Enhancing predictive models for egg donation: time to blastocyst hatching and machine learning insights.

BACKGROUND: Data sciences and artificial intelligence are becoming encouraging tools in assisted reproduction, favored by time-lapse technology incubators. Our objective is to analyze, compare and identify the most predictive machine learning algorithm developed using a known implantation database of embryos transferred in our egg donation program, including morphokinetic and morphological variables, and recognize the most predictive embryo parameters in order to enhance IVF treatments clinical outcomes. METHODS: Multicenter retrospective cohort study carried out in 378 egg donor recipients who performed a fresh single embryo transfer during 2021. All treatments were performed by Intracytoplasmic Sperm Injection, using fresh or frozen oocytes. The embryos were cultured in Geri® time-lapse incubators until transfer on day 5. The embryonic morphokinetic events of 378 blastocysts with known implantation and live birth were analyzed. Classical statistical analysis (binary logistic regression) and 10 machine learning algorithms were applied including Multi-Layer Perceptron, Support Vector Machines, k-Nearest Neighbor, Cart and C0.5 Classification Trees, Random Forest (RF), AdaBoost Classification Trees, Stochastic Gradient boost, Bagged CART and eXtrem Gradient Boosting. These algorithms were developed and optimized by maximizing the area under the curve. RESULTS: The Random Forest emerged as the most predictive algorithm for implantation (area under the curve, AUC = 0.725, IC 95% [0.6232-0826]). Overall, implantation and miscarriage rates stood at 56.08% and 18.39%, respectively. Overall live birth rate was 41.26%. Significant disparities were observed regarding time to hatching out of the zona pellucida (p = 0.039). The Random Forest algorithm demonstrated good predictive capabilities for live birth (AUC = 0.689, IC 95% [0.5821-0.7921]), but the AdaBoost classification trees proved to be the most predictive model for live birth (AUC = 0.749, IC 95% [0.6522-0.8452]). Other important variables with substantial predictive weight for implantation and live birth were duration of visible pronuclei (DESAPPN-APPN), synchronization of cleavage patterns (T8-T5), duration of compaction (TM-TiCOM), duration of compaction until first sign of cavitation (TiCAV-TM) and time to early compaction (TiCOM). CONCLUSIONS: This study highlights Random Forest and AdaBoost as the most effective machine learning models in our Known Implantation and Live Birth Database from our egg donation program. Notably, time to blastocyst hatching out of the zona pellucida emerged as a highly reliable parameter significantly influencing our implantation machine learning predictive models. Processes involving syngamy, genomic imprinting during embryo cleavage, and embryo compaction are also influential and could be crucial for implantation and live birth outcomes.

Feasible Influence of G-CSF on Clinical Pregnancy Outcome in Oocyte Donation Cycles for Patients with Recurrent Implantation Failure.

Background and Objectives: The aim of our single-center cohort study was the determination of the influence of the intrauterine lavage of granulocyte colony-stimulating growth factor (G-CSF) on clinical pregnancy rate in patients with a history of implantation failure older than 40 years. Materials and Methods: The study was conducted in Ferticare Prague SE between May 2018 and June 2020. Overall, 115 patients were distributed into two arms, with 48 subjects in the experimental and 67 in the control arm. All women have had a previous history of unsuccessful history of infertility treatment with their own genetic material and at least one ineffective cycle with the donated oocytes. The experimental arm underwent the intrauterine lavage of 0.5 mL of pure G-CSF from 120 to 48 h prior to embryo transfer. Results: The clinical pregnancy rate was 63.3% in the experimental arm and 47.8% in the control arm (p = 0.097 for Pearsonߣs χ2, and p = 0.133 for Fisher's exact test). However, the mean endometrial thickness on the day of embryo transfer did not appear to be statistically different (p = 0.139). Only the difference in endometrium thickness growth was statistically significant (p = 0.023). The increase in pregnancy rate is still encouraging for the future, even if it is not significant. Conclusion: Our study suggests the trend of increased pregnancy rate after the intrauterine G-CSF lavage in the interval of 120-48 h prior to embryo transfer.

