IVF Stimulation - personalized, optimized, and simplified using an advanced decision-support tool: A randomized trial

Study question Does using a clinical decision support tool, Opt-IVF, to guide hormone dosing during superovulation yield increased clinical pregnancy rates in routine clinical practice? Summary answer Higher clinical pregnancy rates were obtained using Opt-IVF to guide stimulatory hormone dosing during superovulation. What is known already ART success rates and cost depend heavily on the superovulation stage of the cycle. Two prospective single-center trials and one prospective multi-center trial had shown that using Opt-IVF to guide dosing resulted in increased numbers of high-quality embryos, used lower hormone doses, and required less ultrasound testing. This is a retrospective cohort study of the use of Opt-IVF in clinical practice over 12 months compared with the control cohort from the previous 12 months. Study design, size, duration Design: The study examined patients undergoing an IVF cycle using Opt-IVF in a single center for 12 months. Opt-IVF was used in all patients who presented to one of the investigators at Akanksha Hospital during the study period. As a comparison group, we examined patients from the previous 12 months when Opt-IVF was not used, and standard clinical protocols were followed to guide dosing. Duration: The study was conducted over 24 months Participants/materials, setting, methods 204 women aged 25-45 years underwent superovulation using hormone doses suggested by Opt-IVF (intervention). Of the participants, 19% were poor responders, 74% were below 35 years of age, 19% were 35-39 years of age, and 7% were above 39 years of age. The control group included 207 women, of whom 10% were poor responders. 72% were below 35 years of age, 26% were 35-39 years, and 2% were above 39 years of age. Main results and the role of chance The participants in the intervention group required significantly lower cumulative gonadotropin dosage compared to the control group during their controlled ovarian stimulation cycles (p < 0.0001). The average number of total embryos was 20% higher (p < 0.001), and the average number of good-quality embryos was 50% higher (p < 0.0001) in the Opt-IVF group than in the control group. Only 4.9% of cycles were canceled in the intervention group, compared to 12.9% canceled in the control group. Overall, Clinical pregnancy rates (including canceled cycles) increased from 35 % in the control group to 43% in the intervention group. The clinical pregnancy rate for poor responder patients was 39% in the Opt-IVF group but was only 16% in controls (p < 0.0001). Similarly, the clinical pregnancy rates were 34% in patients ages 35-39 years and 33% in patients above 39 years of age, much higher than the corresponding clinical pregnancy rates in controls (27% and 0%, respectively). Higher clinical pregnancy rates were also noted in the intervention group for normal responders and for younger patients. Limitations, reasons for caution This is a single-center retrospective cohort study. Wider implications of the findings Using Opt-IVF to guide dosing resulted in increased numbers of high-quality embryos and higher clinical pregnancy rates, particularly among older patients and poor responders. The proportions of these patients can be expected to grow in the future, so improving results in such patients is essential. Trial registration number not applicable

Day 2 embryo transfer (ET) and day 3 ET afford similar reproductive outcomes in the poor responder

