Objective To study whether microfluidic sperm separation in intracytoplasmic sperm injection cycles provides any benefit over density gradient sperm separation for good quality embryo formation. Design Randomized sibling oocyte study. Subjects Patients undergoing intracytoplasmic sperm injection. Intervention Microfluidic sperm separation vs. density gradient sperm separation Main Outcome Measures Primary outcomes were percentage of good quality blastocyst formation. Secondary outcomes included sperm parameters following sperm separation including percent motility, grade of forward progression, fertilization rates, blastocyst formation rates, and ploidy rates in the event that pre-implantation testing for aneuploidy was performed. Additionally, sub-analysis on those with male factor infertility was performed evaluating primary and secondary outcomes above. Results A total of 34 cycles enrolled into the study yielding 456 oocytes, 231 randomized to microfluidics and 225 to density gradient. Average microfluidic fertilization rate was 76.1% ± 19.2% and 72.4% ± 26.6% for density gradient (p=0.35). Microfluidic blastocyst formation rate was 58.4% ± 31.9% compared to 58.7% ± 30.5% for density gradient (p=0.69). Good quality blastocyst formation rate for microfluidics was 51.4% ± 29.7% and for DG was 51.7% ± 30.9% (p=0.77). Euploid rate from the microfluidics cohort was 43.8% ± 35.5% and 33.7% ± 33.3% for the density gradient cohort (p=0.20). Sub-analysis of cycles with male factor infertility revealed good quality blastocyst formation rate was 45.9% ± 30.9% post microfluidics and 55.1% ± 29.2% for density gradient (P=0.70). Sub-analysis of cycles with male factor infertility revealed euploid rate post-microfluidics of 50.0% ± 37.6% compared to 18.4% ± 24.5% for density gradient (p=0.008). Conclusion There were similar rates of good quality embryo formation following intracytoplasmic sperm injection using sperm separated with microfluidics compared to density gradient, however, sub-analysis of the male factor infertility group revealed higher euploid rates with microfluidics.
Objective To examine the risk of severe ovarian hyperstimulation syndrome (OHSS) when random-start ovarian stimulation (RSOS) is performed during an undetected, spontaneously conceived pregnancy. Design A case-report Subjects A 24-year-old woman with polycystic ovary syndrome, a history of two early pregnancy losses, and 25 months of infertility, who underwent in vitro fertilization (IVF) with RSOS at an external fertility clinic. Exposure RSOS begun while an early intrauterine pregnancy was already present but unrecognized. Main Outcome Measures Onset and severity of OHSS, assessed by clinical symptoms, serum hCG levels, and the need for hospitalization or intervention. Results Following oocyte retrieval, the patient developed severe abdominal pain and significant ascites consistent with OHSS and was found to have a concurrent intrauterine pregnancy. Outpatient management failed to control her symptoms, and she required hospitalization and termination of the pregnancy. She conceived naturally six months later and delivered a healthy infant. Conclusion This case underscores the significant risk of undetected pregnancies during RSOS, which can lead to severe OHSS. It emphasizes the critical need for vigilant monitoring of progesterone and hCG levels and the implementation of strategies to detect potential pregnancies prior to trigger of oocyte maturation. Clinicians must carefully weigh the benefits of flexible stimulation protocols against the risks of unintended pregnancies, especially in patients with a reasonable chance of achieving spontaneous conception.
Objective To describe the retrieval of mature oocytes after an unplanned 6-day gonadotropin-free interval during oncofertility ovarian stimulation. Design Case report. Subjects A 22-year-old active-duty soldier with a serous borderline ovarian tumor undergoing fertility preservation after ovarian surgery. Exposure Progestin-primed ovarian stimulation using follitropin alfa and medroxyprogesterone acetate as the sole luteinizing hormone suppressor. Gonadotropin administration was unexpectedly interrupted for 6 days because of a nondeferrable military summons, while oral medroxyprogesterone acetate was maintained. Main Outcome Measures Metaphase II (MII) oocyte yield and maturation rate. Results The patient had undergone ovarian surgery approximately 9 months before the reference cycle and 12 months before the index cycle. Baseline antimüllerian hormone before fertility preservation was 1.77 ng/mL. In the reference cycle, 13 follicles ≥14 mm were present on the trigger day, and 13 oocytes were retrieved, including six MII oocytes that were vitrified. At the ultrasound assessment immediately preceding the gonadotropin-free interval in the index cycle, ultrasound showed nine visible follicles, including three follicles measuring <14 mm and six follicles measuring ≥14 mm. After the 6-day interval, the trigger-day ultrasound showed seven follicles ≥14 mm in diameter, ranging from 17 to 19 mm. Estradiol remained nearly stable across the interval, from 1,612 to 1,580 pg/mL, and endogenous progesterone on the trigger day was 1.1 ng/mL. Seven oocytes were retrieved, including five MII oocytes that were vitrified. Conclusion In this selected oncofertility patient undergoing progestin-primed ovarian stimulation, an unplanned 6-day gonadotropin-free interval did not preclude retrieval of a clinically meaningful number of mature oocytes. Continuous medroxyprogesterone acetate may represent a biologically plausible protective factor against premature luteinization, although causality cannot be inferred from a single case.
