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The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide.

Is there any difference in clinical outcomes between a human chorionic gonadotrophin (HCG)-only trigger and a dual trigger combining gonadotrophin-releasing hormone agonist (GnRHa) and HCG in a progestin-primed ovarian stimulation (PPOS) protocol?This retrospective cohort study included women younger than 40 years old with a normal ovarian reserve who underwent IVF/intracytoplasmic sperm injection treatment with a PPOS protocol. Participants were allocated to two groups according to the triggering medicines. The clinical outcomes were compared, with cumulative live birth rate (CLBR) being the primary outcome.In total, 1066 women were included, 565 in the HCG-only group and 501 in the dual trigger group. Demographic parameters were comparable between the groups. Fewer oocytes were retrieved in the HCG-only trigger group (dual trigger 12.56 ± 7.12 versus HCG-only trigger 11.62 ± 6.02, P = 0.020). No significant difference was observed in the numbers of two-pronuclear embryos (7.12 ± 4.90 versus 6.76 ± 4.45, P = 0.208) and high-quality embryos (4.01 ± 3.70 versus 3.96 ± 3.32, P = 0.815). The CLBR after one complete cycle was also similar (40.72% versus 43.72%, P = 0.354). Multivariate logistic analysis confirmed that the trigger method had no association with CLBR (odds ratio [OR] 0.763, 95% confidence interval [CI] 0.578-1.005, P = 0.055) in the PPOS-treated patients.Compared with the HCG-only trigger group, comparable embryological and clinical outcomes were achieved, although more oocytes were retrieved in the dual trigger group. This suggests that there may be no extra benefit from dual triggering, and that it should not be recommended for routine use in the general population undergoing PPOS protocols.

What is the effect of letrozole use in patients undergoing frozen embryo transfer (FET) with normal ovulation? Although the number of FETs is increasing, an optimal protocol for FET (particularly vitrified-warmed embryo transfer) is yet to be determined. The aim of this study was to evaluate letrozole use on patients with normal menstrual cycles compared with hormone replacement therapy (HRT) cycles and natural cycles.The study involved 2849 patients. Patients were divided into three groups: HRT cycle (n = 2115), letrozole cycle (n = 532) and natural cycle (n = 202). Inverse probability of treatment weighting aimed to equate each group according to measured baseline covariates to achieve a comparison with reduced selection bias and live birth rate as main pregnancy outcome was analysed.In the crude analysis, the letrozole group had a higher live birth rate compared with the HRT cycle (OR 1.18, 95% CI 1.06 to 1.33) and natural cycle (OR 1.24, 95% CI 1.11 to 1.41); after adjusting for confounding factors, live birth rate was consistently higher in the letrozole group. Moreover, the biochemical pregnancy, clinical pregnancy, ongoing pregnancy and full-term delivery rates were higher in the letrozole group.For infertile women with normal menstrual cycle undergoing FET, mildly stimulated cycles with letrozole present a relatively large advantage compared with HRT cycle and natural cycle, with higher live birth pregnancy, indicating that letrozole administration could improve pregnancy outcomes in this population.

It was suggested in the 1980s that long-term pituitary down-regulation by a gonadotrophin-releasing hormone agonist, termed the ultra-long protocol, inducing a hypo-oestrogenic state, might improve reproductive outcomes in women with endometriosis. Subsequently, international guidelines strongly supported the long-term pituitary down-regulation protocol in women with endometriosis based on a Cochrane review from 2006. The recently published European Society for Human Reproduction and Embryology guideline, based on the updated Cochrane review from 2019 and newer evidence, has reversed this recommendation. This paper explores the past and current evidence that led to these recommendations and calls for a consideration of refinement of the international guidelines to include additional factors and evaluate whether a paradigm shift is needed in the approach to endometriosis-related infertility. We believe that this can optimize evidence-based patient-centred care and benefit women worldwide and improve the design of future studies.

What is the blastocyst conversion rate in embryo cryopreservation cycles, per year of female age?Retrospective cohort study including patients undergoing their first ovarian stimulation cycle at our center with planned freeze-all strategy January 1st, 2014-June 30th, 2020. Primary outcome was blastocyst conversion rate. Secondary outcomes included mature oocyte and fertilization rates. Patients were stratified by year of age to assess oocyte yield and embryo development outcomes.3,362 patients were included. The median blastocyst conversion rate in patients ≤30 was 66.7% (interquartile range 50.0-86.6) and remained statistically comparable through age 40 with a significant decline among ages ≥41 (41-years: marginal effect (ME) -5.2% (-9.7 to -0.7); 42-years: ME -9.6% (-14.3 to -4.8); 43-years: ME -7.7% (-12.8 to -2.6); ≥44-years: ME -20.8% (-26.5 to -15.1)). For the entire cohort, the median mature oocyte rate was 81.8% and the median fertilization rate was 81.8%. The mature oocyte and fertilization rates remained statistically comparable for each year of age except age ≥44 which had a statistically significantly increased mature oocyte rate (ME 4.4% (1.3 to 7.5)) and statistically significantly decreased fertilization rate (ME -5.8% (-9.8 to -1.9)) CONCLUSIONS: In embryo cryopreservation cycles, the blastocyst conversion rate remained statistically comparable through age 40 followed by a statistically significant decline for patients ≥41; however, the mature oocyte and fertilization rates were not impacted by increasing age until age ≥44. Even in women ≥44, over 40% of fertilized oocytes developed to blastocyst. Overall, this information is useful when counseling patients during the embryo culture stage regarding predicted blastocyst yield.

The IVF Lite programme is based on mild ovarian stimulation including up to three fresh/frozen embryo transfers within 12 months. Is it effective and safe in good prognosis patients?Single-centre prospective study on infertile patients at their first IVF attempt (female age ≤38 years, anti-Müllerian hormone concentrations1.5 ng/ml and/or FSH ≤10 mIU/ml). Induction of multiple follicular growth was based on a fixed protocol consisting of clomiphene citrate (100 mg/day) from day 3 to 7 of the menstrual cycle and 150 IU of recombinant FSH on days 5, 7 and 9. In case of low follicular recruitment (fewer than four follicles), the cycle was cancelled. The IVF Lite programme was considered complete after a live birth delivery or up to three embryo transfers within 12 months. The primary outcome was the cumulative live birth rate (cLBR) per couples that completed the programme.A total of 369 patients completed the IVF Lite programme, with 239 live births; 132 patients delivered after one embryo transfer (35.8%), 70 after a second embryo transfer (cLBR 54.7%), and 37 after a third attempt (cLBR 64.8%). No cases of ovarian hyperstimulation syndrome or clinical complications occurred. Spontaneous dropout rate from the programme was 4.5%. The cLBR per intention to treat was 46.8%.The IVF Lite programme proved to be effective and safe in good prognosis patients with a good response to clomiphene citrate stimulation. It was well tolerated and implied low gonadotrophin consumption. Two-thirds of the patients achieved a live birth at the completion of the programme.