Melatonin (MT) is involved in the regulation of various important biological processes related to reproduction. Many studies have investigated the effects of MT supplementation on outcomes following assisted reproductive technology (ART), yielding conflicting results. The aim of this systematic review was to synthesize evidence from clinical studies regarding the impact of MT on the key outcomes of ART. PubMed, Embase, Web of Science, and Google scholar were searched. Clinical trials that studied the effect of MT supplementation on outcomes following ART and published in English from inception to April 2020, were included. One author assessed the risk of bias in the studies using the Cochrane Collaboration checklist. Dichotomous outcomes were analyzed as risk ratios (RR) using the Mantel-Haenszel statistical method and a random/fixed effect model. Continuous outcomes were analyzed as Mean Difference (MD) using the Inverse Variance statistical method. The funnel plot was used to assess the publication bias. Eleven studies conducted between 2008 and 2019 were included in this meta-analysis. Clinical pregnancy rate (CPR), live birth rate (LBR), Miscarriage rate (MR), fertilization rate (FR), Number of oocytes retrieved, MII oocytes, top-quality embryos was reported in 10, 3, 6, 7, 9, 8, and 6 studies, respectively. MT supplementation significantly increased the CPR (RR, 1.24; 95% confidence interval [CI], 1.04, 1.47), the number of MII oocytes (MD, 1.39; 95% CI, 0.74, 2.04), the number of top-quality embryos (MD, 0.56; 95% CI, 0.24, 0.88), and the FR (4 studies with RR, 1.10; 95% CI, 1.03, 1.17; 3 studies with MD, 0.13; 95% CI, 0.01, 0.24). However, there was no significant difference in LBR (RR, 1.23; 95% CI, 0.85, 1.80), the number of oocytes retrieved (MD, 0.58; 95% CI, -0.12, 1.27), and the MR (RR, 0.96; 95% CI, 0.50, 1.82). When studies were sub-grouped by the control interventions, either myoinositol(MI) plus folic acid (FA) or placebo/no treatment, MT supplementation increased number of MII oocytes (MT + MI + FA vs. MI + FA, MD, 0.91; 95% CI, 0.40, 1.41; MT vs. Placebo/no treatment, MD, 2.06; 95% CI, 0.73, 3.39) and number of top-quality embryos (MT + MI + FA vs. MI + FA, MD, 0.70; 95% CI, 0.24, 1.16; MT vs. Placebo/no treatment, MD, 0.33; 95% CI, 0.11, 0.54), while the CPR remained comparable between groups(MT + MI + FA vs. MI + FA, RR, 1.22; 95% CI, 0.96, 1.54; MT vs. Placebo/No treatment, RR, 1.26; 95% CI, 0.97, 1.62). When sub-group analysis was performed basing on women's characteristics, MT supplementation showed no significant beneficial effect on CPR in women with polycystic ovary syndrome (PCOS) (RR, 1.18; 95% CI, 0.92, 1.52), normal ovarian function (RR, 1.15; 95% CI, 0.87, 1.53), or a history of low fertilization rates or poor-quality embryos (RR, 1.71; 95% CI, 0.95, 3.07). However, MT supplementation increased the number of MII oocytes in women with PCOS (MD, 0.97; 95% CI, 0.22, 1.73), but this benefit was not observed in women with normal ovarian function (MD, 1.49; 95% CI, -0.33, 3.31). As the outcomes of ART were influenced by multiple factors, MT supplementation may not significantly improve clinical pregnancy or live birth rate. However, MT appears to have a positive effect on oocyte and embryo quality, particularly in women with PCOS or decreased ovarian reserve (DOR), at least to some extent. Nevertheless, further well-designed, large-scale studies are needed before MT can be recommended for routine use in clinical practice.

Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS?

ObjectiveThis study aimed to evaluate the effect of three days of GnRH antagonist pretreatment on the pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) on GnRH antagonist protocols for IVF/ICSI.MethodsFifty women with PCOS in the control group received conventional antagonist protocols, starting on day 2 of the cycle. In the pretreatment group (n=38), a GnRH antagonist was administered from day 2 of the menstrual cycle for three days.ResultsControlled ovarian stimulation (COS) duration and gonadotropin dosages were similar in both groups. The number of metaphase II (MII) oocytes, 2PN oocytes, embryos, along with implantation and clinical pregnancy rates, were higher in the pretreatment group when compared with controls, although the increment was not significant (P value ≥0.05). The chemical pregnancy rate was significantly higher in the pretreatment group. The rate of OHSS was significantly lower in the pretreatment than in the control group.ConclusionWomen with PCOS offered early follicular phase GnRH antagonist pretreatment for three consecutive days had significantly fewer cases of OHSS and higher chemical pregnancy rates. There were trends toward greater numbers of MII oocytes, 2PN oocytes, and embryos, and higher clinical pregnancy rates in the pretreatment group.