Objective To report live birth and neonatal outcomes across multiple commercial kit brands, including cross-brand combinations, thereby providing clinical validation of a universal warming method on the basis of single-step elution using 1 M nonpermeating solutes (NPS). Human blastocysts are routinely vitrified using commercial kits with minor compositional differences. Previous studies have shown that simplified single-step warming with 1 M NPS can reduce handling time and improve laboratory efficiency. However, this universal ultrafast warming approach has not been systematically evaluated across different warming kits or mixed vitrification–warming combinations. Design Retrospective observational study. Subjects A total of 469 vitrified blastocysts warmed between January 1, 2024 and December 31, 2024. Exposure Blastocysts were vitrified using four commercially available kits and warmed by single-step elution in 1 M NPS from the corresponding thawing solutions, generating 12 vitrification–warming combinations. Vitrification was performed at room temperature (12–15 min in equilibration solution followed by 60 s in vitrification solution before plunging). Warming consisted of a single step in thawing solution (1 M NPS) at 37 °C. Main Outcome Measures Cryosurvival, clinical pregnancy, implantation, live birth and neonatal outcomes. Results Overall, 469 blastocysts were warmed and transferred in 428 cycles, resulting in 100% survival, a clinical pregnancy rate of 45.8%, an implantation rate of 43.1%, and a live birth rate of 36.0%, with 159 babies born. No significant differences were observed between groups in pregnancy, implantation or live birth rates. Mean neonatal weight was 3.2 ± 0.4 kg and was comparable between groups, ranging from 3.0 ± 0.7 to 3.6 ± 0.5 kg, and similar to that observed following fresh embryo transfers during the same period. The preterm live birth rate was 6.3%, with no difference between groups, and was comparable with fresh transfers and national Assisted Reproductive Technology registry data. Sex distribution was balanced (48.4% male, 51.6% female) and comparable between groups, fresh transfers (46.9% male, 53.1% female), and national registry data. No major congenital anomalies or severe neonatal diseases were reported. Some between-group comparisons are limited by small sample sizes and high survival rates, so nonsignificant P values may be due to low statistical power rather than true group similarity. Conclusion This case series of babies born following universal single-step warming (USSW) provides preliminary reassuring evidence supporting the feasibility of this protocol across different commercial vitrification and warming systems, despite compositional differences. However, given the limited sample size of some subgroup combinations, further adequately powered studies are required to confirm its safety and clinical effectiveness. If validated, this approach may help streamline laboratory practice, reduce costs, and broaden access to in vitro fertilization.
Objective To report a case of human meiotic recombination illustrated by the use of preimplantation genetic testing for monogenic disorders (PGT-M) in a female patient found to be heterozygous for pathogenic variants in cis on the X chromosome, highlighting the potential implications of meiotic recombination when performing PGT-M for two or more variants located on the same chromosome of a parental haplotype Design Case report. Subject A G3P3 female patient, heterozygous for two X-linked pathogenic variants in cis, involving the OTC and STS genes, sought to conceive an unaffected pregnancy through the use of in vitro fertilization (IVF) with PGT-M based on her history of having a son with OTC deficiency and steroid sulfatase (STS) deficiency who died following a hyperammonemic crisis. Exposure PGT-M for maternal OTC and STS variants, previously determined to be in cis in the patient and her deceased son. Main Outcome Measures Proportion of embryos that screened positive by PGT-M for both, neither, or only one of the maternal OTC and STS variants. Results PGT-M was performed on 13 embryos. Nine (69%) embryos screened positive for both or neither of the maternal OTC (c.788A>G) and STS (1.6Mb deletion of Xp22.31) variants, as expected given their configuration in cis. Four embryos (31%) screened positive for only one variant (either the OTC or STS variant), suggestive of X-linked meiotic recombination occurring at the frequency predicted based on the genomic distance between STS and OTC. The patient transferred a female euploid embryo low-risk by PGT-M for both the maternal OTC and STS variants, and declined prenatal diagnostic testing via chorionic villus sampling or amniocentesis. The patient delivered a healthy term female infant via repeat Cesarean section. Conclusion Meiotic recombination may lead to unanticipated results when using PGT-M to screen embryos for multiple monogenic conditions involving variants on the same chromosome. Detection of linked variants when screening embryos for genetic conditions (i.e., instead of direct genotyping) could lead to a false negative result. This case underscores the importance of involving medical geneticists and genetic counselors to facilitate comprehensive and accurate clinical genetic evaluations, variant interpretation, confirmatory testing, and risk assessment to promote informed reproductive decision-making.
