Visual interpretability of image-based classification models by generative latent space disentanglement applied to in vitro fertilization.

The success of deep learning in identifying complex patterns exceeding human intuition comes at the cost of interpretability. Non-linear entanglement of image features makes deep learning a "black box" lacking human meaningful explanations for the models' decision. We present DISCOVER, a generative model designed to discover the underlying visual properties driving image-based classification models. DISCOVER learns disentangled latent representations, where each latent feature encodes a unique classification-driving visual property. This design enables "human-in-the-loop" interpretation by generating disentangled exaggerated counterfactual explanations. We apply DISCOVER to interpret classification of in vitro fertilization embryo morphology quality. We quantitatively and systematically confirm the interpretation of known embryo properties, discover properties without previous explicit measurements, and quantitatively determine and empirically verify the classification decision of specific embryo instances. We show that DISCOVER provides human-interpretable understanding of "black box" classification models, proposes hypotheses to decipher underlying biomedical mechanisms, and provides transparency for the classification of individual predictions.

Hormonal contraception for female athletes presents special needs and concerns.

PURPOSE: Oral contraceptives (OCs) are commonly used by female athletes raising concerns regarding the possible adverse effects of OCs on physical performance, musculoskeletal injuries, and bone density. We aimed to review all current studies on the physiological effects of OCs in physically active women. MATERIALS AND METHODS: A review of literature in electronic search in PubMed and Google Scholar databases from December 2002 to December 2022 using relevant keywords. The reference lists of the articles found eligible were also reviewed. RESULTS: Out of 344 articles in the initial database, 54 clinical studies were eligible for inclusion in our literature review. OCs are used by about two-thirds of female athletes. Current research suggests that OCs' effects on endurance performance and muscle strength are mostly reassuring. OCs do not seem to have a major negative impact on bone health or sports injuries. In fact, new data suggests that they may even significantly reduce the risk of anterior cruciate ligament (ACL) injury. CONCLUSIONS: OCs can be safely used by young female athletes, who may also benefit from better menstrual cycle control. OCs offer newly realised protection from ACL injuries. The use of OCs must be carefully individualised according to their preferences, expectations, and experience.

Hormonal contraception can be safely prescribed to active women. The International Olympic Committee advocates a new and wider definition for the 'athlete triad', where low energy availability presents a special challenge for these athletes. New data suggests that the use of oral contraceptives may protect against ACL injury.

Using Unlabeled Information of Embryo Siblings from the Same Cohort Cycle to Enhance In Vitro Fertilization Implantation Prediction.

High-content time-lapse embryo imaging assessed by machine learning is revolutionizing the field of in vitro fertilization (IVF). However, the vast majority of IVF embryos are not transferred to the uterus, and these masses of embryos with unknown implantation outcomes are ignored in current efforts that aim to predict implantation. Here, whether, and to what extent the information encoded within "sibling" embryos from the same IVF cohort contributes to the performance of machine learning-based implantation prediction is explored. First, it is shown that the implantation outcome is correlated with attributes derived from the cohort siblings. Second, it is demonstrated that this unlabeled data boosts implantation prediction performance. Third, the cohort properties driving embryo prediction, especially those that rescued erroneous predictions, are characterized. The results suggest that predictive models for embryo implantation can benefit from the overlooked, widely available unlabeled data of sibling embryos by reducing the inherent noise of the individual transferred embryo.

Sonographic Signs of Adenomyosis in Women with Endometriosis Are Associated with Infertility.

We compared the prevalence of ultrasound signs of adenomyosis in women with endometriosis who underwent surgery to those who were managed conservatively. This was a retrospective study of women evaluated at a tertiary endometriosis referral center who underwent 2D/3D transvaginal ultrasound. Adenomyosis diagnosis was based on the presence of at least three sonographic signs. The study group subsequently underwent laparoscopic surgery while the control group continued conservative management. Statistical analysis compared the two groups for demographics, symptoms, clinical data, and sonographic findings. The study and control groups included 244 and 158 women, respectively. The presence of any, 3+, or 5+ sonographic signs of adenomyosis was significantly more prevalent in the study group (OR = 1.93-2.7, p < 0.004, 95% CI; 1.24-4.09). After controlling for age, for all findings but linear striations, the OR for having a specific feature was higher in the study group. Women in the study group with ≥ 5 sonographic signs of adenomyosis had more than twice the risk of experiencing infertility (OR = 2.31, p = 0.012, 95% CI; 1.20-4.45). Sonographic signs of adenomyosis are more prevalent in women with symptomatic endometriosis who underwent surgery compared with those who continued conservative management. Women with 5+ findings have a significantly increased risk of infertility. Adenomyosis on ultrasound should be considered in the management decisions regarding these patients.