The DuoStim protocol has been proposed as an alternative to conventional single and double stimulation cycles in the treatment of infertility. However, its efficacy in improving pregnancy outcomes remains uncertain. To systematically evaluate the impact of the DuoStim protocol on pregnancy outcomes in infertile patients by comparing it with single and double conventional stimulation cycles. An online systematic search was conducted using PubMed, Cochrane Library, and EMBASE databases, covering the period from their inception to March 2024. Randomized controlled trials (RCTs) comparing the DuoStim protocol with single and double conventional stimulation cycles in infertile patients were identified. Data were extracted by two independent investigators who screened the literature and assessed the quality of the studies. Meta-analysis was performed using RevMan 5.4 software. A total of six RCTs involving 414 infertile patients were included. The DuoStim protocol significantly increased the total number of oocytes compared to single and double conventional stimulation (MD = - 1.47; 95% CI, - 2.12 to - 0.82; P < 0.00001). There were no statistically significant differences in the number of MII oocytes, total embryos, pregnancy rate, and live birth rate. Subgroup Analysis: compared to single stimulation, the DuoStim protocol significantly increased the number of MII oocytes (MD = 1.71; 95% CI, 0.77 to 2.66; P = 0.0004) and total embryos (MD = 1.34; 95% CI, 0.61 to 2.08; P = 0.0003). There were no significant differences in pregnancy rate and live birth rate. Secondary outcomes showed the effect of the DuoStim protocol in patients undergoing preimplantation genetic testing for aneuploidies (PGT-A). The time to obtain euploid blastocysts was significantly reduced in the DuoStim group compared to the control group (23.3 ± 2.8days vs. 44.1 ± 2.0days; P < 0.001). The DuoStim protocol shows a significant advantage in increasing the total number of oocytes, MII oocytes, and embryos compared to single stimulation. However, it does not significantly improve pregnancy and live birth rates. The protocol also shortens the time to obtain euploid blastocysts in patients undergoing PGT-A, indicating potential benefits for specific patient groups. Further research is needed to confirm these findings and evaluate long-term outcomes. Thus, the quality of evidence should be considered moderate, warranting cautious interpretation of the results.

Clinical Decision Support Tools

Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting

Objective: To evaluate the clinical effect of oral contraceptive (OC) pretreatment on the outcome of gonadotropin releasing hormone antagonist (GnRH-a) protocol in patients with non-polycystic ovary syndrome. Methods: From January 2017 to May 2019, a total of 436 patients undergoing in vitro fertilization and embryo transfer/Intracytoplasmic sperm injection (IVF-ET/ICSI) treatment in Peking University First Hospital reproductive center clinic were included in this retrospective cohort study. A total of 144 patients (147 cycles) used OC pretreatment prior to GnRH-a protocol and 292 patients (306 cycles) used GnRH-a protocol without OC pretreatment. The drug usage as well as pregnant outcomes between groups were examined. The primary outcome was the cumulative clinical pregnancy rate of oocyte retrieval cycle and the secondary outcome included the number of oocytes, MⅡ oocytes, embryos and clinical pregnancy rate of fresh embryo transfer cycle. Results: The median ages (and Q1, Q3) of OC pretreatment group and non-OC group were 33 (30,36) and 34 (30,38) years old, respectively. The number of MⅡ oocytes was higher in OC pretreatment group (7/9) than in non-OC group (6/8) (P=0.002). The significant difference were not found in the cumulative clinical pregnancy rate of each oocyte retrieval cycle (61.7% vs 54.6%), the clinical pregnancy rate of fresh embryo transfer cycle (34.4% vs 35.6%), and the number of oocytes (9 vs 8) and embryos (6 vs 6) between groups. Conclusion: Our findings suggest that compared to non-OC pretreatment group, pretreatment with OC is associated with more MⅡ oocytes, and with an increasing trend of the cumulative clinical pregnancy rate in non-polycystic ovary syndrome patients undergoing fresh IVF-ET/ICSI.

The purpose of this study was to determine the incidence of premature luteinization in patients with polycystic ovary syndrome and compared the main determinants of success in in-vitro fertilization in PCOS patients with and without premature luteinization. Retrospective analysis of 180 PCOS women of Chinese Han origin with infertility who underwent controlled ovarian hyperstimulation (COH) with an exogenous gonadotropin/GnRH antagonist protocol. Hormone levels on the hCG day and IVF outcomes were assessed. The incidence of premature luteinization was 23.3 %. Compared with PCOS patients without premature luteinization, PCOS patients with premature luteinization(PL) had a higher number of oocytes retrieved (18.20 ± 6.6 vs 15.08 ± 7.3, p = 0.037) and a higher fertilization rate (72.9 ± 1.9 vs63.1 ± 2.3, p = 0.033), but clinical pregnancy rates were no statistical significance (53.3 vs 56.0, p = 0.836). Though the implantation rate was higher in no premature luteinization patients, but the difference was not statistically significant (37.7 vs 30.3, p = 0.115). The PCOS patients with premature luteinization had a higher fertilization rate and high number of oocytes retrieved, and the similar implantation rate and clinical PRs as PCOS patients without premature luteinization.