The use of donor gametes has increased substantially in recent decades. In response to the psychosocial and both short- and long-term implications of third-party reproduction, the American Society for Reproductive Medicine (ASRM) recommends psychoeducational counseling for recipient parents. Yet mental health referrals are often experienced as anxiety-provoking or discriminatory, particularly among LGBTQ+ individuals and those pursuing solo parenting, reflecting longstanding heteronormative bias in reproductive medicine. The ASRM has called for fertility care models that move beyond mere acceptance toward affirming, patient-centered care. This review describes over 15 years of experience implementing a psychoeducational, class-based model for gamete recipients in an academic medical center and, more recently, a private multisite fertility clinic. We present preliminary findings, highlight patient-centered benefits, outline practical implementation strategies, and discuss limitations of this approach. Preliminary quality improvement data were drawn from a 1-year survey of patients at a private multisite fertility practice who were eligible to complete either a class-based consultation with an embedded clinical psychologist or a traditional individual consultation. Overall, the majority of patients opted into the class format and found the class moderately to extremely helpful. Primary reasons for opting into the class included reduced financial burden, interest in community-building, and the perceptions of greater inclusivity. To better align required psychoeducational counseling with principles of inclusivity and patient-centered care, alternative models are needed. A class-based mental health consultation offers a practical and scalable approach that delivers essential education while reducing fears of judgment, fostering community, and improving access to care. Ongoing research is examining the impact of this model on patient knowledge, confidence, and the perceived inclusivity of care across diverse family types.
Objective To evaluate the efficacy, safety, and pharmacodynamics of linzagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in patients with heavy menstrual bleeding (HMB) and pain because of uterine fibroids. Design Phase 3, multicenter, placebo-controlled, randomized, double-blind, parallel-group, confirmatory study (NCT05445167). Subjects Premenopausal Japanese women with HMB and moderate-to-severe pain because of uterine fibroids. Intervention Patients were randomized 1:1 to once-daily linzagolix 200 mg (n = 48) or placebo (n = 41) for 12 weeks. Main Outcome Measures The primary endpoints were the proportion of patients with a total pictorial blood loss assessment chart (PBAC) score <10 from week 6–12, and the proportion of patients with a maximum numeric rating scale (NRS) score ≤1 during the 28 days before the end of treatment. Secondary endpoints included time to a total PBAC score <10 or maximum NRS score ≤1, analgesic use, blood hemoglobin, myoma and uterine volumes, patient-reported symptom severity and quality of life, and plasma estradiol levels. Safety endpoints included adverse events (AEs) and time to menstrual recovery. Results The superiority of linzagolix vs. placebo was demonstrated for both the proportion of patients with a total PBAC score <10 from week 6–12 (91.5% vs. 2.5%; difference [95% confidence interval], 89.0% [76.0–96.2]), and the proportion of patients with a maximum NRS score ≤1 during the 28 days before the end of treatment (70.8% vs. 9.8%; difference, 61.1% [42.1–75.8]). Reductions in HMB and pain with linzagolix were rapidly achieved, occurred alongside improvements in other efficacy endpoints (e.g., analgesic use, blood hemoglobin, myoma and uterine volumes, patient-reported outcomes), and coincided with rapid and sustained reductions in plasma estradiol levels. The incidence of AEs was 91.7% in the linzagolix group and 75.6% with placebo; the most common AE in the linzagolix group was hot flush (47.9%). At the end of study treatment, mean plasma estradiol in the linzagolix group returned to pretreatment levels within 4 weeks, and the median time to menstrual recovery was 29 days. Conclusion These data reaffirm that GnRH receptor inhibition with linzagolix is a tolerable and efficacious strategy to manage the signs and symptoms of uterine fibroids.
