive of the response to controlled ovarian stimulation during assisted reproduction treatment (ART). DESIGN: Prospective study. SETTING: University-based Assisted Conception Unit. PATIENT(S): One hundred thirteen women undergoing first cycle of ART. INTERVENTION(S): Transvaginal 3D-ultrasound assessment and venipuncture in the early-follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Serum AMH levels, number of mature oocytes retrieved and poor ovarian response. RESULT(S): The antral follicle cohorts measuring 2 to 3 mm, >3 to 4 mm, >4 to 5 mm, and >5 to 6 mm were most significantly correlated with AMH (r = .30, .27, .30, and .41, respectively) and the number of mature oocytes retrieved (r = .28, .23, .29, and .34, respectively). Although these follicle cohorts of 2-6 mm were significant predictors of the number of mature oocytes retrieved on regression analysis, their discriminative ability (area under the curve [AUC]: 0.829) for the prediction of poor ovarian response was similar to total counts made using cohorts of 2 to 4 mm, 2 to 5 mm, 2 to 8 mm, and 2 to 10 mm (AUCs: 0.794, 0.812, 0.852, and 0.826, respectively). CONCLUSION(S): The number of antral follicles measuring 2 to 6 mm is most reflective of the quantitative ovarian reserve. However, the ability of this group of antral follicles to predict poor ovarian response appears similar to that of the follicular cohorts of 2 to 4 mm, 2 to 5 mm, 2 to 8 mm, and 2 to 10 mm.