Does paternal age affect the live birth rate in donor oocyte cycles? A systematic review and meta-analysis.

PURPOSE: While delayed parenthood is increasing worldwide, the effect of paternal age on in vitro fertilization (IVF) outcomes remains unclear. The egg donation model appears to be relevant to studying the independent impact of paternal age on clinical outcome, but the available studies are heterogeneous and contradictory. This systematic review and meta-analysis aimed to assess the relationship between paternal age and live birth rate (LBR) in egg donation cycles. METHODS: A systematic search of the literature was conducted in PubMed, Embase, and the Cochrane Library from inception to June 30, 2021. All studies on egg donation cycles where LBR is reported according to male age were included. Study selection, bias assessment, and data extraction were performed by two independent reviewers according to the Cochrane methods. RESULTS: Eleven studies involving 10,527 egg donation cycles were finally included. The meta-analysis showed a slight but significant and linear decrease in LBR with increasing paternal age (estimate - 0.0055; 95% CI (- 0.0093; - 0.0016), p = 0.006), with low heterogeneity (I2 = 25%). No specific threshold was identified. A similar trend toward decreased clinical pregnancy rate with advancing paternal age was found but did not reach statistical significance (p = 0.07). CONCLUSION: This meta-analysis demonstrates that increasing paternal age is associated with a slight but significant and linear decrease in the live birth rate in egg donation cycles, with no apparent threshold effect. Although this requires further confirmation, this information is important for counseling men who are considering delayed childbearing.

Assisted reproductive technology and hypertensive disorders of pregnancy: systematic review and meta-analyses.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is one of the most common pregnancy complications and causes of maternal morbidity and mortality. Assisted reproductive technology (ART) has been associated with adverse pregnancy outcomes, including HDP. However, the impact of multiple pregnancies, oocyte donation, as well as fresh and frozen embryo transfer needs to be further studied. We conducted a systematic review and meta-analyses to evaluate the association between ART and HDP or preeclampsia relative to spontaneous conception (SC). METHODS: We identified studies from EMBASE, MEDLINE, and Cochrane Library (up to April 8, 2020) and manually using structured search strategies. Cohort studies that included pregnancies after in vitro fertilization (IVF) with or without intracytoplasmic sperm fertilization (ICSI) relative to SC with HDP or preeclampsia as the outcome of interest were included. The control group was women who conceived spontaneously without ART or fertility medications. The pooled results were reported in odds ratios (OR) with 95% confidence intervals based on random effects models. Numbers needed to harm (NNH) were calculated based on absolute risk differences between exposure and control groups. RESULTS: Eighty-five studies were included after a screening of 1879 abstracts and 283 full text articles. Compared to SC, IVF/ICSI singleton pregnancies (OR 1.70; 95% CI 1.60-1.80; I2 = 80%) and multiple pregnancies (OR 1.34; 95% CI 1.20-1.50; I2 = 76%) were both associated with higher odds of HDP. Singleton pregnancies with oocyte donation had the highest odds of HDP out of all groups analyzed (OR 4.42; 95% CI 3.00-6.51; I2 = 83%). Frozen embryo transfer resulted in higher odds of HDP (OR 1.74; 95% CI 1.58-1.92; I2 = 55%) than fresh embryo transfer (OR 1.43; 95% CI 1.33-1.53; I2 = 72%). The associations between IVF/ICSI pregnancies and SC were similar for preeclampsia. Most interventions had an NNH of 40 to 100, while singleton and multiple oocyte donation pregnancies had particularly low NNH for HDP (16 and 10, respectively). CONCLUSIONS: Our meta-analysis confirmed that IVF/ICSI pregnancies are at higher odds of HDP and preeclampsia than SC, irrespective of the plurality. The odds were especially high in frozen embryo transfer and oocyte donation pregnancies.