Objective To describe a case of false-negative preimplantation genetic testing for aneuploidy (PGT-A) and noninvasive prenatal test (NIPT) resulting in a neonate born with Down Syndrome. Design Case report Subjects A 40-year-old multiparous woman with in vitro fertilization pregnancy due to a history of tubal ligation presenting to an academic medical center. Exposure Prenatal aneuploidy screening with PGT-A and cell-free DNA. Main Outcome Measures PGT-A test was conducted on a day 5 blastocyst which resulted as euploid. Subsequent NIPT test was obtained at 10 weeks and reported low-risk results. Results The patient underwent vacuum-assisted vaginal delivery of a liveborn male infant with features of Down Syndrome. Postnatal karyotype confirmed nonmosaic trisomy 21. Conclusion PGT-A and NIPT are powerful tools used for risk reduction, but they do not eliminate risk.
Objective To investigate sociodemographic and clinical variables associated with Whole Systems Traditional Chinese Medicine (WS-TCM) utilization alongside frozen embryo transfers (FETs) after in vitro fertilization. Design We conducted a retrospective review of all autologous FETs performed within an academic medical center’s fertility clinic between January 2019 and March 2024. One FET cycle per patient was randomly selected for analysis. After conducting bivariate analyses, a logistic regression model was employed to examine independent associations with WS-TCM utilization. Subjects Women aged 21–42 who underwent an FET after in vitro fertilization. FETs involving donor egg embryos, gestational carriers, and those with missing live birth outcome data were excluded. Exposure Attending ≥1 WS-TCM appointment between 120 days pre- and 12 days post-FET. Whole Systems Traditional Chinese Medicine treatment modalities included individualized acupuncture, nutritional and lifestyle modifications, and focused dietary supplements. Main Outcome Measures Sociodemographic and clinical variables associated with WS-TCM utilization. Results Of 799 women studied, 162 (20.3%) utilized WS-TCM, receiving a median of 5.5 treatments between 120 days pre- and 12 days post-FET. Whole Systems Traditional Chinese Medicine users resided in neighborhoods with higher median income ($83,025 vs. $75,602). Previous medical histories of women incorporating WS-TCM included higher rates of migraine/headache (21.6% vs. 13.3%), musculoskeletal pain (37.0% vs. 27.5%), recurrent pregnancy loss (RPL; 25.9% vs. 12.9%), pain associated with genital organs (21.0% vs. 14.1%), and undergoing more assisted reproductive technology cycles. Higher neighborhood median income (adjusted odds ratio and 95% confidence interval: 1.36 [1.13, 1.64]), recurrent pregnancy loss (2.15 [1.33, 3.47]), and undergoing ≥3 vs. 0–1 assisted reproductive technology cycles (1.78 [1.02, 3.06]) were independently associated with higher odds of WS-TCM engagement, whereas higher body mass index (0.79 [0.64, 0.97]), undergoing preimplantation genetic testing (0.61 [0.39, 0.94]), and having a history of salpingitis/oophoritis/pelvic inflammatory disease (0.59 [0.37, 0.92]) or high-risk pregnancy supervision (0.53 [0.30, 0.93]) were associated with lower odds. Conclusion Within this cohort, multiple pain- and reproductive health-related diagnoses were more prevalent among individuals utilizing WS-TCM. Findings inform factors that may influence clinicians’ and patients’ decisions to refer or pursue WS-TCM (e.g., migraine, musculoskeletal pain, RPL) and covariates that should be accounted for in future observational studies of WS-TCM’s effectiveness.