Comparison of survival rate of cleavage stage embryos produced from in vitro maturation cycles after slow freezing and after vitrification

Study question How can we find an ovarian stimulation method that does not cause hyper stimulation syndrome but can produce a high pregnancy rate at one cycle? Summary answer This newly developed method for PCOS has a higher accumulative clinical outcome for one trial and no OHSS. What is known already Almost all conventional treatments for PCOS have managed to avoid OHSS by reducing the number of growing follicles, which are associated with high Estradiol levels and stimulate the production of vessel endothelial growth hormone (VEGF), leading to increased vessel permeability. Low dose FSH administration, In vitro maturation (IVM), Ovarian Drilling and Coasting have been performed to achieve this. However, their actual clinical outcome is still unsatisfactory. Study design, size, duration Evaluation of the efficiency of this method was conducted retrospectively at St. Mother Clinic. The embryonic development and the clinical outcome were studied for 34 PCOS patients during the period between November 2018 and December 2019. Participants/materials, setting, methods We started injections of FSH (150iu/ml), then we did ultrasound follicle monitoring. GnRH antagonist shots were started when the leading follicle reached 18mm and continued until the largest follicle was 22–24mm and the E2 value was over 4000pg/ml. Letrozole (2.5mg) and leuprorelin acetate (1.88mg) was injected as trigger. Two tablets each of Letrozole, Cabergoline and GnRH antagonist were given for 5 consecutive days after the oocyte retrieval. All embryos were cryopreserved. Main results and the role of chance Number of patients and cycles were 34 and 59. Average number of cryopreserved blastocysts was 6.12 (1–16). The frequencies of OHSS (mild, moderate, severe) were 29.4% (10/34), 0% (0/34), 0% (0/34). Average days between oocyte collection and withdrawal hemorrhage was 5.44(5–7). Cryopreservation rate was 100.0% (34/34). Clinical pregnancy rate and miscarriage rate was 42.3% (25/59) and 16.0% (4/25). The cumulative pregnancy rate was 73.7% (25/34). The four remaining unsuccessful cases still have 10,6,3 and 7 frozen embryos. So, there is a high possibility that they become successful, that would bring the cumulative pregnancy rate up to 82.3% (28/34). Limitations, reasons for caution This COS for PCOS seems promising, however it is premature to conclude that this method is established. This method requires caution monitoring for hormone level, follicle size and number and coagulant function. It also accompanied with the risk of ovarian hemorrhage on aspiration of a great number of oocytes. Wider implications of the findings: This COS seems viable for PCOS cases. It could control the cohort of antral follicles with different doses of Letrozole to find the optimal COH method and it could become the first option for COS of PCOS. Trial registration number N/A