The detrimental effects of endometriosis on IVF success are well known, but the underlying mechanisms are still uncertain. The objective of this study was to investigate the possible detrimental effects of the disease on ovarian response and embryo development.IVF cycles performed in the authors' unit between 2014 and 2020 were retrospectively reviewed. Women with a good ovarian reserve who underwent their first IVF cycle were included. A total of 248 women with endometriosis were identified and matched to 248 women without the disease, according to age, type of stimulation, anti-Müllerian hormone concentration and study period. The primary outcome was the number of women without good-quality embryos. Secondary outcomes included the rate of unexpected poor response (retrieval of ≤3 oocytes), the cumulative clinical pregnancy rate and the cumulative live birth rate.The number of women without good-quality embryos did not differ between women with endometriosis (exposed group) and those without it (unexposed group). The adjusted odds ratio was 0.85 (95% CI 0.51-1.44, P = 0.56). The clinical pregnancy rate and the live birth rate were also similar. Conversely, the rate of unexpected poor response was higher among women with endometriosis (23% versus 13%, P = 0.005).Overall, endometriosis does not markedly affect folliculogenesis and embryo development in the context of IVF. Only an increased risk of unexpected poor response emerged.

Research question: What is the influence of ethnicity on the outcome of ovulation induction with clomifene citrate in women with polycystic ovary syndrome (PCOS)? Design: This was a retrospective cohort study. In total, 420 women diagnosed with PCOS who were of Northern European, Mediterranean, African, South-East Asian or South American descent, and who started ovulation induction treatment with clomifene citrate, were included. All women were treated with clomifene citrate according to a standardized treatment regimen. The minimal effective dose of clomifene citrate and prevalence of clomifene resistance (CRA) were assessed, and the chance of becoming ovulatory was predicted. Results: Differences were observed in body mass index (P = 0.008), waist circumference (P = 0.036) and serum LH, insulin and androgen concentrations (all P < 0.001) in women of different ethnicities with PCOS. Compared with women of Northern European descent, the minimal effective dose of clomifene citrate in women of other ethnic groups was not significantly different. The prevalence of CRA (P = 0.574) was similar in all ethnic groups A similar chance of ovulation (P = 0.504) was predicted for the different ethnic groups. Conclusions: This is the first study aiming to link ethnicity to ovulation induction outcome in PCOS. Although women of different ethnicities who have PCOS exhibit a variation in phenotypic expression, there do not appear to be differences in the prevalence of clomifene-resistant anovulation or the minimal effective dose of clomifene citrate. Furthermore, a prediction model revealed no significant differences in the predicted chance of ovulation. A larger cohort is needed to validate these findings.

Letrozole reduces serum oestradiol by inhibiting the aromatase enzyme and has growing clinical indications in fertility. The available evidence of letrozole's role in ovarian stimulation for IVF and intracytoplasmic sperm injection (ICSI) and clinical outcomes was assessed. Medline, Cochrane, and ClinicalTrials.gov databases were systematically searched up until August 2021, including 31 studies (n = 16 randomized controlled trials [RCTs]; n = 15 observational studies). Live birth rate (LBR) in poor responders significantly increased by 7% (95% CI, 1% to 13%, P = 0.03) with letrozole co-treatment. Concomitantly, the gonadotrophin consumption was significantly reduced, without decreasing the number of retrieved oocytes. In normal responders, number of oocytes increased with 1.8 oocytes (95% CI 0.35 to 3.27, P = 0.01) with letrozole co-treatment. No significant effect on LBR, clinical pregnancy rate (CPR), or ovarian hyperstimulation syndrome rate was demonstrated. Only two studies reported on high responders and revealed no effect on LBR or CPR. Overall, the endometrium thickness was slightly affected, where as the, miscarriage rate and cancellation rate were unaffected by letrozole co-treatment. None of the included studies reported on neonatal outcomes. The quality of evidence was high or moderate in the RCTs and low in the observational studies. In conclusion, poor responders may benefit from co-treatment with letrozole during ovarian stimulation for IVF, whereas letrozole for normal and high responders requires further investigation with larger, high-quality studies.

Research question Do cumulative live birth rates (CLBR) differ between polycystic ovary syndrome (PCOS) phenotypes when a freeze-all strategy is used to prevent ovarian hyperstimulation syndrome (OHSS) after ovarian stimulation (OS)? Design This is a single-centre, retrospective cohort study including 422 women with PCOS as defined by Rotterdam criteria or with PCO-like ovarian morphology-only (PCOM) in whom, between January 2015 and December 2019, a freeze-all strategy was applied after GnRH agonist triggering in the context of hyper-response defined as ≥18 follicles of ≥11 mm in their first or second IVF/ICSI cycle in a tertiary referral hospital. The primary outcome was CLBR resulting from the transfer of all cryopreserved embryos from the same IVF/ICSI cycle. Analysis was performed by multivariate logistic regression analysis adjusting for confounders. Results In total, 91/422 (21.6%) patients had PCOS phenotype A (hyperandrogenism + ovulation disorder + PCOM = HOP), 33/422 (7.8%) had phenotype C (hyperandrogenism + PCOM = HP), 161/422 (38.2%) had phenotype D (ovulation disorder + PCOM = OP) and 137/422 (32.5%) had PCOM. Unadjusted CLBR was similar among the groups (69.2%, 69.7%, 79.5% and 67.9%, respectively; p= 0.11). The multivariate logistic regression model adjusting for age, BMI, number of oocytes, fertilization rate and embryo stage at vitrification confirmed that the PCOS/PCOM phenotype did not have any impact on CLBR [OR 0.72, CI 0.24-2.14 (phenotype C); OR 1.55, CI 0.71-3.36 (phenotype D); OR 0.84, CI 0.39-1.83 (PCOM); p= 0.2, with phenotype A as reference]. Conclusions In subfertile women with PCOS eligible for ART, hyper-response after OS confers excellent cumulative live birth rates of ∼70%, irrespective of the phenotype, when a freeze-all strategy is used. This contrasts with the unfavourable clinical outcomes that have previously been observed in hyperandrogenic PCOS women who underwent mild OS targeting normal ovarian response and fresh embryo transfer. The data should however be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. The results cannot be generalized to all ART cycles in women with polycystic ovaries as they pertain to those cycles in which hyper-response is observed after OS.

