Development of an AI-based support system for controlled ovarian stimulation.

Purpose: Controlled ovarian stimulation (COS) is vital for IVF. We have developed an AI system to support the implementation of COS protocols in our clinical group. Methods: We developed two models as AI algorithms of the AI system. One was the oocyte retrieval decision model, to determine the timing of oocyte retrieval, and the other was the prescription inference model, to provide a prescription similar to that of an expert physician. Data was obtained from IVF treatment records from the In Vitro Fertilization (IVF) management system at the Asada Ladies Clinic, and these models were trained with this data. Results: The oocyte retrieval decision model achieved superior sensitivity and specificity with 0.964 area under the curve (AUC). The prescription inference model achieved an AUC value of 0.948. Four models, namely the hCG prediction model, the hMG prediction model, the Cetrorelix prediction model, and the Estradiol prediction model included in the prescription inference model, achieved AUC values of 0.914, 0.937, 0.966, and 0.976, respectively. Conclusion: The AI algorithm achieved high accuracy and was confirmed to be useful. The AI system has now been implemented as a COS tool in our clinical group for self-funded treatments.

Pregnancy co-treated with oral gonadotropin-releasing hormone antagonist in a woman with premature ovarian insufficiency: a case report.

To the best of our knowledge, this is the first case of pregnancy with a healthy baby after treatment with an oral gonadotropin-releasing hormone (GnRH) antagonist in women with premature ovarian insufficiency. A 36-year-old female presented at our hospital after being diagnosed with premature ovarian insufficiency by a previous doctor. We administered clomiphene, human menopausal gonadotropin (hMG), and GnRH antagonist (injection) together with estrogen replacement for 11 cycles (27 months), but no follicular development was observed. When the oral GnRH antagonist (relugolix), which has recently become available, was used in the 12th cycle, follicular growth of 13 mm was confirmed on the 14th day of stimulation. After stimulation, the use of hMG and GnRH antagonist (injection) was continued, and a maturation trigger, human chorionic gonadotropin 10000 IU, was administered. Oocyte retrieval was performed successfully, intracytoplasmic sperm injection and frozen embryo transfer were performed, and fetal heartbeat was confirmed. The patient was admitted to the perinatal management facility. She delivered a healthy baby of 3,732 g via cesarean section at 41 weeks +2. This case shows the possibility of using an oral GnRH antagonist as an option for infertility treatment.

Risk factors for empty follicle syndrome in assisted reproductive technology with gonadotropin-releasing hormone agonist trigger.

Purpose: To analyze whether response to the GnRH test is a predictor of empty follicle syndrome (EFS) and to analyze independent risk factors for EFS. Methods: The GnRH test results of 3765 patients from 2016 to 2018 were used to define the reference range of the GnRH test. Risk factors for EFS were estimated by multivariate logistic analysis of 5282 cycles (5247 oocyte-retrieved cycles with GnRH agonist trigger and 35 cycles of EFS) conducted from 2016 to 2019. Results: GnRH testing showed basal hormone values as follows: median LH 5.2 (95 percentile; 1.3-12.6) mIU/mL, LH 30 min 22.0 (6.8-57.1), basal FSH 7.3 (3.0-20.5), FSH 30 min 11.5 (5.1-30.4) and FSH/LH ratio 1.5 (0.6-4.1). Independent risk factors for EFS were antral follicle count (adjusted odds ratio; 0.94, 95% CI; 0.89-0.99), basal LH (0.78, 0.66-0.90), and days duration of ovarian stimulation (1.41, 1.21-1. 60). The respective thresholds were 8 for AFC, 5.0 for basal LH, and 16 days for duration. Conclusions: LH 30 min values of the GnRH test did not predict EFS. Independent risk factors for EFS were AFC, basal LH and days duration of ovarian stimulation.

Performance of anti-Müllerian hormone (AMH) levels measured by Beckman Coulter Access AMH assay to predict oocyte yield following controlled ovarian stimulation for in vitro fertilization.

PURPOSE: We evaluated the performance of anti-Müllerian hormone (AMH) measured by the Beckman Coulter fully automated Access assay to predict oocyte yield following controlled ovarian stimulation (COS) for in vitro fertilization (IVF). METHODS: The correlation between the Access assay and the pre-mixing method with Generation II ELISA assay (Gen II pre-mix assay) was assessed using 230 blood samples. The relationship of AMH level measured by the Access assay and the actual number of oocytes retrieved following COS was assessed using 3296 IVF cycles. The performances of AMH, follicle stimulating hormone (FSH), and estradiol (E2) in predicting the responses to COS were also evaluated by constructing receiver operating characteristic (ROC) curves. RESULTS: The AMH levels measured just before oocyte retrieval by the Access assay and the number of oocytes retrieved following COS showed a good correlation with R = 0.655. The ROC analysis revealed that the sensitivity of AMH was comparable with or lower than that of E2 but higher than that of FSH. CONCLUSIONS: With the improved Access AMH assays, AMH was as sensitive as E2 and could become an accurate marker of ovarian response to COS in more than 3000 Japanese IVF patients.

