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Research Question: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules?, Design: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection., Results: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups., Conclusions: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research Question: Can medroxyprogesterone acetate (MPA) be used as a pituitary suppressor instead of a gonadotrophin releasing hormone (GnRH) antagonist during ovarian stimulation in elective fertility preservation and preimplantation genetic testing for aneuploidy (PGT-A) cycles?, Design: A multicentre, retrospective, observational, cohort study conducted in 11 IVIRMA centres affiliated to private universities. Of a total of 1652 cycles of social fertility preservation, 267 patients were stimulated using a progestin-primed ovarian stimulation protocol (PPOS), and 1385 patients received a GnRH antagonist. In the PGT-A cycles, 5661 treatments were analysed: 635 patients received MPA and 5026 patients received GnRH antagonist. A further 66 fertility preservation and 1299 PGT-A cycles were cancelled. All cycles took place between June 2019 and December 2021., Results: In the social fertility preservation cycles, the number of mature oocytes vitrified in MPA was similar to the number of those treated with an antagonist, a trend that was seen regardless of age (≤35 or >35 years). In the PGT-A cycles, no differences were found in number of metaphase II, two pronuclei, number of biopsied embryos (4.4 ± 3.1 versus 4.5 ± 3.1), rate of euploidy (57.9% versus 56.4%) or ongoing pregnancy rate (50.4% versus 47.1%, P = 0.119) between the group receiving MPA versus a GnRH antagonist, whereas the clinical miscarriage rate was higher in the antagonist group (10.4% versus 14.8%, P = 0.019)., Conclusions: Administration of PPOS yields similar results to GnRH antagonists in oocytes retrieved, rate of euploid embryos and clinical outcome. Hence, PPOS can be recommended for ovarian stimulation in social fertility preservation and PGT-A cycles, as it allows greater patient comfort., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: What is the capability of serum anti-Müllerian hormone (AMH) measured using the automated Elecsys® AMH immunoassay to (Roche Diagnostics International Ltd) determine ovarian response after fertility treatment?, Design: Single-centre, retrospective, observational, cohort study including women undergoing ovarian stimulation. Serum AMH concentrations were determined using the Elecsys AMH immunoassay based on one blood sample drawn 6 months or less before treatment. Stimulation was conducted in accordance with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Patients were divided into four ovarian response categories based on their oocyte yield: low (0-3), suboptimal (4-9), optimal (10-15) and high (>15). Areas under the curve were calculated for each ovarian response group., Results: Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P < 0.001). Areas under the curve (95% CI) for AMH predicting ovarian response were 0.85 (0.83 to 0.88) for low and 0.89 (0.87 to 0.91) for high response. Optimal serum AMH cut-offs for predicting a low and high response using the Elecsys AMH immunoassay were 6.4 pmol/l (0.89 ng/ml) and 14.2 pmol/l (1.99 ng/ml), respectively. Multivariable regression analysis showed that 47% (R 2  = 0.470) of variation in ovarian response could be attributed to AMH alone, increasing to 50.9% (R 2  = 0.509) with the addition of age, body weight, and total dose of gonadotrophin., Conclusion: Ovarian response and oocyte yield after stimulation in a GnRH antagonist cycle can be predicted with high accuracy using a single determination of serum AMH before ovarian stimulation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As in any other healthcare discipline, the debate around standardization of practice versus individualized care is also present in the field of infertility. While the former looks for the efficiency of diagnostic and therapeutic processes in the average population supported by evidence-based medicine (EBM), the later looks for patient-centred care, integrating individual clinical expertise and patients' rights and preferences. Both approaches have been compared in a few randomized controlled trials (RCT) having as end-points live birth rates and incidences of adverse effects. However, the available evidence is arguable and too weak to clearly proclaim that one is better than the other. Indeed, it has been suggested that RCT, the keystone of EBM, are not the best tools to evaluate the efficacy of personalized care. A different design, named 'N-of-1' trials, has been proposed as the most appropriate methodology to this end. Infertile patients are still undertreated worldwide. Poor outcomes, fear of adverse events and financial reasons are behind this. In this context, a more personalized approach, aimed at optimizing the outcome while fulfilling the patient's preferences, is necessary to overcome these barriers., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Is