Research question Can workflow during IVF be facilitated by artificial intelligence to limit monitoring during ovarian stimulation to a single day and enable level-loading of retrievals? Design The dataset consisted of 1591 autologous cycles in unique patients with complete data including age, FSH, oestradiol and anti-Mullerian concentrations, follicle counts and body mass index. Observations during ovarian stimulation included oestradiol concentrations and follicle diameters. An algorithm was designed to identify the single best day for monitoring and predict trigger day options and total number of oocytes retrieved. Results The mean error to predict the single best day for monitoring was 1.355 days. After identifying the single best day for evaluation, the algorithm identified the trigger date and range of three oocyte retrieval days specified by the earliest and the latest day on which the number of oocytes retrieved was minimally changed with a variance of 0–3 oocytes. Accuracy for prediction of total number of oocytes with baseline testing alone or in combination with data on the day of observation was 0.76 and 0.80, respectively. The sensitivities for estimating the total number and number of mature oocytes based solely on pre-IVF profiles in group I (0–10) were 0.76 and 0.78, and in group II (>10) 0.76 and 0.81, respectively. Conclusions A first-iteration algorithm is described designed to improve workflow, minimize visits and level-load embryology work. This algorithm enables decisions at three interrelated nodal points for IVF workflow management to include monitoring on the single best day, assign trigger days to enable a range of 3 days for level-loading and estimate oocyte number.

Research Question To evaluate whether endometrial scratch improved the chance of a live birth in women with PCOS undergoing ovulation induction and trying to conceive. Design An international, multicentre, randomised, sham-controlled trial across six fertility clinics in three countries (New Zealand, United Kingdom and Brazil). Women with a diagnosis of PCOS who were planning to commence ovulation induction cycles (at least three cycles) in order to conceive were randomly assigned to receive the pipelle (scratch) procedure or a sham (placebo) procedure in the first cycle of ovulation induction. Women kept a diary of ovulation induction and sexual intercourse timing over three consecutive cycles and pregnancies were followed-up to live birth. Primary outcome was live birth and secondary outcomes were clinical pregnancy, ongoing pregnancy, multiple pregnancy, adverse pregnancy outcomes, neonatal outcomes, bleeding following procedure and pain score following procedure. Results 117 women were randomised; 58 to the scratch group and 59 to the sham group. Live birth occurred in 11 (19%) women in the scratch group and 14 (24%) in the sham group (OR 0.76, 95% confidence interval of 0.30 to 1.92). Secondary outcomes were similar in each group. Significantly higher pain scores were reported in the scratch group (adjusted mean difference 3.2, 95% confidence interval of 2.5 to 3.9) when measured on a visual-analogue scale. Conclusion We did not detect a difference in live birth rate for women with PCOS who received an endometrial scratch when trying to conceive using ovulation induction, however, uncertainty remains due to the small sample size in our study.

The preservation of fertility in women of childbearing age with breast cancer is challenging because the time for ovarian stimulation is restricted and only a limited number of oocytes can be retrieved before gonadotoxic therapies. The aim of this meta-analysis was to evaluate the fertility preservation outcomes after ovarian stimulation with various protocols in women with breast cancer. PubMed, Embase and the Cochrane Library were searched. Twenty-two studies comparing the outcomes of women with breast cancer receiving random-start ovarian stimulation or conventional protocol; single or double ovarian stimulation cycles; and coadministration of aromatase inhibitors or tamoxifen were included. Random-start ovarian stimulation resulted in a comparable number of retrieved oocytes to the conventional protocol. Two ovarian stimulation cycles had significantly higher numbers of total retrieved oocytes than one cycle (mean difference 7.91, 95% confidence interval [CI] 3.42 to 12.40). Coadministration of letrozole and tamoxifen showed similar results for retrieved oocytes to those without. A significantly lower peak serum oestradiol concentration was observed in letrozole-based groups than in letrozole-free groups (mean difference -1.22; 95% CI -1.42 to -1.02). In conclusion, this study indicated that implementing random-start protocols to shorten the duration of waiting for ovarian stimulation, applying two ovarian stimulation cycles, and coadministration of letrozole can lead to more desirable outcomes.

Research question In women at advanced age of 43–45 years undergoing repeated IVF cycles with autologous oocytes, who has the highest chance for birth and who should be referred early to receive donor oocytes? Design A retrospective cohort study was conducted at a university hospital reproductive center. The computerized database of 394 women aged 43–45 undergoing 1528 non-donor IVF or ICSI cycles between 2010 and 2019 was analyzed. a decision tree was developed, enabling a comprehensive study of a set of clinical parameters and the expected outcomes. Results The analysis included the outcomes of 394 women undergoing a total of 1528 cycles. The cumulative clinical pregnancy rate was 15% (59/394) and the cumulative live birth rate was 8.4% (33/394). The decision tree developed to predict women that should be offered egg donation included age, poor ovarian response to stimulation, the number of top-quality embryos, dominant follicles, previous pregnancy or live birth, fertilized oocytes and BMI. The model showed that a good ovarian response in the first cycle was the best predictor for live birth (13.3% gave birth). However, among women with poor responses, 7.1% of those who were younger than 43.5 years gave birth, and none of the women who were older than 43.5 years did. Conclusion Women over 43.5 years old with less than four oocytes collected in their first IVF cycle should be offered ovum donation, since their live birth rate in subsequent cycles is negligible.

RESEARCH QUESTION Is ovarian response associated with individualized follitropin delta dosing regimen comparable across different ethnic populations? DESIGN Post-hoc analysis of ovarian response in 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) undergoing stimulation with individualized follitropin delta dosing based on serum anti-Mullerian hormone concentration and body weight in two randomized controlled trials conducted in Japan (NCT03228680) and in Europe, North America and South America (NCT01956110). RESULTS On average, Japanese women weighed 10 kg less, which affected the total follitropin delta dose, compared with White women (83.5 ± 28.9 versus 90.2 ± 25.2 µg). At the end of stimulation, serum FSH concentrations were not significantly different between Japanese and White women (median 14.3 versus 14.0 IU/l), whereas serum oestradiol concentrations were significantly higher in Japanese women (median 6517 versus 5298 pmol/l, P < 0.0001). Japanese and White women had a similar number of oocytes retrieved with no significant differences among all women who started stimulation (9.3 ± 5.4 versus 9.5 ± 5.7), potential low responders (7.2 ± 3.7 versus 7.6 ± 4.6) or potential high responders (10.8 ± 5.9 versus 11.0 ± 6.0). At each level of ovarian response, serum oestradiol concentrations were significantly higher in Japanese women (P = 0.024). The incidence of early ovarian hyperstimulation syndrome was significantly higher in Japanese women compared with White women; overall (10.0% versus 2.2%, P = 0.0124) and at similar serum oestradiol concentrations (P = 0.0137). CONCLUSIONS The individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients, but the oestradiol response is higher in Japanese women.