Clinical utility of chlormadinone acetate (Lutoral™) in frozen-thawed embryo transfer with hormone replacement.

PURPOSE: The clinical utility of chlormadinone acetate tablets (Lutoral™), an orally active progestin which has been available since June 2007, was compared to an in-house vaginal suppository formulation of progesterone used between 2006 and 2007 for assisted reproductive technology (ART). METHODS: We retrospectively evaluated the efficacy and safety of chlormadinone acetate by comparing the pregnancy rates and the incidences of birth defects and hypospadias in frozen-thawed embryo transfer cycles using the in-house vaginal progesterone and those using chlormadinone acetate for luteal phase support. RESULTS: The pregnancy rates in the frozen-thawed embryo transfer cycles were 31.2% (259/831) with vaginal progesterone for luteal phase support and 31.6% (4228/13 381) with chlormadinone acetate (no significant difference). In the cycles resulting in live birth following administration of chlormadinone acetate between July 2007 and December 2015, the incidence of birth defects was 2.8% (80/2893), and the incidence of hypospadias was 0.03% (1/2893). CONCLUSIONS: These results indicate that the pregnancy rate following frozen-thawed embryo transfer using chlormadinone acetate for luteal phase support was comparable with that using vaginal progesterone, with no increased risk of birth defects, including hypospadias, which has been a concern following the use of progestins.

Long-term outcomes of freeze-all strategy: A retrospective analysis from a single ART center in Japan.

PURPOSE: To demonstrate the benefits of the freeze-all strategy for in vitro fertilization treatment based on retrospective analyses. METHODS: Post-thaw embryo survival rates of slow-frozen embryos in 294 cycles and vitrified embryos in 12 195 cycles were assessed. Progesterone (P4) and estradiol (E2) levels per mature oocyte by age category were assessed in 9081 cycles and pregnancy rates with fresh embryo transfer and frozen-thawed embryo transfer by P4 level were assessed in 1535 cycles. RESULTS: The survival rates of frozen-thawed embryos were 92.5% with slow freezing and 99.1% with vitrification. P4 levels on the day of human chorionic gonadotropin (hCG) injection showed a trend toward an increase with age. The pregnancy rate per mature oocyte with fresh embryo transfer decreased dependently upon P4 level, while that with frozen-thawed embryo transfer was not affected by P4 level. The pregnancy rates with frozen-thawed embryo transfer were higher than those with fresh embryo transfer in patients aged 42 years or younger. CONCLUSIONS: The freeze-all strategy is a valuable treatment option which allows the separation of an embryo transfer cycle from an oocyte retrieval cycle, especially for patients with high P4 levels at oocyte retrieval and patients of advanced maternal age.

Failure of GnRH agonist-triggered oocyte maturation: its cause and management.

OBJECTIVE: In the present study we investigated the cause of GnRHa's failure to trigger oocyte maturation and present an effective rescue protocol for use when failure occurs. DESIGN: Case reports. SETTING: One in vitro fertilization (IVF) center. PATIENT(S): Eight cases of failure of GnRH agonist (GnRHa)-triggered oocyte maturation and one case of GnRHa successfully triggered oocyte maturation, despite a weak response in the LH-RH test. MAIN OUTCOME MEASURE(S): All cases were successfully rescued by re-triggering maturation using HCG, with seven of the eight patients achieving ongoing pregnancy and successful delivery. RESULT(S): In three patients the cause of the oocyte maturation failure was likely temporal or continuous severe down-regulation of the hypothalamus-pituitary-axis, the cause was unknown in the other five patients. CONCLUSION(S): In cases where GnRHa fails to trigger oocyte maturation, a rescue protocol entailing re-triggering with HCG can produce successful outcomes.

Serum anti-Mullerian hormone levels affect the rate of ongoing pregnancy after in vitro fertilization.