measurement of hyperglycosylated HCG (hHCG) superior to beta-HCG (HCG+β) for early pregnancy detection after IVF and embryo transfer?, Design: Blood samples were collected on day 4 (+1), 7 (+1) and 11 (+2) after embryo transfer from women aged 18-45 years undergoing first or second fresh or frozen IVF embryo transfer cycles. Biochemical pregnancy was assessed on-site by HCG determination on day 11; clinical pregnancy was assessed by ultrasound on day 21 (+4/-3). Serum hHCG (immunochemiluminometric assay) and HCG+β (Elecsys® HCG+β assay) concentrations were measured. Performance of hHCG and HCG+β for predicting pregnancy was evaluated and cut-offs selected., Results: In total, 155 women were enrolled and underwent IVF and embryo transfer. Area under the curve (AUC) (95% CI) on day 4 was not significantly different for hHCG (AUC 0.88; 95% CI 0.83 to 0.94) and HCG+β (AUC 0.90; 95% CI 0.84 to 0.95), as was predictive performance on day 7 and 11, with higher AUC estimates compared with day 4. Applying cut-offs derived according to Youden's index on day 4 (hHCG, 100 pg/ml; HCG+β, 1.30 mIU/ml), both biomarkers demonstrated high negative predictive values for ruling out pregnancy (hHCG, 83.8%; HCG+β, 82.8%) and high positive predictive values for ruling in pregnancy (hHCG, 89.0%; HCG+β, 84.9%) on day 21. Diagnostic performance improved from day 4 to day 11., Conclusions: Predictive performance for early pregnancy post-IVF embryo transfer of day-5 blastocysts was not significantly different for hHCG and HCG+β; hHCG superiority over HCG+β was not shown., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The value of artificial intelligence to benefit infertile patients is a subject of debate. This paper presents the experience of one aspect of artificial intelligence, machine learning, coupled with patient empathy to improve utilization of assisted reproductive technology (ART), which is an important aspect of care that is under-recognized. Although ART provides very effective options for infertile patients to build families, patients often discontinue ART when further treatment is likely to be beneficial and most of these patients do not achieve pregnancy without medical aid. Use of ART is only in part dependent on financial considerations; stress and other factors play a major role, as shown by high discontinuation rates despite reimbursement. This commentary discusses challenges and strategies to providing personalized ART prognostics based on machine learning, and presents a case study where appropriate use of such prognostics in ART centres is associated with a trend towards increased ART utilization., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Second-generation preimplantation genetic testing for aneuploidy (PGT-A 2.0) in patients with an unfavourable reproductive and IVF prognosis is becoming common practice, with the aim of improving reproductive outcomes. However, there is still no clear evidence on the possible advantages and drawbacks with regard to this procedure. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Current evidence suggests that PGT-A 2.0 should not at present have an indiscriminate application, but it might be indicated in cases in which the risk of aneuploidy is increased., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: To evaluate the immunogenicity of follitropin delta in repeated ovarian stimulation., Design: Controlled, assessor-blind trial in IVF/intracytoplasmic sperm injection patients undergoing repeated cycles of ovarian stimulation (cycles 2 and 3), following initial stimulation with follitropin delta or follitropin alfa (cycle 1) in a preceding randomized trial. In cycles 2 and 3, 513 and 188 women, respectively, were treated as randomized in cycle 1, with dosing based on ovarian response in the previous cycle., Results: The incidence of treatment-induced anti-FSH antibodies with follitropin delta was 0.8% and 1.1% in cycles 2 and 3, respectively, which was similar to the incidence in cycle 1 (1.1%). No antibodies were of neutralizing capacity. Women with pre-existing anti-FSH antibodies were safely treated with follitropin delta without boosting an immune response. Treatment with follitropin delta and follitropin alfa gave similar outcomes for mean number of oocytes retrieved (9.2 versus 8.6 [cycle 2]; 8.3 versus 8.9 [cycle 3]), ongoing pregnancy (27.8% versus 25.7%; 27.4% versus 28.0%) and live birth rates (27.4% versus 25.3%; 26.3% versus 26.9%). The presence of anti-FSH antibodies did not affect the ovarian response., Conclusions: The trial demonstrated the low immunogenicity potential of follitropin delta in repeated ovarian stimulation, and confirmed the appropriateness of the follitropin delta dosing regimen in repeated cycles, with documented efficacy and safety., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research Question: How might time to healthy singleton delivery affect decision-making during infertility treatment?, Design: This was a Delphi consensus investigating expert opinion that comprised three steps. In Step 1, 12 