Does late-follicular phase progesterone elevation have a deleterious effect on embryo euploidy, blastocyst formation rate and cumulative live birth rates (CLBR)?A multicentre retrospective cross-sectional study including infertile patients aged 18-40 years who underwent ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol and preimplantation genetic testing for aneuploidies (PGT-A) followed by a freeze-all strategy and euploid embryo transfer between August 2017 and December 2019. The sample was stratified according to the progesterone concentrations on the day of trigger: normal (≤1.50 ng/ml) and high (1.50 ng/ml). Moreover, sensitivity analyses were performed to determine whether different conclusions would have been drawn if different cut-offs had been adopted. The primary outcome was the embryo euploidy rate. Secondary outcomes were the blastocyst formation rate, the number of euploid blastocysts and CLBR.Overall 1495 intracytoplasmic sperm injection PGT-A cycles were analysed. Late-follicular phase progesterone elevation was associated with significantly higher late-follicular oestradiol concentrations (2847.56 ± 1091.10 versus 2240.94 ± 996.37 pg/ml, P 0.001) and significantly more oocytes retrieved (17.67 ± 8.86 versus 12.70 ± 7.00, P 0.001). The number of euploid embryos was significantly higher in the progesterone elevation group (2.32 ± 1.74 versus 1.86 ± 1.42, P = 0.001), whereas the blastocyst formation rate (47.1% [43.7-50.5%] versus 51.0% [49.7-52.4%]), the embryo euploidy rate (48.3% [44.9-51.7%] versus 49.1% [47.7-50.6%], the live birth rate in the first frozen embryo transfer (34.1% versus 31.1%, P = 0.427) and CLBR (38.9% versus 37.0%, P = 0.637) were not significantly different between the two groups.Euploidy rate and CLBR do not significantly differ among PGT-A cycles with and without late-follicular progesterone elevation in a freeze-all approach.

Research question Recombinant FSH administration in ovarian stimulation for IVF is a standard procedure, whereas the role of LH is controversial. MicroRNAs (mRNA) are small endogenous non-coding transcripts that are involved in the regulation of many cellular processes, including foliculogenesis and gonadotrophin function. The aim was to study the possible role of miRNA in ovarian follicular development in groups having different ovarian stimulation protocols. Are there different miRNA expression profiles in cumulus cells of infertile women undergoing IVF? What are the regulated pathways? Design This prospective observational study included 13 patients who fulfilled the following inclusion criteria: younger than 38 years of age; a tubal infertility factor; a male factor; or idiopathic infertility. This is a pilot study in which the patients were aleatory enrolled into two groups: seven in FSH group (recombinant FSH, 225 IU) and six in FSH plus LH group (recombinant FSH, 150 IU + recombinant LH, 75 IU). The granulosa cells obtained from the follicular ovarian retrieval were analysed using polyerase chain reaction. Results were analysed using DIANA Tools, an online bioinformatics tool. Results Among the 84 microRNAs evaluated, 11 were differentially expressed between the groups, all of which were upregulated in the FSH plus LH group, compared with the FSH group. Differentially expressed miRNA profiles are related to oestrogen signalling, oocyte meiosis and pluripotent cells regulation. Conclusion miRNA overexpression in the FSH plus LH group is consistent with the independent and fundamental role of LH in folliculogenesis, leading to a distinct molecular response between groups.

What prognostic factors relate to a high oocyte yield in fertility preservation for women affected by endometriosis?Observational cohort study conducted in a tertiary care university hospital between April 2015 and January 2019. Women who had undergone fertility preservation with ovarian stimulation for oocytes and embryo vitrification for endometriosis were included. Prognostic factors associated with the number of oocytes retrieved after the first ovarian stimulation were analysed.A total of 146 women who had undergone 258 ovarian stimulation cycles were included; 82 (56.2%) had undergone more than one ovarian stimulation cycle; 72.6% had at least one endometrioma lesion; and 36.3% had previously undergone surgery for endometriosis. After adjustment by multiple linear regression, the factors that significantly reduced the number of oocytes retrieved were previous history of surgery for ovarian endometriosis (coefficient -1.08; 95% CI -2.02 to -0.15; P = 0.024); women's age (-0.21; 95% CI -0.41 to -0.01; P = 0.039); and total dose of gonadotrophin used (-0.01; 95% CI -0.01 to -0.00; P = 0.047). Anti-Müllerian hormone serum level and gravidity positively correlated with an increase in the number of oocytes retrieved (1.65; 95% CI 1.13 to 2.17; P0.001 and 3.30; 95% CI 0.91 to 5.68; P = 0.007, respectively) after the first ovarian stimulation cycle.A history of surgery for ovarian endometriosis was associated with significantly lower oocyte yields. Fertility preservation should be integrated into endometriosis management. Fertility preservation should ideally be made available to the patient before surgery.

Research question Are there any associations between the variants of FSHR c.2039 G>A (p. Ser680Asn, rs6166) and LHCGR c.935A>G (p. Asn312Ser, rs2293275) and ovarian reserve, ovarian response, clinical pregnancy rate and POSEIDON group? Design A total of 210 infertile women were enrolled in this prospective study. The gene variants were analysed by the Sanger method. The clinical parameters were analysed based on genotypes. Results The frequency of heterozygous and homozygous G allele for FSHR c.2039 G>A in the low prognosis group was significantly higher than that in other response groups (P = 0.034); there was no significant association between LHCGR c.935 A>G and ovarian response. Moreover, the serum anti-Mullerian hormone (AMH) concentration, antral follicle count (AFC), oocytes retrieved, metaphase II (MII) oocytes and two-pronuclear (2PN) oocytes in patients with AG genotype for FSHR c.2039 G>A were significantly lower than those with AA genotype. The serum LH concentrations and clinical pregnancy rate of fresh embryo transfer in patients with GG genotype for LHCGR c.935 A>G were significantly higher than that of the AG genotype. In POSEIDON analysis, the low prognosis women with AA genotype for FSHR c.2039 G>A were more likely to appear in subgroup 1 (P = 0.038). Conclusion The FSHR c.2039 G>A variant has a significant beneficial influence on ovarian reserve and ovarian response. The LHCGR c.935 A>G variant is associated with increased clinical pregnancy rate of fresh embryo transfer in infertile women. In addition, the low prognosis women with AA genotype for FSHR c.2039 G>A tend to show better ovarian reserve and prognosis.

Research question : What are the most pressing educational needs of fertility healthcare professionals using assisted reproductive technologies (ART)? Design : This mixed-methods study combined qualitative interviews with quantitative surveys. Participants included physicians and nurses specialised in reproductive endocrinology or in obstetrics/gynaecology, and laboratory specialists, with a minimum of three years of experience, practicing in Australia, Brazil, Canada, China, France, Germany, India, Italy, Japan, Mexico, Spain, or the UK. Maximum variation purposive sampling was used to ensure a mix of experience and settings. Interviews were transcribed and coded through thematic analysis. Quantitative data were analysed using frequency tables, cross-tabulations and Chi-square tests to compare results by reimbursement context. Results : A total of 535 participants were included (273 physicians, 145 nurses and 117 laboratory specialists). Knowledge gaps, skill gaps, and attitude issues were identified in relation to: 1) ovarian stimulation (e.g. knowledge of treatments and instruction protocols for ovarian stimulation), 2) embryo culture and cryopreservation / vitrification (e.g., diverging opinions on embryo freezing, 3) embryo assessment (e.g., performing genetic testing), 4) support of luteal phase and optimising pregnancy outcomes (e.g., knowledge of assessment methods for endometrial receptivity), and 5) communication with patients (e.g., reluctance to address emotional distress). Conclusions : This descriptive, exploratory study corroborates previously reported gaps in fertility care and identify potential causes of these gaps. Findings provide evidence to inform educational programmes for healthcare professionals who use ART in their practice and calls for the development of case-based education and interprofessional training program to improve care for patients with fertility issues.