Mode of delivery of women with Swyer syndrome in a German case series.

OBJECTIVES: For women with Swyer Syndrome, a 46,XY gonadal dysgenesis, full term pregnancies are possible after oocyte donation. According to literature, mode of delivery is almost always by Caesarean section for various reasons. Medical indications are multiple pregnancies and related complications, preeclampsia, an androgynous shaped pelvis and failed induction of labor. Elective Caesarean sections were performed based on maternal request and medical recommendation. METHODS: Following careful examination and shared decision making, we planned a spontaneous delivery with a patient with Swyer syndrome and tested the different hypotheses regarding anatomical and functional features according to literature. In addition, deliveries of women with Swyer Syndrome were analyzed in a German multicenter case series. RESULTS: A total of seven women with Swyer syndrome with a total of 10 pregnancies were identified, who later gave birth to twelve live-born children. Seven out of 10 births were performed by elective and non-elective Caesarean section, three births took place vaginally. CONCLUSIONS: In summary, the risk of Caesarean section delivery has increased, but spontaneous delivery can be attempted in the event of inconspicuous findings.

Differential sperm proteomic profiles according to pregnancy achievement in intracytoplasmic sperm injection cycles: a pilot study.

PURPOSE: To describe the proteomic profiles in semen samples and define the differences in sperm proteomic profiles among samples that ultimately achieved pregnancy (P) via intracytoplasmic sperm injection (ICSI) in an oocyte donation program and those that were unsuccessful (NP). METHODS: Prospective, analytical, observational nested case and control study evaluating the proteomic profile of spermatozoa from patients' ejaculates where pregnancies were (group pregnant (P), n= 4) or were not (group non-pregnant (NP), n=4) achieved after ICSI in an oocyte donation program aiming to standardize female factor. Proteins were separated and analyzed by means of SWATH-MS) and compared between P/NP groups to identify sperm biomarkers of fertility/infertility. Proteins are available via ProteomeXchange. RESULTS: We identified and quantified 2228 proteins, with 37 significantly higher in the P group and 16 higher in NP. Enrichment analysis revealed that the increased proteins in P group sperm were related to motility, anaerobic metabolism, and protein biosynthesis functions, while the increased proteins in the NP group were involved in protein biosynthesis, protein folding, aerobic metabolism, and signal transduction, all of which are functions not previously described as influencing sperm success. Some proteins identified (e.g., SLC2A3, or CD81) are located in the cell membrane and thus may be employed to select spermatozoa by magnetic-activated cell sorting (MACS). CONCLUSION(S): This work revealed differences in the proteomic profiles of sperm samples successful in achieving pregnancy and those that were not, expanding our understanding of sperm function and infertility-related molecular markers, and enabling the future development of male fertility diagnostic tools and therapies.

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle.

PURPOSE: Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)? METHODS: Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement. RESULTS: In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4-28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03). CONCLUSION: A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

Preimplantation genetic testing for aneuploidies does not increase success rates in fresh oocyte donation cycles: a paired cohort study.

PURPOSE: To determine whether in vitro fertilization cycles using fresh oocyte donations benefit from preimplantation genetic testing for aneuploidies. METHODS: A paired cohort study compared 44 fresh oocyte donation cycles with or without preimplantation genetic testing for aneuploidy (PGT-A). The sibling oocyte study analyzed fertilized oocytes, blastocyst development, and euploidy rate. Only frozen embryo transfers were performed. Pregnancy, implantation, biochemical pregnancy, miscarriage, stillbirth, live birth, and twin pregnancy rates were analyzed between groups. RESULTS: Fresh oocyte donation cycles between PGT-A and non-PGT-A groups were similar in all laboratory and clinical outcomes. A euploidy rate of 74.2% was observed in the PGT-A group. Although a slight trend was observed for implantation rate in the PGT-A group, it was not statistically significant. No difference was observed for live birth between groups. CONCLUSION: PGT-A associated with fresh oocyte donation cycles does not improve clinical outcomes and can be seen as over-treatment for patients.