Study question How does low-dose follitropin delta administration affect follicular growth and sex steroid levels in patients with polycystic ovary syndrome (PCOS) during ovarian stimulation for IUI? Summary answer In PCOS, low-dose follitropin delta safely induces follicular growth. Predictors of ovarian response are follicular pool size and AMH levels. Algorithm shows comparable pregnancy rates What is known already PCOS affects 8-13% of reproductive-age women. Controlled ovarian stimulation (COS) for IUI is a primary treatment. Elevated BMI and AMH levels in PCOS disrupt gonadotropin secretion, impair follicular growth, and increase FSH threshold compared to non-PCOS women. Follitropin delta (FD), effective in IVF cycles, induces a stronger ovarian response than traditional rFSH and uses an AMH/weight-based dosing algorithm to optimize results. Recent research has indicated that FD can be used for COS in IUI cycles. PCOS patients were excluded from prior studies, leaving a gap in understanding FD’s effect on ovarian response using a low-dose AMH/weight algorithm in COS-IUI cycles. Study design, size, duration This study is a prospective cohort dose-response investigation designed to evaluate ovarian response in patients undergoing controlled ovarian stimulation for intrauterine insemination (IUI) cycles, utilizing a low-dose follitropin delta based on an AMH/weight algorithm. The cohort includes 35 patients diagnosed with PCOS by Rotterdam Criteria. Each participant underwent 3 COS consecutive cycles, with recruitment initiated in 2023. This report presents the findings for 20 participants, corresponding to 38 Follitropin delta-COS cycles Participants/materials, setting, methods PCOS women (20) corresponding to 38 cycles were assessed. FD dosing (2–9µg/day) tailored to AMH and weight, discontinued with a follicle ≥15mm. Measurements: Follicular pools(&amp;lt;10mm, 10–15mm,≥16mm), LH, testosterone, and estradiol. Ovarian responses (OR): non-responders (no dominance by day 22), expected (1–2 follicles ≥17mm), hyper-response (≥3follicles). Dose adjustments: 50% increase in non-responders, 33% decrease in hyper-responders in next cycle.OR rates, follicular growth patterns, hormonal profiles were compared across FD dose groups(2–3.66, 4–5.66, 6–13.66µg/day). Main results and the role of chance The PCOS group was characterized by a median age of 31 years median BMI of 30.9 kg/m², and median waist-to-hip ratio of 0.9. Obesity was present in 63.2% of participants, and phenotype A (55%) was significantly more prevalent than phenotypes B, C, and D (p&amp;lt;0.005). A higher proportion of patients weighed 70–90kg (44.7%) compared to those &amp;lt;70kg or &amp;gt; 90kg (p&amp;lt;0.05). A progressive decline in NR rates was observed with increasing FD dose (p&amp;lt;0.05). NR patients exhibited higher antral follicle counts and more follicles &amp;lt;10mm during COS compared to ER and HR (p&amp;lt;0.005). ER rates were lower in the 6–13.66µg/day group compared to &amp;lt; 6µg/day (p&amp;lt;0.005), while HR occurred exclusively in the 6–13.66µg/day group, showing a larger pool of follicles measuring 10–16mm after day 5 of stimulation (p&amp;lt;0.01). Stimulation days were significantly longer in NR compared to ER and HR (p&amp;lt;0.005). Estradiol levels increased progressively from day 5 in ER and HR (p&amp;lt;0.005), but not in NR. AMH levels on day 1 were higher in NR than ER and HR (p&amp;lt;0.01), while LH and testosterone levels remained similar across all groups. The clinical pregnancy rate was 13.6% (3 pregnancies) per inseminated cycle, with no multiple pregnancies or hyperstimulation syndrome reported. Limitations, reasons for caution This is a preliminary report from a prospective study that is recruiting 40 subjects across 120 cycles. Although the small sample size may introduce some bias, it also highlights the need for further research. Conducting larger, multicenter trials could provide a more comprehensive understanding of the issue at hand. Wider implications of the findings Interim results suggest that Low-dose follitropin delta, using an AMH/weight algorithm for PCOS patients in COS-IUI cycles, is promising. Incorporating antral follicle count may reduce hyperstimulation risk while preserving pregnancy rates comparable to other treatments. Larger trials are required to validate results and optimize protocols. Trial registration number No

Introduction AMH, is a member of the transforming growth factor (TGF-β) produced by granulosa cells with the highest expression being in small antral follicles. Our objective is to evaluate the predictive value of follicular AMH levels as an indicator of IVF outcomes in PCOS patients. Material and methods A total of 63 patients undergoing the IVF trail were recruited for this prospective case-control study. The patients were classified into three groups: Group I: 43 patients with Polycystic ovary syndrome (PCOS). Group II: 20 normo-ovulatory patients were recruited for the IVF trail because of the male infertility factor (control group). Group III: consists of 33 patients from group I recruited to determine the effect of controlled ovarian hyperstimulation (COH) on serum AMH levels. Serum AMH levels were performed on day 3 of the menstrual cycle whereas the follicular fluid AMH level has been evaluated at the time of oocyte retrieval by enzyme linked immune-sorbent assay (AMH Gen II ELISA kit, Beckman Coulter, Inc. USA). AMH concentrations were adjusted to its protein content, to avoid possible bias due to FF volume variability. The relationship between follicular fluid AMH (FF AMH) levels and the number of oocytes retrieved, number of mature oocytes, number of embryos, fertilization and clinical pregnancy rate were assessed. The demographic data were similar between two groups as regards age and BMI. Results Both serum AMH levels and FF AMH levels were significantly higher in PCOS patients than in the controls, the values for serum levels were (5.07 ± 3.39 ng/ml, 3.07 ± 2.09 ng/ml) respectively and for follicular fluid levels were (67 ± 50.7 ng/g∗, 38.5 ± 44.4 ng/g) respectively. Serum AMH levels showed a positive correlation with oocytes retrieved and mature oocyte number, but there was no significant correlation with good quality embryo number, fertilization rate or clinical pregnancy rate in PCOS patients. On the other hand FF AMH levels do not show correlation with any of the IVF outcomes mentioned above in PCOS patients. Interestingly, the interval change in serum AMH levels between baseline AMH levels and levels after COH had a significant predictive value of pregnancy. Conclusions Serum AMH levels can predict the number of the retrieved oocytes and mature oocytes, whereas FF AMH may not be a valuable predictor for IVF outcomes in PCOS patients.