RESEARCH QUESTION: Is the reproductive outcome similar after gonadotrophin-releasing hormone agonist (GnRHa) trigger followed by luteal human chorionic gonadotrophin (HCG) boluses compared with HCG trigger and a standard luteal phase support (LPS)?DESIGN: Two open-label pilot randomized controlled trials (RCT) with 250 patients from 2014 to 2019, with a primary outcome of ongoing pregnancy per embryo transfer. Patients with ≤13 follicles on the trigger day were randomized (RCT 1) to: Group A (n = 65): GnRHa trigger followed by a bolus of 1500 IU HCG s.c. on the oocyte retrieval day (ORD) and 1000 IU HCG s.c. 4 days later, and no vaginal LPS; or Group B (n = 65): 6500 IU HCG trigger, followed by a standard vaginal progesterone LPS. Patients with 14-25 follicles on the trigger day were randomized (RCT 2) to Group C (n = 60): GnRHa trigger followed by 1000 IU HCG s.c. on ORD and 500 IU HCG s.c. 4 days later, and no vaginal LPS; or Group D (n = 60): 6500 IU HCG trigger and a standard vaginal LPS.RESULTS: In RCT 1, the ongoing pregnancy rate was 44% (22/50) in the GnRHa group versus 46% (25/54) in the HCG trigger group (RR 0.95, 95% CI 0.62-1.45). No ovarian hyperstimulation syndrome (OHSS) was seen in Groups A or B. In RCT 2, the ongoing pregnancy rate was 51% (25/49) in the GnRHa group versus 60% (31/52) in the HCG trigger group (RR 0.86, 95% CI 0.60-1.22). The OHSS rates were 3.3% and 6.7%, respectively.CONCLUSIONS: Although a larger-scale study is needed before standard clinical implementation, the present study supports that the exogenous progesterone-free LPS is efficacious, simple and patient-friendly.

During ovarian stimulation for IVF-embryo transfer treatment, a premature LH surge may lead to progesterone elevation that disrupts endometrial maturation and affects the probability of pregnancy following fresh embryo transfer. Preventing this LH surge and progesterone elevation using gonadotrophin-releasing hormone (GnRH) analogues is considered a standard practice. The same policy applies to cycles in which the 'freeze-all' protocol has been selected from the outset (e.g. donors), but the need for this has not been discussed. Moreover, in 'freeze-all' cycles, exogenous progesterone administration tends to replace GnRH antagonists, without reducing efficacy after embryo transfer in frozen-thawed cycles. Nevertheless, as exogenous progesterone is expected to have the same impact on the endometrium as endogenous progesterone, it is clear that, unlike in fresh cycles, in 'freeze-all' cycles an endogenous LH surge prevention does not seem necessary. Therefore, both GnRH antagonists and exogenous progesterone appear to be redundant in 'freeze-all' cycles, and in this context the indications for the use of GnRH analogues in ovarian stimulation protocols need to be revisited.

The benefit of LH supplementation (LHS) over sole use of FSH during controlled ovarian stimulation (COS) remains controversial. Meta-analyses have provided some evidence that the benefit of LHS is limited to women with poor ovarian response (POR). This study aimed to assess the effectiveness of LHS on cumulative live birth rate (CLBR) in POR using a large controlled study in a real-world context.This retrospective multicentre controlled study used data from registries at 12 French ART centres. All instances of POR undergoing ovarian stimulation and treated with follitrophin-alfa (FSH-α) with or without lutrophin-α were selected following an intention-to-treat principle. POR was defined according to the ESHRE Bologna criteria, and classified into three categories (Mild, Moderate and Severe) according to the Poor Responder Outcome Prediction (PROsPeR) score. The primary end-point was the CLBR associated with fresh and frozen embryos originating from the same ovarian stimulation.A total of 9787 instances of ovarian stimulation (5218 LHS, 4569 FSH-α only) were analysed, 33.0%, 52.4% and 14.6% being allocated to the Mild, Moderate and Severe PROsPeR categories, respectively. Using a mixed logistic model and adjusting for matched subclasses and baseline POR severity, it was found that the benefit of LHS compared with use of FSH alone differed between baseline severity categories (interaction test, P = 0.007): a significant benefit of LHS for CLBR was found for patients in the Moderate (14.3% versus 11.3%, odds ratio [OR] = 1.37, 95% confidence interval [CI] 1.07-1.75, risk ratio [RR] = 1.29, P = 0.013) and Severe (9.8% versus 4.4%, OR = 2.40, 95% CI- 1.48-3.89, RR = 1.89, P 0.001) categories, but not for the Mild category (18.8% versus 19.6%, OR = 0.95, 95% CI 0.78-1.15, RR = 0.95, P = 0.60).LHS has a significant effect on increasing CLBR in moderately and severely poor ovarian responders.

Research question Ovarian stimulation during IVF cycles involves close monitoring of oestradiol, progesterone and ultrasound measurements of follicle growth. In contrast to blood draws, sampling saliva is less invasive. Here, a blind validation is presented of a novel saliva-based oestradiol and progesterone assay carried out in samples collected in independent IVF clinics. Design Concurrent serum and saliva samples were collected from 324 patients at six large independent IVF laboratories. Saliva samples were frozen and run blinded. A further 18 patients had samples collected more frequently around the time of HCG trigger. Saliva samples were analysed using an immunoassay developed with Salimetrics LLC. Results In total, 652 pairs of saliva and serum oestradiol were evaluated, with correlation coefficients ranging from 0.68 to 0.91. In the European clinics, a further 237 of saliva and serum progesterone samples were evaluated; however, the correlations were generally poorer, ranging from –0.02 to 0.22. In the patients collected more frequently, five out of 18 patients (27.8%) showed an immediate decrease in oestradiol after trigger. When progesterone samples were assessed after trigger, eight out of 18 (44.4%) showed a continued rise. Conclusions Salivary oestradiol hormone testing correlates well to serum-based assessment, whereas progesterone values, around the time of trigger, are not consistent from patient to patient.

