Improving IVF Utilization with Patient-Centric Artificial Intelligence-Machine Learning (AI/ML): A Retrospective Multicenter Experience.

Objectives: In vitro fertilization (IVF) has the potential to give babies to millions more people globally, yet it continues to be underutilized. We established a globally applicable and locally adaptable IVF prognostics report and framework to support patient-provider counseling and enable validated, data-driven treatment decisions. This study investigates the IVF utilization rates associated with the usage of machine learning, center-specific (MLCS) prognostic reports (the Univfy® report) in provider-patient pre-treatment and IVF counseling. Methods: We used a retrospective cohort comprising 24,238 patients with new patient visits (NPV) from 2016 to 2022 across seven fertility centers in 17 locations in seven US states and Ontario, Canada. We tested the association of Univfy report usage and first intra-uterine insemination (IUI) and/or first IVF usage (a.k.a. conversion) within 180 days, 360 days, and "Ever" of NPV as primary outcomes. Results: Univfy report usage was associated with higher direct IVF conversion (without prior IUI), with odds ratios (OR) 3.13 (95% CI 2.83, 3.46), 2.89 (95% CI 2.63, 3.17), and 2.04 (95% CI 1.90, 2.20) and total IVF conversion (with or without prior IUI), OR 3.41 (95% CI 3.09, 3.75), 3.81 (95% CI 3.49, 4.16), and 2.78 (95% CI 2.59, 2.98) in 180-day, 360-day, and Ever analyses, respectively; p < 0.05. Among patients with Univfy report usage, after accounting for center as a factor, older age was a small yet independent predictor of IVF conversion. Conclusions: Usage of a patient-centric, MLCS-based prognostics report was associated with increased IVF conversion among new fertility patients. Further research to study factors influencing treatment decision making and real-world optimization of patient-centric workflows utilizing the MLCS reports is warranted.

Integrated Behavioral Health Care in Reproductive Medicine: How and Why to Include Mental Health Professionals in Infertility Care Teams.

Despite fertility patients' reports of significant distress, few have access to integrated mental health care services. We elucidate the benefits and challenges of mental health integration in infertility practices from the perspective of both patients and providers. We outline specific models of integration, financial viability, and the first steps fertility clinics could take to improve their patients' access to these critical supports.

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's).

OBJECTIVE: Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX). METHODS: Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml. RESULTS: Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC (P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose (P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC. CONCLUSION: Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.

Late ovarian hyperstimulation syndrome after controlled ovarian stimulation in a woman with systemic lupus erythematosus and lupus nephritis.

OBJECTIVE: To report a case of late ovarian hyperstimulation syndrome (OHSS) in a woman with lupus nephritis undergoing controlled ovarian stimulation and in vitro fertilization (IVF) with subsequent transfer into a gestational surrogate. DESIGN: A case report. SETTING: Academic reproductive medicine clinic. PATIENT(S): A 33-year-old woman who presented 10 days after recombinant human chorionic gonadotropin (hCG) injection with fatigue, abdominal pain, and bloating, diagnosed as OHSS. INTERVENTION(S): Patient admitted for intravenous fluid hydration, anticoagulation, and gonadotropin-releasing hormone (GnRH) antagonist therapy. MAIN OUTCOME MEASURE(S): Successful detection and management of severe OHSS in a patient with chronically impaired kidney function. RESULT(S): The patient has returned to her baseline condition, and the gestational carrier was noted to have a twin gestation. CONCLUSION(S): In patients with impaired renal function, final oocyte maturation should be triggered with a GnRH agonist rather than hCG.

Diagnosis of pelvic tuberculosis in a patient with tubal infertility.

OBJECTIVE: To describe a case of pelvic tuberculosis presenting as primary infertility and discuss the various diagnostic modalities. DESIGN: Case report. SETTING: Academic reproductive medicine center. PATIENT(S): A 28-year-old nulliparous Indian immigrant presenting with primary infertility and known tubal pathology. INTERVENTION(S): Laparoscopic bilateral salpingectomy and adhesiolysis and diagnostic endometrial sampling. MAIN OUTCOME MEASURE(S): Acid-fast bacilli were obtained on polymerase chain reaction and culture of endometrial sample. RESULT(S): The patient was diagnosed with pelvic tuberculosis and treated with a directly observed multidrug regimen. CONCLUSION(S): Tuberculosis is an important cause of gynecologic morbidity and should be considered in the appropriate patients.