We used logistic regression analysis to investigate the relationship between serum anti-Mullerian hormone (AMH) levels and the rate of ongoing pregnancy. Retrospective data were collected from 1043 women who had undergone their first cycle of in vitro fertilization (IVF), including 540 cycles of fresh embryo transfer and 503 cycles of frozen-thawed embryo transfer. The patients were divided into 4 groups based on the cutoff values from a receiver-operating characteristic curve: 0.0 to 12.4, 12.5 to 25.5, 25.6 to 44.1, and >44.2 pmol/L. After adjustment for multiple confounders, the serum AMH group was found to be significantly related to the rate of ongoing pregnancy in total cycles (0.0-12.4 vs 12.5-25.5 pmol/L; P = .0088, odds ratio, 1.909: vs 25.6-44.1 pmol/L; P = .0281, odds ratio, 2.109: vs >44.2 pmol/L; P = .0008, odds ratio, 2.840). In conclusion, there appears to be a significant relationship between serum AMH levels and the ongoing pregnancy rate in first IVF treatment cycles after adjustment for multiple confounders.

Trophectoderm morphology significantly affects the rates of ongoing pregnancy and miscarriage in frozen-thawed single-blastocyst transfer cycle in vitro fertilization.

OBJECTIVE: To determine which parameter of blastocyst morphology is the most important predictor of ongoing pregnancy or miscarriage. DESIGN: Retrospective analysis. SETTING: One in vitro fertilization (IVF) center. PATIENT(S): Women who underwent a total of 1,087 frozen-thawed single-blastocyst transfer cycles. INTERVENTION(S): First IVF treatment with blastocysts after frozen-thawed cycle. MAIN OUTCOME MEASURE(S): Ongoing pregnancy and miscarriage rates as related to blastocyst morphology (blastocyst expansion, inner cell mass, and trophectoderm), and interaction tests in unadjusted logistic regression models to assess clinical factors affecting outcomes. RESULT(S): After adjustment for trophectoderm, inner cell mass, and age as confounders, trophectoderm was determined to be statistically significantly related to the rate of ongoing pregnancy. Trophectoderm was also statistically significantly related to the miscarriage rate. By contrast, neither inner cell mass nor blastocyst expansion was statistically significantly related. CONCLUSION(S): In frozen-thawed embryo transfer cycles, trophectoderm morphology is statistically significantly related to the rates of ongoing pregnancy and miscarriage after adjusting for confounders. Trophectoderm morphology may be the most important parameter when selecting a single blastocyst for transfer.

Different ovarian response by age in an anti-Müllerian hormone-matched group undergoing in vitro fertilization.

BACKGROUND: Recently, serum anti-Müllerian hormone (AMH) has been used as a good marker of ovarian response during in vitro fertilization (IVF). However, in the clinical setting, we felt that ovarian response was clearly different by age with the same AMH level. Then in this study we evaluated the relationship between serum AMH, age and parameters related to ovarian response and compared these parameters in regard to age within serum AMH-matched group. METHODS AND RESULTS: The relationship of these parameters were evaluated retrospectively in patients undergoing their first IVF cycle under a GnRH agonist flare up protocol (n = 456) between October 2008 and October 2010 in our clinic. To understand the relations between variables described above, principal component analysis (PCA) was performed. PCA revealed patients' age was at the different dimension from serum AMH and other variables. Therefore at first we segregated all patients into Low, Normal and High responder groups by their serum AMH using cut-off value of receiver operator characteristics curve analysis. Secondary, we divided each responder group into four subgroups according to patients' age. The high aged subgroups required a significantly higher dose of gonadotropin and a longer duration of stimulation; however, they had significantly lower peak E2 and a smaller number of total oocytes as well as M2 oocytes compared to the low aged subgroups. CONCLUSIONS: The influence of aging on the ovarian response was clearly seen in all groups; the ovarian response tended to decrease as patients' age increased with the same AMH level. Therefore serum AMH in combination with age is a better indicator than AMH alone.

Retrograde vasal sperm aspiration in anejaculatory patients with spinal cord injury.

Aim: This paper describes our experience with retrograde vasal sperm aspiration (ReVSA) in anejaculatory patients with spinal cord injury. Methods: We performed 11 vasal sperm aspiration procedures on eight patients presenting with neurogenic anejaculation associated with spinal cord injury at our institute between 2004 and 2007. This procedure was conducted under local anesthesia with a spermatic block. A 24G needle was inserted into the vas in a retrograde fashion. Sperm-washing medium was gently injected into the proximal vas several times and collected. Aspirated sperm was cryopreserved for intracytoplasmic sperm injection. Results: Adequate motile sperm was obtained from all patients. All couples underwent intracytoplasmic sperm injection; clinical pregnancies were achieved in eight cases (two ongoing pregnancies and the births of six healthy babies). Conclusion: Retrograde vasal sperm aspiration is a reliable method for the consistent recovery of sperm of sufficient quality to afford a high pregnancy rate and in sufficient quantity to permit cryopreservation of excess sperm for future use. (Reprod Med Biol 2008; 7: 115-118).