High-security closed devices are efficient and safe to protect human oocytes from potential risk of viral contamination during vitrification and storage especially in the COVID-19 pandemic.

PURPOSE: The main purpose and research question of the study are to compare the efficacy of high-security closed versus open devices for human oocytes' vitrification. METHODS: A prospective randomized study was conducted. A total of 737 patients attending the Infertility and IVF Unit at S.Orsola University Hospital (Italy) between October 2015 and April 2020 were randomly assigned to two groups. A total of 368 patients were assigned to group 1 (High-Security Vitrification™ - HSV) and 369 to group 2 (Cryotop® open system). Oocyte survival, fertilization, cleavage, pregnancy, implantation, and miscarriage rate were compared between the two groups. RESULTS: No statistically significant differences were observed on survival rate (70.3% vs. 73.3%), fertilization rate (70.8% vs. 74.9%), cleavage rate (90.6% vs. 90.3%), pregnancy/transfer ratio (32.0% vs. 31.8%), implantation rate (19.7% vs. 19.9%), nor miscarriage rates (22.1% vs. 21.5%) between the two groups. Women's mean age in group 1 (36.18 ± 3.92) and group 2 (35.88 ± 3.88) was not significantly different (P = .297). A total of 4029 oocytes were vitrified (1980 and 2049 in groups 1 and 2 respectively). A total of 2564 were warmed (1469 and 1095 in groups 1 and 2 respectively). A total of 1386 morphologically eligible oocytes were inseminated by intracytoplasmic sperm injection (792 and 594 respectively, P = .304). CONCLUSIONS: The present study shows that the replacement of the open vitrification system by a closed one has no impact on in vitro and in vivo survival, development, pregnancy and implantation rate. Furthermore, to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential samples' contamination during vitrification and storage.

Ovarian hyperstimulation syndrome following GnRH agonist trigger for final follicular maturation in a patient undergoing random start ovarian stimulation for egg-donation cycle with an inadvertent concomitant early pregnancy.

We report the first case of OHSS following GnRH agonist trigger for final follicular maturation in random start ovarian stimulation for egg-donation cycles during inadvertent concomitant early pregnancy. As an additional note, the sustained activity exerted by the increasing endogenous hCG production seemed to be responsible for the suboptimal performance in terms of oocyte yield in the current case. OHSS can occur in random-start stimulations protocols even after the use of a GnRH agonist for triggering in case of concomitant unnoticed early pregnancy especially if stimulation is commenced in the periovulatory/luteal phase. The present case report introduces a note of extreme caution when proceeding with this protocol in an otherwise fertile population (egg-donors, elective or oncologic oocyte cryopreservation).

Closed vs. Open Oocyte Vitrification Methods Are Equally Effective for Blastocyst Embryo Transfers: Prospective Study from a Sibling Oocyte Donation Program.

PURPOSE: To assess whether open and closed vitrification protocols are equally effective for sibling-oocyte cycles when performing blastocyst embryo transfers. MATERIALS AND METHODS: A prospective study was set up comparing the open and the closed vitrification techniques in oocyte recipients sharing sibling oocytes between 2014 and 2016. Sibling oocytes were randomly and equally assigned into the closed group (oocytes vitrified in a closed system) or the open group (oocytes vitrified in an open system). Intracytoplasmic sperm injection was performed on all cases. Embryo transfers were performed on day 5. Power analysis calculation showed that 94 cycles would be needed for each group in the study in order to achieve statistical significance at a 5% level with power 80%. RESULTS: The final number of donors included was 95. A total of 190 recipients matched with their donors were included in the study. There was no difference in the mean number of oocytes vitrified with the closed or the open system (8.26 ± 2.54 vs. 8.31 ± 2.57). No significant difference was observed between the 2 groups regarding survival rate, fertilization rate, cleavage rate, top-quality embryos on day 3, blastocyst rate, and top-quality blastocyst rate. Moreover, no statistically significant difference in the b-human chorionic gonadotropin-positive rate, clinical pregnancy rate per cycle, implantation rate, ongoing pregnancy rate, and live birth rate between closed and open groups. CONCLUSION: Οpen and closed vitrification protocols are equally effective for sibling-oocyte cycles.