RESEARCH QUESTION Does adenomyosis affect IVF independent of decreased ovarian reserve, and what are the characteristics and IVF outcome of the ultra-long gonadotrophin-releasing hormone (GnRH) agonist protocol in adenomyosis? DESIGN Observational cohort study of three groups of patients undergoing first cycle of IVF treatment with normal ovarian reserve: (A) 362 patients with adenomyosis using the ultra-long GnRH agonist protocol; (B) 127 patients with adenomyosis using the long GnRH agonist protocol; (C) 3471 patients with tubal infertility using the long GnRH agonist protocol. RESULTS Compared with groups B and C, the number of oocytes retrieved in group A decreased, and the gonadotrophin dosage and duration in group A were higher (P < 0.001). In long GnRH agonist treatment, clinical pregnancy rate (OR 0.492, 95% CI 0.327 to 0.742, P < 0.001), implantation rate (OR 0.527, 95% CI 0.350 to 0.794, P = 0.002) and live birth rate (OR 0.442, 95% CI 0.291 to 0.673, P < 0.001) decreased and miscarriage rate (OR 3.078, 95% CI 1.593 to 5.948, P < 0.001) increased in adenomyosis patients compared with tubal infertility. For adenomyosis patients, clinical pregnancy rate (OR 1.925, 95% CI 1.137 to 3.250, P = 0.015), implantation rate (OR 1.694, 95% CI 1.006 to 2.854, P = 0.047) and live birth rate (OR 1.704, 95% CI 1.012 to 2.859, P = 0.044) increased in the ultra-long GnRH agonist treatment compared with long GnRH agonist treatments. CONCLUSION Adenomyosis could negatively affect IVF outcomes independent of ovarian reserve after long GnRH agonist protocol. Patients with adenomyosis following the ultra-long GnRH agonist protocol could have a better pregnancy outcome than those following the long GnRH agonist protocol.

The major causes of IVF failure in women with endometriosis have been attributed to decreased ovarian reserve, low embryo quality and impaired receptivity of the endometrium. Dienogest (DNG) has anti-inflammatory and anti-angiogenic activity and so may theoretically improve IVF outcomes in women with endometriosis. This study aimed to evaluate the administration of DNG before IVF in women with endometriosis who had previously failed one IVF cycle.This study was based on the retrospective analysis of a prospectively collected database, including 151 women who had failed a previous IVF cycle and all subsequent embryo transfers and had an imaging diagnosis of endometriosis. Patients either directly underwent IVF without receiving hormonal treatment or received 3 months of treatment with DNG (2 mg/daily) before IVF.Eighty-eight (58.3%) patients underwent IVF without previous hormonal treatment, and 63 (41.7%) received pretreatment with DNG. The cumulative implantation, clinical pregnancy and live birth rates were significantly higher in the DNG-treated group (39.7%, 33.3% and 28.6%) than in the non-treated group (23.9%, 18.2% and 14.8%; P = 0.049, 0.037 and 0.043, respectively). The largest diameter of endometriomas significantly decreased after DNG pretreatment (P 0.001). The use of DNG increased significantly the number of oocytes retrieved (P = 0.031), two-pronuclear embryos (P = 0.039) and blastocysts (P = 0.005) in women with endometriomas of diameter ≥4 cm.This study suggest that in patients with endometriosis, IVF outcomes can be improved by pretreatment with DNG. In particular, the use of DNG allows for better oocyte retrieval and blastocysts in patients with large endometriomas.

The COVID-19 pandemic has significantly increased mortality in many countries, with the number of infected cases increasing exponentially worldwide. One of the main determining factors of the poor prognosis in these patients is the development of coagulopathy. Moreover, it is well known that assisted reproductive technology procedures confer a risk of thromboembolic complications. This commentary analyses specific aspects coexisting between the thrombotic risk described during virus infection and that reported in the context of assisted reproduction treatments. Based on known pathophysiological aspects of virus infection and of ovarian stimulation, there are common elements that deserve to be taken into account. In the present context, any risk of hyperstimulation should be avoided. Gonadotrophin-releasing hormone agonist triggering should be mandatory in high-responder patients and/or those with COVID-19 infection. In both cases, the cycle should be segmented. A proposal is made for the use of prophylactic low molecular weight heparin not only in those cases in which oocyte retrieval has been performed, but also in those in which cancellation has been decided. In addition, endometrial preparation for frozen-thawed embryo transfers should use the transdermal route in order to minimize the higher thrombotic risk associated with the oral route.

Research question Is there a difference in live birth rate between a freeze-only strategy and fresh embryo transfer, and what is the effect of varying progesterone concentrations on the day of human chorionic gonadotrophin (HCG) administration? Design A secondary analysis of data from three randomized trials comparing the live birth rate after elective frozen versus fresh embryo transfer, which respectively enrolled 1508 women with polycystic ovary syndrome, 2157 ovulatory women who underwent cleavage-stage embryo transfer and 1650 ovulatory women who underwent single blastocyst transfer. Women were randomly assigned to the frozen or fresh embryo transfer group in the original trials. The primary outcome was live birth rate after the initial embryo transfer. Results The live birth rate after a freeze-only strategy was consistently higher than fresh embryo transfer at any progesterone concentration on the day of HCG administration. Nonetheless, the between-group difference in live birth rate after frozen versus fresh embryo transfer was greater in women with progesterone concentrations ≥1.14 ng/ml (52.7% versus 37.3%, odds ratio (OR) 1.88, 95% confidence interval (CI) 1.55–2.27, P = 7.89 × 10–11) than in women with progesterone concentrations Conclusion In women with normal or high ovarian response, a freeze-only strategy resulted in a higher live birth rate than fresh embryo transfer, irrespective of progesterone concentration. Moreover, women with progesterone concentration ≥1.14 ng/ml may benefit more from a freeze-only strategy.

Research question Is there a difference in ovarian reserve biomarkers and ovarian response between the right and left ovaries of infertile women undergoing IVF treatments? Design A total of 100 infertile women aged 27 to 37 years, diagnosed with either unexplained male factor or mechanical factor infertility, participated in the study. All women had both ovaries intact, and regular menstrual cycles with no previous diagnosis of polycystic ovaries or endometriosis. The data were collected separately for each ovary, and included parameters of basal sonographic ovarian reserve, as well as ovarian response to ovarian stimulation. Results Basal sonographic ovarian reserve markers were similar between the two ovaries. The right and left ovaries did not differ in their basal antral follicle count (AFC) (6.9 ± 3.9 versus 6.8 ± 3.8, respectively, P = 0.672), nor did they differ in their ovarian volume (10.3 ± 6.7 versus 9.8 ± 8.0 cm3, respectively, P = 0.636). Nevertheless, a superior right-sided ovarian response to ovarian stimulation was observed, with a significantly higher total number of follicles in the right compared with the left ovary (7.8 ± 4.3 versus 6.8 ± 4.2 follicles, respectively, P = 0.006), and a higher number of follicles ≥14 mm on the day of human chorionic gonadotrophin administration (4.9 ± 3.2 versus 3.8 ± 2.4 follicles, respectively, P = 0.002). Conclusions Despite comparable basal AFC and ovarian volume, the two ovaries are distinguishable in their response to ovarian stimulation with a clear right-side preference. These findings imply that the superiority of right ovarian response may be derived from local pelvic factors, presumably a more efficient vascularization.