Discontinuation of rLH two days before hCG may increase the number of oocytes retrieved in IVF.

BACKGROUND: Administration of recombinant luteinizing hormone (rLH) in controlled ovarian hyperstimulation may benefit a subpopulation of patients. However, late follicular phase administration of high doses of rLH may also reduce the size of the follicular cohort and promote monofollicular development. METHODS: To determine if rLH in late follicular development had a negative impact on follicular growth and oocyte yield, IVF patients in our practice who received rFSH and rLH for the entire stimulation were retrospectively compared with those that had the rLH discontinued at least two days prior to hCG trigger. RESULTS: The two groups had similar baseline characteristics before stimulation with respect to age, FSH level and antral follicle count. However, the group which had the rLH discontinued at least two days prior to their hCG shot, had a significantly higher number of oocytes retrieved, including a higher number of MII oocytes and number of 2PN embryos. CONCLUSIONS: When using rLH for controlled ovarian hyperstimulation, administering it from the start of stimulation and stopping it in the late follicular phase, at least two days prior to hCG trigger, may increase oocyte and embryo yield.

Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.

PURPOSE: Treatment with cyclophosphamide (CYC) confers up to a 40% risk of ovarian failure in women of reproductive age. The use of GnRH agonists (GnRHa) to preserve ovarian function has been investigated in several small studies. We performed a systematic review of studies examining whether a GnRHa administered during chemotherapy is protective of ovarian function and fertility. METHODS: We searched the English-language literature (1966-April 2007) using MEDLINE and meeting abstracts and included studies that reported an association between GnRHa and ovarian preservation in women receiving chemotherapy. Studies without a control group were excluded. Ovarian preservation was defined as the resumption of menstrual cycles and a premenopausal follicle-stimulating hormone (FSH) after chemotherapy. Fertility was determined by a woman's ability to become pregnant. We estimated the summary relative risk (RR) and associated 95% confidence intervals (95% CI) using a random-effects model. RESULTS: Nine studies included 366 women. Three studies included women with autoimmune disease receiving CYC; six included women with hematologic malignancy receiving combination chemotherapy. In total, 178 women were treated with GnRHa during chemotherapy, 93% of whom maintained ovarian function. Of the 188 women not treated with GnRHa, 48% maintained ovarian function. The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR = 1.68, 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR = 1.65, CI 1.03-2.6). CONCLUSIONS: Based on the available studies, GnRHa appear to improve ovarian function and the ability to achieve pregnancy following chemotherapy. Several randomized trials are underway to define the role and mechanism of GnRHa in ovarian function preservation. In the meantime, premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.

The mouse gamete adhesin, SED1, is expressed on the surface of acrosome-intact human sperm.

OBJECTIVE: To determine whether SED1, a protein secreted by the mouse epididymis that coats sperm and participates in sperm adhesion to the zona pellucida, is present on human sperm and in human epididymal tissue. DESIGN: SED1 expression was analyzed by immunoblot and indirect immunofluorescence assays. SETTING: Academic clinical and research laboratories. PATIENT(S): Human breast milk was donated. Unused semen was donated by men presenting for semen analysis or in vitro fertilization (IVF). Cadaveric epididymal tissue was obtained from the institutional body donor program. INTERVENTION(S): Human milk fat globule membranes and human seminal plasma proteins were analyzed by immunoblot. Human sperm and epididymis were analyzed by indirect immunofluorescence microscopy. Acrosomal status was determined by staining with fluorescein isothiocyanate-Pisum sativum agglutinin. MAIN OUTCOME MEASURE(S): Immunoblot and indirect immunofluorescence assays. RESULT(S): Human SED1 is recognized by two different polyclonal anti-SED1 antisera. SED1 is localized to the plasma membrane of human sperm overlying the intact acrosome. In acrosome-reacted sperm, SED1 is localized to the equatorial segment. SED1 is expressed by the epithelium of the anterior caput epididymis. CONCLUSION(S): SED1 is expressed on the surface of acrosome-intact human sperm and in the anterior caput of the human epididymis, similar to that seen in mouse.

A case of female epispadias.