Euploid rates among oocyte donors: is there an optimal age for donation?

PURPOSE: To examine cycle blastocyst euploid rates among age subgroups of oocyte donors. METHODS: Retrospective cohort analysis of ova donation in vitro fertilization cycles (OD-IVF) for which trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) by array comparative genomic hybridization (aCGH) or next generation gene sequencing (NGS) was employed between January 2015 and December 2018 in a single high-volume fertility center. RESULTS: Compared to oocyte donors age 26-30, oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates (80 [66.7, 87.5]%, vs. 75 [62.5, 87.5]%, median [IQR], p = 0.07), blastocyst formation rates (66.7 [50, 75]%, vs. 62.5 [52, 75]%, p = 0.55), and number of retrieved oocytes (29 [23, 37] vs. 27 [20, 35], p = 0.18). Age of oocyte donor from 18 to 34 was not correlated with cycle blastocyst euploid rate. CONCLUSION: Oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates, blastocyst formation rates, and number of retrieved oocytes compared to donors age 26-30. There was no correlation between cycle blastocyst euploid rates and age of the oocyte donor from 18 to 34 years. Given the lack of significant age-related change in cycle blastocyst euploid rates, our data support existing practices which do not favor a specific age subgroup of young oocyte donors.

'Two countries-two labs': the transnational gamete donation (TGD) programme to support egg donation.

PURPOSE: To evaluate the effectiveness, efficiency, and safety of a transnational gamete donation (TGD) programme based on the shipping of vitrified donor oocytes. METHODS: A retro-prospective observational study was conducted in the Assisted Reproductive Technology Center of the University Hospital of Florence, Italy. The study population included 622 consecutive donor oocyte cycles. A mean number of 6 vitrified oocytes per couple were shipped from two Spanish biobanks. In the receiving centre, gametes were warmed and inseminated and the subsequent embryo transfer (ET) was performed. The main outcome measurement was LBR. Secondary outcomes included oocyte survival rate, ICSI damage rate, normal fertilization, cleavage, and implantation rate (IR) in both 'fresh' and cryotransfer cycles. RESULTS: A total number of 3536 mature oocytes were warmed with 81.4% surviving oocytes. 2PN oocytes were 1941 with an ICSI normal fertilization rate of 70.4% and a cleavage rate of 93.4%; 857 day-3 embryos were transferred in 498 women, 63 blastocysts in 44. Couples with at least one vitrified embryo were 181 (32.3%). IR was 25.1% and 33.1% for day-3 ET and blastocyst stage respectively. Crude pregnancy rate and LBR after the first ET were 35.5% and 27% correspondingly with a conservative cumulative LBR of 34% and an optimal LBR of 51.4%. CONCLUSION: Imported vitrified donor oocytes retain their competence and are capable of resulting in ongoing pregnancies and healthy babies in a proportion comparable to other existing systems as egg donation with vitrification/warming in the same laboratory and transnational fresh oocyte donation.

Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies.

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.

Ovarian stimulation outcomes among transgender men compared with fertile cisgender women.