What are the main risk factors associated with ectopic pregnancy and what is the true incidence of ectopic pregnancies in an IVF programme?Retrospective single-centre study of 12,429 blastocyst transfers (8182 fresh and 4247 frozen embryo transfers) conducted between January 2010 and December 2017. IVF outcome was analysed, and ectopic pregnancy risk evaluated according to patient's characteristics and assisted reproductive technology treatment factors.Of 5061 patients reporting a positive pregnancy test, 43 were diagnosed with ectopic pregnancy (0.85%). Neither female age (36.7 versus 35.8 years), body mass index, quality of transfer nor stimulation protocol affected the ectopic pregnancy rate, but history of previous ectopic pregnancy (OR 3.26; P = 0.0080), tubal surgery, or both (OR 6.20; P0.0001) did. The incidence of ectopic pregnancy was increased in women with uterine malformations (OR 3.85; P = 0.0052), uterine pathologies (OR 5.35; P = 0.0001), uterine surgeries (OR 2.29; P = 0.0154) or sub-optimal endometrial build-up (OR 4.46 to 5.31; P0.0001). Transfer of slow-developing blastocysts (expressed by expansion) significantly increased the risk of ectopic pregnancy (OR 2.59; P = 0.0102).Unfavourable uterine environment, including uterine pathologies, uterine or tubal surgery and suboptimal endometrial build-up were related to ectopic pregnancy. Low expansion grade of blastocysts was identified as an additional putative risk factor for ectopic pregnancy, indicating the importance of proper embryonal-maternal synchronization. The overall ectopic pregnancy rate after blastocyst transfer was low, comparable with reported ectopic pregnancy rates in spontaneous conceptions. Proper evaluation of tubal and uterine pathologies, optimizing endometrial preparation and the transfer of expanded blastocysts in a frozen embryo transfer cycle, might be beneficial.

Research question Available evidence shows that the presence of ovarian endometriomas does not interfere with the ovarian response to ovarian stimulation. However, the mean size of the endometriomas in these studies is generally small, and two recent investigations suggested that follicular development could be impaired when focusing on larger endometriomas. However, these studies could not identify a clear threshold above which endometriomas could become detrimental. Design To identify this threshold, the study retrospectively selected women without a history of surgery for ovarian cysts who underwent IVF in the presence of unilateral endometriomas with a mean diameter between 20 and 49 mm. Selected women were divided into three categories of endometrioma size: 20–29 mm (group 1, n = 23), 30–39 mm (group 2, n = 2323), and 40–49 mm (group 3, n = 2321). Recruitment for each category was censored at about 21 women to ensure equal statistical power for each group. Results The response to ovarian stimulation was equal or superior in the affected gonads in eight women (35%, 95% confidence interval [CI] 16–57%), seven women (30%, 95% CI 13–53%) and two women (10%, 95% CI 2–30%) in groups 1, 2 and 3, respectively. The median (interquartile range) number of developed follicles in the affected and intact ovaries was 6 (3–7) and 5 (4–9) in group 1 (P = 0.21), 4 (1–6) and 4 (3–7) in group 2 (P = 0.08), 5 (3–7), and 7 (4–8) in group 3 (P = 0.01), respectively. Conclusions The threshold to be used to distinguish between endometriomas that might and might not interfere with ovarian response is 4 cm in diameter.

Research question Is there an association between ovarian response and perinatal outcomes? Design A retrospective, single-centre cohort study including all women undergoing their first ovarian stimulation cycle in a gonadotrophin releasing hormone antagonist protocol, with a fresh embryo transfer that resulted in a singleton live birth from January 2009 to December 2015. Patients were categorized into four groups according to the number of oocytes retrieved: one to three (category 1), four to nine (category 2), 10–15 (category 3), or over 15 oocytes (category 4). Results The overall number of patients analysed was 964. No relevant statistical difference was found among neonatal outcomes across the four ovarian response categories. Neonatal weight (in grams) was comparable between all groups (3222 ± 607 versus 3254 ± 537 versus 3235 ± 575 versus 3200 ± 622; P = 0.85, in categories 1, 2, 3 and 4, respectively). No statistically significant differences were found among the ovarian response categories for birth weight z-scores (taking into account neonatal sex and delivery term). The incidence of pre-term birth and low birth weight was comparable across the different ovarian response groups (P = 0.127 and P = 0.19, respectively). Finally, the occurrence of adverse obstetric outcomes did not differ among the ovarian response categories. Multivariate regression analysis revealed that the number of oocytes was not associated with neonatal birth weight. Conclusions No association was found between ovarian response and adverse perinatal outcomes in antagonist IVF and intracytoplasmic sperm injection cycles. Future, larger scale and prospectively designed investigations are needed to validate these results.

Mild ovarian stimulation is a treatment option for poor responders in IVF treatment. Our updated review evaluated mild IVF solely from randomized controlled trials (RCTs) that used genuine low-dose gonadotrophin (≤150 IU daily) alone or in combination with oral medications, comparing it with conventional-dose (>150 IU/ daily) IVF for poor responders. Electronic searches on MEDLINE, Embase, The Cochrane Central Register of Controlled Trials and PreMEDLINE, and hand searches from 2002 up to 31 January 2019, identified 14 RCTs, which were compiled with the above inclusion criteria. The risk of bias (ROB) and quality of evidence (QOE) were assessed as per Cochrane Collaboration. Meta-analyses found no difference in live birth rate (four RCTs, n = 1057, RR 0.91, CI 0.66 to 1.25) (moderate QOE), ongoing pregnancy rate (six RCTs, n = 1782, RR 1.01, CI 0.86 to 1.20) (moderate-high QOE) and cycle cancellation rates (14 RCTs, n = 2746, RR 1.38, CI 0.99 to 1.92) (low QOE). Fewer oocytes and embryos were obtained from mild IVF; however, the number and proportion of high-grade embryos were similar. Mild IVF resulted in reduced gonadotrophin use and cost. The inference remained unchanged when smaller studies with ROB were excluded, or whether gonadotrophin alone or combination with oral medication was used. The evidence of equal efficacy from a pooled population, which was adequately powered for live birth, supported a mild IVF strategy for poor responders in preference to more expensive conventional IVF. Although clinical heterogeneity remained a limiting factor, it increased the generalizability of the findings.