OBJECTIVE: To present a case of unrecognized female epispadias. DESIGN: Case report. SETTING: University-based reproductive endocrinology and fertility clinic. PATIENT(S): A 16-year-old girl with epispadias, history of mild urinary incontinence, auditory neuropathy, and functional hyperandrogenism. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Peripheral blood array-based comparative genomic hybridization. RESULT(S): The patient was referred for evaluation of excessive weight gain, secondary amenorrhea, and abnormal external genitalia. Examination under anesthesia revealed bilateral labia minora hypertrophy, bifid clitoris, and a patulous urethra, consistent with female epispadias. Hormonal evaluation showed functional hyperandrogenism, and peripheral blood array-based comparative genomic hybridization showed no chromosomal deletions or duplications. CONCLUSION(S): Female epispadias is a rare abnormality, not commonly recognized by most practitioners. The diagnosis is supported by a history of urinary incontinence and physical findings of bifid clitoris and patulous urethra. The condition can have serious physical and psychological consequences leading to a gross disruption of social function.

A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer.

BACKGROUND: Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed. PATIENTS AND METHODS: Premenopausal women with ESBC and planned chemotherapy (>/= 25% risk of amenorrhea) were evaluated. Follicle stimulating hormone (FSH), estradiol, Inhibin A and B, anti-Müllerian hormone (AMH), and quality of life (QOL) were prospectively evaluated pre-, post-, 6 months and 1 year post-chemotherapy and correlated with age and menstrual status. CRA was defined as absence of menses 1 year post-chemotherapy. RESULTS: Forty-four women were evaluated at the time of analysis. Median age at diagnosis and FSH 1 year post-chemotherapy were higher among women with CRA (44 yrs [33-51] vs. 40 yrs [31-43]; p = 0.03; 39.8 vs. 5.0 mLU/mL, p = 0.0058, respectively). Median estradiol 1 year post-chemotherapy was higher among women who resumed menses (108.3 vs. 41.3 pg/mL, p = 0.01). Pre-chemotherapy median Inhibin B and AMH were lower among women with CRA (33.2 vs. 108.8 pg/mL; p = 0.03; 0.16 vs. 1.09 ng/mL, p = 0.02, respectively). The risk of CRA was increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and AMH (RR = 1.83, p = 0.05). Amongst women whose pre-chemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%. CONCLUSIONS: RESULTS indicate that pre-chemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women facing chemotherapy for ESBC.

Novel gamete receptors that facilitate sperm adhesion to the egg coat.

Mammalian fertilization is initiated by species-specific binding of the sperm to the zona pellucida, or egg coat. Previous studies suggested that sperm adhesion to the egg coat is facilitated, at least in part, through the binding of sperm surface beta1 ,4-galactosyltransferase I (GaIT) to glycoside chains on the egg coat glycoprotein, ZP3. Binding of multiple ZP3 oligosaccharides induces aggregation of GaIT within the sperm membrane, triggering, directly or indirectly, a pertussis toxin sensitive G-protein cascade leading to induction of the acrosome reaction. Consistent with this, spermatozoa bearing targeted deletions in GaIT are unable to bind ZP3 or undergo ZP3-dependent acrosomal exocytosis; however, unexpectedly, GaIT-null sperm are still able to bind to the egg coat. This indicates that sperm-egg binding requires at least two independent binding mechanisms; a GaIT-ZP3-independent event that mediates initial adhesion, followed by a GaIT-ZP3 interaction that facilitates acrosomal exocytosis. Our recent efforts have focused on the identification and characterization of these novel gamete receptors. One recently identified sperm protein that is required for sperm adhesion to the egg coat is SED1. SED1 is a bimotif protein composed of two Notch-like EGF repeats and two discoidin/complement F5/8 domains. SED1 is secreted by the epididymal epithelium and coats spermatozoa as they progress through the epididymis. Spermatozoa null for SED1 fail to bind the egg coat, illustrating its requirement for gamete adhesion. Interestingly, SED1 is also expressed by a variety of other epithelial tissues, where it appears to be required for epithelial morphogenesis and/or maintenance. A second novel gamete receptor has recently been identified on the coat of ovulated oocytes. This ZP3-independent, egg coat component is a high molecular weight, wheat germ agglutinin (WGA)-reactive glycoprotein that is derived from oviduct secretions and appears to participate in initial sperm adhesion. The amino acid sequence of this oviduct-derived ligand is currently being determined for the generation of peptide-specific antibodies and for the creation of knock out mice. The identification of novel gamete receptors that are required for sperm-egg binding opens up new avenues for the development of specific contraceptive strategies.