PURPOSE: To compare assisted reproductive technology (ART) outcomes among transgender men with those of fertile cisgender women. METHODS: This retrospective cohort study included 12 transgender men, six with no testosterone exposure and six after testosterone treatment, and 12 cisgender women (oocyte donors) who underwent ART in our institution between June 2017 and December 2019. Statistical analyses compared ART data and outcomes between three groups: cisgender women, transgender men without testosterone exposure, and transgender men after testosterone exposure. Comparisons were also made between transgender men with and without testosterone exposure. RESULTS: The transgender men with no testosterone exposure (23.3 ± 4 years) were significantly younger than the transgender men who had undergone testosterone treatment (30.3 ± 3.8 years; P = 0.012) and the cisgender women (29.1 ± 3.1 years; P = 0.004). The amount of FSH used for ovulation induction (1999 ± 683 mIU/mL) was significantly lower among transgender men without prior testosterone exposure compared with that among cisgender women (3150 ± 487 mIU/mL; P = 0.007). There were no differences in the peak estradiol levels, the number of oocytes retrieved, the number of MII oocytes, and the oocyte maturity rates between the three groups. Five out of six testosterone-treated transgender men underwent embryo cryopreservation, and they all achieved good-quality embryos. CONCLUSIONS: Transgender men have an excellent response to ovulation stimulation even after long-term exposure to testosterone. Oocyte/embryo cryopreservation is, therefore, a feasible and effective way for them to preserve their fertility for future biological parenting.

The Role of Macrophages in Oocyte Donation Pregnancy: A Systematic Review.

The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by acting in immunomodulation and spiral arterial remodeling. OD pregnancies represent an interesting model to study complex immunologic interactions between the fetus and the pregnant woman since the embryo is totally allogeneic compared to the mother. Here, we describe a narrative review on the role of macrophages and pregnancy and a systematic review was performed on the role of macrophages in OD pregnancies. Searches were made in different databases and the titles and abstracts were evaluated by three independent authors. In total, four articles were included on OD pregnancies and macrophages. Among these articles, some findings are conflicting between studies, indicating that more research is needed in this area. From current research, we could identify that there are multiple subtypes of macrophages, having diverse biological effects, and that the ratio between subtypes is altered during gestation and in aberrant pregnancy. The study of macrophages' phenotypes and their functions in OD pregnancies might be beneficial to better understand the maternal-fetal tolerance system.

Public attitudes towards novel reproductive technologies: a citizens' jury on mitochondrial donation.

STUDY QUESTION: Does an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted? SUMMARY ANSWER: After hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens' jury believed that children should be able to be born using mitochondrial donation. WHAT IS KNOWN ALREADY: Research suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods. STUDY DESIGN, SIZE, DURATION: This study comprised a citizens' jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Jurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: 'Should Australia allow children to be born following mitochondrial donation?' MAIN RESULTS AND THE ROLE OF CHANCE: Eleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors. LIMITATIONS, REASONS FOR CAUTION: Jurors' views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population. WIDER IMPLICATIONS OF THE FINDINGS: When presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data. TRIAL REGISTRATION NUMBER: Not applicable.

Medroxyprogesterone acetate versus ganirelix in oocyte donation: a randomized controlled trial.