Objective: To describe a novel surgical approach for the detection and excision of peritoneal endometriosis using intraoperative Aqua Blue Contrast (ABC) with real-time AI-assisted detection. Design: Case report describing a novel intraoperative surgical technique. Subjects: A 28-year-old woman presenting with cardinal symptoms of endometriosis. Exposure: Peritoneal endometriosis presents a significant diagnostic and surgical challenge due to the heterogeneity of lesion subtypes, including pigmented, occult, and microscopic forms. In this approach, intraoperative ABC was applied as a contrast-enhancing technique to improve visualization of the peritoneal surface. In parallel, AI-assisted lesion recognition was used as an adjunctive tool to augment intraoperative recognition of suspicious peritoneal areas. The technique enhances color differentiation, allowing identification of subtle peritoneal abnormalities that may not be easily visible under standard white-light laparoscopy. Main Outcome Measures: Intraoperative visualization and identification of peritoneal endometriotic lesions. Results: The ABC enhanced visual contrast between normal and abnormal peritoneal tissue, facilitating identification of occult lesions. The improved visualization with AI-assisted lesion recognition system supported more precise localization and excision of suspected endometriotic areas during surgery. Conclusion: ABC with real time AI augmentation represents a promising intraoperative visualization technique for improving detection of peritoneal endometriosis. By enhancing lesion visibility, this approach may contribute to more accurate identification and more complete surgical excision.
Dopamine D2 receptor (DRD2) agonists represent a promising targeted, nonhormonal therapeutic strategy for endometriosis. These agents selectively downregulate vascular endothelial growth factor-A signaling, thereby inhibiting the aberrant angiogenesis that supports the survival and proliferation of endometriotic lesions. This review synthesizes preclinical and early clinical evidence on DRD2 targeting, with a focus on the clinical translation of cabergoline and quinagolide. In a randomized, double-blind, placebo-controlled pilot trial, a 6-month cabergoline regimen significantly reduced chronic pelvic pain scores and improved pain relief without serious adverse events. Additionally, post hoc analysis of lesion regression showed that 61.3% of lesions in the quinagolide group demonstrated regression, while ovulatory function was preserved in 93% of participants, consistent with maintenance of the hypothalamic–pituitary–ovarian axis. Collectively, these data suggest that DRD2 agonists may represent a fertility-compatible, mechanistically targeted therapeutic approach and underscore the need for adequately powered phase 3 clinical trials.
Objective:To evaluate the efficacy and long-term safety of a user-driven flexible extended regimen of desogestrel 150 μg/ethinylestradiol 20 μg (DSG/EE 150/20) for the treatment of primary or secondary dysmenorrhea in women from Japan. Design:Phase 3, randomized, placebo-controlled, parallel-group, double-blind study with an open-label extension period. Subjects:Two hundred and eleven women with regular menstrual cycles and primary or secondary dysmenorrhea in 21 centres across Japan. Intervention:Participants were randomly assigned (3:1) to receive DSG/EE 150/20 μg or placebo once daily for 24-80 consecutive days, with each treatment period followed by a 4-day tablet-free interval. After the double-blind phase (three 28-day cycles), participants entered an open-label phase (≤10 cycles); participants initially receiving placebo were switched to DSG/EE. Main Outcome Measures:Primary endpoint was change from baseline through day 84 in total dysmenorrhea score (TDS). Secondary endpoints included number of days with dysmenorrheic pain, patient global impression of change (PGI-C), treatment satisfaction questionnaire for medication (TSQM-9), quality of life (QoL) measured by the 36-item short form health survey version 2.0 (SF-36v2), and safety outcomes. Results:In the 211 participants randomized to DSG/EE (n = 159) and placebo (n = 52), the mean (SD) age was 32.3 (7.56) years, and body mass index was 21.94 (3.18). A significant reduction in TDS from baseline through day 84 was observed in the DSG/EE group vs. placebo (least squares mean: -2.50 vs. -0.84; treatment difference [95% confidence interval: -1.67 [-2.08, -1.26]). The number of days with mild, moderate, and severe pain were 12.9 vs. 12.1, 4.8 vs. 6.5, and 0.8 vs. 1.1 days in the DSG/EE vs. placebo group. Over 80% of DSG/EE-treated participants reported improvement in PGI-C scores compared with <30% on placebo. TSQM-9 global satisfaction and effectiveness least squares mean scores were higher with DSG/EE (63.69 vs. 36.62 and 62.86 vs. 35.5) compared with placebo. DSG/EE improved SF-36v2 scores, particularly in the physical component summary, bodily pain, and role-physical domains. Overall, the most frequent treatment-emergent adverse events were intermenstrual bleeding, nasopharyngitis, and nausea. No deaths were reported during the entire study period. Conclusion:DSG/EE 150/20 effectively reduced dysmenorrhea severity, improved SF-36v2 scores and treatment satisfaction, offered dosing flexibility, and was well-tolerated with a safety profile consistent with combined oral contraceptives. Trial Registration:jRCT2031230276 (https://jrct.mhlw.go.jp/en-latest-detail/jRCT2031230276).