Research question Does subcutaneous progesterone provide similar live birth or ongoing pregnancy rates as vaginal progesterone in frozen embryo transfer (FET) cycles? Design Retrospective cohort study (n = 214 women), consisting of 107 women who received subcutaneous progesterone for FET in artificial cycles and 107 women receiving vaginal progesterone who were matched for age and treatment cycle rank acted as controls. All embryos were transferred in an artificial cycle with 6 mg per day oral oestradiol valerate starting on the second or third day of the menstrual cycle. Patients underwent transvaginal ultrasound on the 10th day of priming, and subcutaneous progesterone (50 mg/day) or vaginal progesterone (180 mg/day) was started if the endometrium had a trilinear pattern regardless of its thickness. Embryo transfer was carried out on the sixth day of progesterone administration. Oestradiol and progesterone were continued until a negative pregnancy test, 10 days after the transfer, or until the completion of 10th gestational week. Main outcome measures were live birth or ongoing pregnancy rates. Results Baseline characteristics were similar between the groups. Positive pregnancy test rates (64.5% versus 58.9%; P = 0.40; RR 1.1; 95% CI 0.89 to 1.35), live birth or ongoing pregnancy rates (39.3% versus 35.5%; P = 0.57; RR 1.11; 95% CI 0.78 to 1.56) and miscarriage rates (29% versus 25.5%; P = 0.68; RR 1.08; 95% CI 0.76 to 1.55) were similar in the subcutaneous progesterone and vaginal progesterone groups, respectively. Conclusions Subcutaneous progesterone seems to be an effective alternative to vaginal progesterone in patients undergoing FET. Randomized controlled trials comparing it with different progesterone preparations, routes and protocols are needed to better define its role.

Research question Does the presence of ovarian endometriomas affect ovarian response to ovarian stimulation after adjusting for age and ovarian reserve markers? Design This retrospective cross-sectional study compared the ovarian response between patients with ovarian endometriomas and women with other infertility factors undergoing their first ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). An age-specific nomogram model for the number of oocytes retrieved was built for both groups, and ovarian response was compared after adjusting for age, gonadotrophin dose, anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC). Results A total of 923 patients were included: 101 women with at least one ovarian endometrioma, and 822 patients with other infertility factors. Comparisons of the nomograms for the number of oocytes retrieved demonstrated that response was significantly lower for women with endometrioma when the results were adjusted for age the z-score for the number of oocytes retrieved (–0.49 ± 0.71 versus –0.20 ± 0.86; 95% confidence interval [CI] –0.47 to –0.12) and also after adjustment for the total dose of gonadotrophins and AMH values (z-score mean difference –0.338; 95% CI –0.54, –0.14). When the z-score was adjusted for gonadotrophin dose and AFC, the number of oocytes retrieved was comparable between the two groups (z-score mean difference –0.038; 95% CI –0.34 to 0.27). Conclusions Ovarian response after ovarian stimulation for IVF/ICSI in women with endometriomas is significantly lower than in controls after adjusting for age, gonadotrophin dose and AMH. Dose and protocol selection for ovarian stimulation in patients with endometrioma should be based on AFC rather than AMH, as the latter may be overestimated.

This systematic review and meta-analysis of comparative studies investigated whether progestins are as effective as gonadotrophin releasing hormone (GnRH) analogues for pituitary suppression in assisted reproduction. The primary outcome was live birth rate per woman. Secondary outcomes were live birth or ongoing pregnancy per woman and per embryo transfer, ongoing pregnancy, clinical pregnancy, numbers of oocytes and metaphase-two oocytes, duration of stimulation and gonadotrophin consumption. Adverse events included miscarriage, ectopic pregnancy and multiple pregnancy rates. The GRADE system was used to assess the quality of evidence. Seven studies involving a total of 2047 women were included. Three studies compared a progestin with a GnRH antagonist and four studies compared a progestin with a GnRH agonist. Most studies are non-randomized and report outcomes per embryo transfer, rather than per woman. Although progestins were similar to GnRH antagonists in effectiveness and safety parameters, they were associated with significantly higher live birth or ongoing pregnancy per embryo transfer compared with the short GnRH agonist protocol (RR 1.49, 95% CI 1.16 to 1.91). Progestin primed stimulation lasted significantly longer (mean difference 0.61 days, 95% CI 0.33 to 0.89) and required significantly more gonadotrophins (mean difference 433.2 IU, 95% CI 311.11 to 555.19) than the short GnRH agonist protocol, but the differences were clinically negligible. Safety parameters were similar between progestins and GnRH agonists. In conclusion, progestins can effectively prevent premature ovulation in assisted reproductive technology cycles. If larger and well-designed studies confirm these findings, progestins may be an effective and low-cost alternative to GnRH analogues when a fresh embryo transfer is not planned owing to a medical indication.

Research question The cost of IVF treatment remains high, among other factors because of the medication needed for ovarian stimulation. This study investigated the effect of using low-dose human chorionic gonadotrophin (HCG) for the second phase of follicular maturation after corifollitropin alfa induction, to replace the more expensive, either recombinant or human menopausal gonadotrophin (HMG), on the cost of ovarian stimulation. Design One hundred and five patients were randomly divided into two groups: patients in the HCG group (n = 50) received low-dose HCG from Day 7 until the diameter of at least three follicles reached 17 mm or more, while patients in the FSH group (n = 55) received conventional ovarian stimulation with highly purified HMG injections. Results The clinical pregnancy rate in the HCG group was 38% higher than in the FSH group (number needed to treat, NNT = 13). The cost per pregnancy needed for ovarian stimulation was reduced from €4902 in the FSH group to €2684 in the HCG group. Hence, the cost of ovarian stimulation medication to obtain 10 pregnancies using the conventional FSH protocol is sufficient to attain 18 pregnancies when applying the low-dose HCG protocol. Conclusion This study provides evidence that using HCG instead of HMG/FSH for ovarian stimulation results in a significant reduction in the cost of IVF with, at least, an equivalent pregnancy rate.

Research question Can single-nucleotide polymorphisms (SNP) of genes related to progesterone synthesis predict the risk of premature serum progesterone elevation in women undergoing gonadotrophin-releasing hormone agonist protocols for ovarian stimulation? Design A total of 765 women were divided into high progesterone and normal progesterone groups according to progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration, with the 75th percentile as the threshold between the group. Associations were analysed of genetic information from whole exome sequencing and the clinical characteristics of the two groups to identify the relationship between SNP, haplotypes and serum progesterone elevation. Results Among 40 common SNP of eight genes (FSHR, LHCGR, ESR1, ESR2, PGR, HSD3B1, CYP11A1 and CYP17A1), no statistical significance between the high and normal progesterone groups was identified in the distribution of genotypes and allele frequencies after multiple test correction to adjust the false discovery rate (PFDR > 0.05). When compared with the most common haplotypes of each gene, haplotype GAAG in CYP17A1 was associated with a 1.44-fold increased risk of progesterone elevation (95% confidence interval [CI] 1.22–1.69, PFDR Conclusions Polymorphism in genes involved in enzymes or hormone receptors in the progesterone synthesis pathway may have a role in modifying risk of serum progesterone elevation.