STUDY QUESTION: Is oral medroxiprogesterone acetate (MPA) non-inferior compared to ganirelix with respect to the number of mature oocytes (MII) retrieved at ovum pick-up (OPU) in oocyte donation cycles? SUMMARY ANSWER: MPA is comparable to ganirelix in terms of number of MII retrieved at OPU in oocyte donation cycles. WHAT IS KNOWN ALREADY: Oral treatment with MPA inhibits the pituitary LH surge during ovarian stimulation in infertile patients. Because of its negative effect on the endometrium, MPA suppression is combined with freeze-all. Published reports indicate that both the number of MII retrieved and pregnancy rates from these oocytes are comparable to short protocol of GnRH agonists during IVF cycles with freeze-all. MPA might allow for more comfortable and cost-effective ovarian stimulation. STUDY DESIGN, SIZE, DURATION: Randomized clinical trial, open-label, single center, to assess the non-inferiority of MPA (10 mg/day) versus ganirelix (0.25 mg/day) from Day 7, in ovarian stimulation cycles triggered with triptoreline acetate. Trigger criterion was ≥3 follicles of diameter >18 mm. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 252 oocyte donors were selected (eligible), 216 were randomized and 173 reached OPU: 86 under MPA and 87 under ganirelix. The main outcome was the number of MII retrieved at OPU. Secondary outcomes were embryological laboratory outcomes and reproductive outcomes in recipients. The study was powered to test that the lower limit of the 95% confidence interval of the difference in retrieved MII between groups will be above the non-inferiority limit of -3. Differences were tested using a two-sided Student's t-test or a Pearson's Chi2 test, as appropriate. MAIN RESULTS AND THE ROLE OF CHANCE: All participants were in their first cycle of oocyte donation. On average, donors were 24 (SD 4.5) years old and with a BMI of 23 (SD 2.9) kg/m2. Duration of stimulation was similar in both groups (11.2 days), as well as the total gonadotropin dose up to trigger (2162 IU in MPA and 2163 IU in ganirelix). The number of MII retrieved was no different: 15.1 (SD 8.3) with MPA and 14.6 (SD 7.0), 95% CI of the difference -2.78, -1.83 excluding the pre-defined non-inferiority limit (-3). Recipients and embryo transfer (ET) characteristics were also similar between groups. The average age of recipients was 42 (SD 4.8) years and the BMI was 24 (SD 4.4) kg/m2. The mean number of MII assigned to each recipients was 6.7 (SD 1.2) in MPA and 6.6 (SD 1.2) in ganirelix (P = 0.58). MII were fertilized with partner sperm in 84% cycles overall and fertilization rate was 76% in MPA versus 74% in ganirelix (P = 0.34). Overall, there was 54% of double ET and 46% of single ET, with 40% of ETs were performed in D5. In spite of similar recipients and cycle characteristics, reproductive outcomes were unexpectedly lower with MPA. Biochemical pregnancy rate was 44 versus 57% (P = 0.023); clinical pregnancy rate 31 versus 46% (P = 0.006); ongoing pregnancy rate 27 versus 40%, (P = 0.015) and live birth rate 22 versus 31%, (P = 0.10). LIMITATIONS, REASONS FOR CAUTION: Although oocyte recipient and ET characteristics are similar among groups, this RCT has been designed under a hypothesis of non-inferiority in the number of MII obtained and recipients were not randomized; therefore, the reproductive outcomes in recipients should be evaluated with extreme caution. WIDER IMPLICATION OF THE FINDINGS: Ovarian stimulation using MPA for prevention of LH surge yields comparable number of MII oocytes compared to ganirelix in oocyte donation cycles. The unexpected finding in reproductive outcomes should be further investigated. STUDY FUNDING/COMPETING INTEREST(S): None to report. TRIAL REGISTRATION NUMBER: EudraCT number: 2015-004328-73; ClinicalTrials.gov Identifier: NCT02796105. TRIAL REGISTRATION DATE: 29 September 2015 (EudraCT); 9 June 2016 (ClinicalTrials.gov). DATE OF FIRST PATIENT'S ENROLLMENT: The date of enrollment of the first participant was 07 July 2016, and the last participant last visit in the study was on 10 July 2017.

Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation.