experts developed statements. In Step 2, 27 experts (including 12 from Step 1) voted (online survey) on their agreement/disagreement with each statement (providing reasons). Consensus was reached if ≥66% of participants agreed/disagreed. Statements not reaching consensus were revised and the process repeated until consensus was achieved. In Step 3 details of the final agreed statements were communicated., Results: Twelve statements were developed, and consensus (agreement) was reached on all after one round of voting., Conclusions: Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over- or under-treatment. In all subfertile women <40 years old, IVF outcomes could be optimized by performing up to six single-embryo transfers and certain procedures might reduce time to healthy singleton delivery. These procedures include preimplantation genetic testing for aneuploidies, frozen replacement cycles immediately after failed fresh cycles and use of gonadotrophin-releasing hormone antagonists. Finally, the number of oocytes retrieved should be maximized to increase cumulative live birth rate., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hysteroscopic septum resection in women with unfavourable reproductive and clinical outcomes has become common practice worldwide to improve reproductive results. No clear evidence on the possible advantages and drawbacks of this procedure has been published. In this opinion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Currently, no level 1 published evidence supports uterine resection in women with septate uterus. Clinical evidence from the studies analysed matches the more recent guidelines and suggests an improvement in reproductive outcomes after hysteroscopic resection of the septum, particularly in infertile women and women who have experienced recurrent miscarriages. In a patient with no history of infertility or prior pregnancy loss, it may be reasonable to consider septum incision after counselling about the potential risks and benefits of the procedure. Published clinical data in favour of the intervention, however, are based on studies with important methodological limitations. In this situation, the clinician and patient should reach an agreement together, based on the pros and cons of this intervention. Well-designed randomized controlled trials are required to confirm the clinical benefits and cost-effectiveness of this procedure., (Copyright © 2018. Published by Elsevier Ltd.)

Research Question: Is minimal ovarian stimulation (MOS) as effective as conventional ovarian stimulation (COS) in ovarian response and embryo quality in the same 46 poor-responder patients according to the Bologna criteria?, Design: An intra-patient comparison of patients undergoing both protocols. Ovaries were stimulated with either a gonadotrophin-releasing hormone antagonist protocol and a combination of recombinant FSH and highly purified human menotrophin (HP-HMG) daily (COS), or with the use of clomiphene citrate 50 mg daily and 150 IU of HP-HMG or recombinant FSH every other day from simulation day 4 (MOS)., Results: After MOS, significantly more good-quality embryos (1.0 ± 1.2 versus 0.3 ± 0.6) (P = 0.002), oocytes (3.2 ± 1.9 versus 2.0 ± 1.8) (P = 0.002), and mature (metaphase II) oocytes (2.6 ± 1.7 versus 1.6 ± 1.7) (P = 0.001) were obtained. In COS cycles, a significantly higher total gonadotrophin dose was needed per good-quality embryo (+2194 IU; 95% CI 618 to 3170)., Conclusions: In poor responder patients, MOS is a good alternative when COS has failed, or even as a first-line treatment. It offered a significantly greater number of good-quality embryos as well as a higher number of oocytes, using significantly lower doses of gonadotrophins per oocyte and embryo obtained., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

The current study evaluated how a sudden fall in serum oestradiol during ovarian stimulation in donors affects recipient outcome. After the assessment of pregnancy rate in cases of oestradiol falls of <10 or > or =10% (57.0 versus 45.6%), <20 or > or = 20% (55.2 versus 44.9%), <25 or > or =25% (57.2 versus 41.2%), and < 30 or > or =30% (57.1 versus 32.0%; P < 0.05), a significantly lower pregnancy rate was observed when the fall was > or =30%. Therefore, the study group (n = 25) included recipients who received oocytes from donors with a fall of > or =30%, and the control group included patients (n = 197) in which the fall in oestradiol was <30% and all cases with no fall in oestradiol concentrations. Pregnancy rates in both groups were 32.0 versus 57.1%; P < 0.05. The number of morphologically normal oocytes was similar (14.2 versus 18.1%) and good quality embryos was lower (8.0 versus 21.0%; P < 0.05) for study group. This seems related to a lower capability of the embryos to implant (15.2 versus 37.4%; P < 0.001). These data indicate that a fall of > or =30% in serum oestradiol concentration during ovarian stimulation in donors negatively affects pregnancy rates and embryo quality in recipients. In these cases, cycle cancellation should be considered.