Due to the complexity of controlled ovarian stimulation (COS), in its decision-making process, there are a number of factors that should be taken into consideration, like the choices of gonadotropins (Gn) and gonadotropin releasing hormone (GnRH) analogues, COS and luteal phase support protocols, et al. Based on experience from over 30 years of practice, physicians have come to an agreement that more oocytes resulted from an aggressive COS strategy is not always better, while we should do a comprehensive evaluation about the trade-off between maximal accumulative live birth rate and the medical and monetary burden, including the risk of ovarian hyperstimulation syndrome (OHSS) and high-order multiple gestations. In order to individualize COS treatment, the key is to standardize evaluation and categorization of the patients undergoing COS treatment. All the patients could be generally divided into four categories: normal responders, slow responders, hyper responders and poor responders. Most young patients undergoing COS treatment with undiminished ovarian reserve should be categorized as normal responders. For these patients, large-scale meta-analysis suggests that the optimal daily recombinant follicular stimulating hormone (recFSH) stimulation dose is 150-225 IU/day, and patient-tailored adjustment should done based on individual patients characteristics including basal FSH, Anti-Müllerian hormone (AMH), body mass index and age et al. The definition of the term ‘hyper response’ refers to the retrieval of >15 oocytes and a rapid rise in estradiol levels. Previous history of OHSS and makers of ovarian reserve, in particular AMH and antral follicle counting (AFC) strongly suggest the possibility of showing a high response to a standard COS protocol. The prevalence of hyper response in all IVF cycles is estimated to be 3-6%. Patients with polycystic ovary syndrome (PCOS) have increased Gn sensitivities and present a higher risk of developing OHSS. The narrow margin between an inadequate Gn dose and excessive stimulation (OHSS) is a challenging situation. An inadequate Gn dose is not capable to stimulate multiple follicles development, resulting in cycle cancellation, while excessive ovarian stimulation in these patients commonly leading to a certain degree of OHSS. A low starting dose of Gn, 37.5 IU, is recommended by the consensus on PCOS infertility treatment endorsed by both the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine. Poor ovarian response indicates a reduction in follicular response, at least two of the following features must be present: (I) advanced maternal age (≥40 years) or any other risk factor for poor ovarian response; (II) a previous poor ovarian response (≤3 oocytes with a conventional stimulation protocol); (III) an abnormal ovarian reserve test (i.e., AFC <5-7 follicles or AMH <0.5-1.1 ng/mL). For these poor responders, the supplementation of recLH is beneficial. Significantly more oocytes and better clinical pregnancy rate could be achieved in women treated with recFSH plus recLH vs. recFSH alone. In our reproductive medical center, a comprehensive protocol is employed to better the outcomes of the poor responders, including DHEA pretreatment, oral contraceptive pretreatment, high-dose recFSH priming, supplementation of recLH et al. Besides these categories of patients with different sensitivity to ovarian stimulation, slow responders are featured by no follicles larger than 10 mm and low estradiol level (E2 <180 pg/mL) on the 6th day of stimulation. The velocity of their follicle development is also reduced (<2 mm for three consecutive days). According to our practice, adding recombinant luteinizing hormone might be beneficial.