STUDY QUESTION: Are the LH levels at the start of ovarian stimulation predictive of suboptimal oocyte yield from GnRH agonist triggering in GnRH antagonist down-regulated cycles? SUMMARY ANSWER: LH levels at the start of ovarian stimulation are an independent predictor of suboptimal oocyte yield following a GnRH agonist trigger. WHAT IS KNOWN ALREADY: A GnRH agonist ovulation trigger may result in an inadequate oocyte yield in a small subset of patients. This failure can range from empty follicle syndrome to the retrieval of much fewer oocytes than expected. Suboptimal response to a GnRH agonist trigger has been defined as the presence of circulating LH levels <15 IU/l 12 h after triggering. It has been shown that patients with immeasurable LH levels on trigger day have an up to 25% risk of suboptimal response. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort study, all patients (n = 3334) who received GnRH agonist triggering (using Triptoreline 0.2 mg) for final oocyte maturation undergoing a GnRH antagonist cycle in our centre from 2011 to 2017 were included. The primary outcome of the study was oocyte yield, defined as the ratio between the total number of collected oocytes and the number of follicles with a mean diameter >10 mm prior to GnRH agonist trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endocrine profile of all patients was studied at initiation as well as at the end of ovarian stimulation. In order to evaluate whether LH levels, not only at the end but also at the start, of ovarian stimulation predicted oocyte yield, we performed multivariable regression analysis adjusting for the following confounding factors: female age, body mass index, oral contraceptives before treatment, basal and trigger day estradiol levels, starting FSH levels, use of highly purified human menopausal gonadotrophin and total gonadotropin dose. Suboptimal response to GnRH agonist trigger was defined as <10th percentile of oocyte yield. MAIN RESULTS AND THE ROLE OF CHANCE: The average age was 31.9 years, and the mean oocyte yield was 89%. The suboptimal response to GnRH agonist trigger cut-off (<10th percentile) was 45%, which was exhibited by 340 patients. Following confounder adjustment, multivariable regression analysis showed that LH levels at the initiation of ovarian stimulation remained an independent predictor of suboptimal response even in the multivariable model (adjusted OR 0.920, 95% CI 0.871-0.971). Patients with immeasurable LH levels at the start of stimulation (<0.1 IU/l) had a 45.2% risk of suboptimal response, while the risk decreased with increasing basal LH levels; baseline circulating LH <0.5 IU/L, <2 IU/L and <5 IU/L were associated with a 39.1%, 25.2% and 13.6% risk, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is its retrospective design. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study of GnRH agonist trigger cycles only, since most of the previous research on the predictive value of basal LH levels was performed in dual trigger cycles. LH values should be measured prior to start of ovarian stimulation. In cases where they are immeasurable, suboptimal response to GnRH agonist trigger can be anticipated, and an individualized approach is warranted. STUDY FUNDING/COMPETING INTEREST(S): There was no funding and no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

The effect of repeated controlled ovarian stimulation cycles on the gamete and embryo development.

The aim of this study was to investigate if there is an adverse effect of multiple controlled ovarian stimulation (COS) on the maturity of oocytes (MI and MII), fertilization rate, embryo developmental qualities and clinical pregnancy rates in donation cycles. In total, 65 patients undergoing oocyte donation cycles multiple times were included in this study. Patients were grouped as group A that consisted of donors with ≤2 stimulation cycles while B consisted of donors with ≥3 stimulation cycles; and group C included donors who had ≤15 oocytes, while group D had donors with ≥16 oocytes. Numbers of oocytes obtained, MI and MII oocytes, fertilization, embryo quality and clinical pregnancy outcomes were compared. Significant statistical differences were observed in total number of oocytes obtained, maturity of oocytes (MI and MII), fertilization rate, embryo qualities and clinical pregnancy outcomes of donors in groups A-D. Donors with ≤2 ovarian stimulation cycles had lower numbers of immature oocytes than donors with three or more stimulation cycles. However, donors with ≥3 stimulation cycles had higher numbers of mature oocytes, zygotes, with better day 3 embryo qualities and higher clinical pregnancy rates than donors with ≤2 stimulation cycles. Repeated COS does not seem to have any adverse effect on ovarian response to higher dose of artificial gonadotropin, as quality of oocytes collected and their embryological developmental potential were not affected by the number of successive stimulation cycles. The effect of multiple COS on the health of the oocyte donor needs to be assessed for future purpose.