Why do women choose to undergo oocyte aspiration without sedation or analgesia?

OBJECTIVE: Oocyte pick-up (OPU) is a painful but essential part of in-vitro fertilization (IVF) that is usually performed under sedation and analgesia (SaA). Our aim was to study that why some women decide to undergo OPU without SaA? METHODS: This was a prospective study using patient questionnaires and the standardized 7-item generalized anxiety disorder (GAD-7) score. The patients were asked to assess the pain experienced during OPU using a visual analog scale (VAS). The study sample was a convenience sample of 100 healthy women undergoing OPU at our unit with or without SaA. RESULTS: Women who chose to undergo OPU without SaA were significantly more likely to express the fear of anesthesia. A high pain score (VAS ≥ 6) was reported by significantly more patients who underwent OPU without SaA than with SaA. Yet, 98% of the patients who underwent OPU without SaA stated that in future IVF cycles, they would still choose to undergo OPU without SaA. More patients had high anxiety scores among those who underwent OPU with than without SaA. CONCLUSIONS: Women who chose to undergo OPU without SaA reported more often fear of anesthesia. Although these women experienced significantly more pain during OPU, almost all of them suggested that they would still choose to undergo OPU without SaA. Increased anxiety, as expressed by higher GAD-7 scores, was not associated with a tendency to choose SaA during OPU. The option of OPU without SaA seems to be an acceptable option for selected women. LAY SUMMARY: Egg retrieval from the ovaries is a painful part of in vitro fertilization (IVF). It is, therefore, usually performed under sedation and pain relief (analgesia). The aim of this study was to investigate: Why some women decide to undergo egg retrieval without sedation? We prospectively studied 100 women using patient questionnaires and standardized scores in order to measure patient's pain and anxiety levels. We found that women who chose to undergo egg retrieval without sedation were significantly more likely to express fear of anesthesia. As expected, women who decided to forgo sedation experienced more pain during egg retrieval, yet, 98% of them decided that in future IVF cycles, they would still choose to undergo egg retrieval without sedation. Surprisingly, women who had high anxiety scores were not more likely to ask for sedation during egg retrieval. The option to undergo egg retrieval without sedation during IVF seems to be acceptable for some women.

Assessment of a double freezing approach in the management of surplus embryos in IVF.

RESEARCH QUESTION: What pregnancy rates are achieved after transfer of cryopreserved double slow-frozen embryos in IVF cycles? Patients in whom surplus thawed cleaved embryos (day 2 or 3) were grown to the blastocyst stage, re-frozen and then re-thawed for transfer (double freezing) were included. DESIGN: Data were collected on all patients who had undergone the above procedure at the IVF unit of Assuta Ramat Hachayal Hospital, Tel Aviv, during a 7-year period. For each patient in the study group, the two-consecutive, matched-by-age patients treated with frozen-thawed single blastocyst transfer were selected to form a 2:1 ratio control group. All embryos were frozen using the slow freeze protocol. RESULTS: A total of 54 patients had 70 embryos that were re-frozen at the blastocyst stage. Twenty-eight of these blastocysts were thawed and 27 underwent transfer to 25 patients. A single embryo was transferred to 23 patients and two embryos were transferred to two patients. The survival rate of the second thawing was 96.4% (27/28). Clinical pregnancy rate was 16% (4/25) and implantation rate was 14.8% (4/27). In the study group, pregnancies were achieved in 22 out of the 25 patients using IVF treatment, indicating good receptivity of the uterus. In the control group, the implantation/pregnancy rates were significantly higher (44.2% [23/52]; P < 0.01). CONCLUSION: The transfer of twice slow-frozen and thawed embryos does not seem to be a beneficial approach in the planned management of cryopreserved surplus embryos owing to the low pregnancy rate achieved after transfer of the re-frozen blastocyst embryos.

Significant increase in serum hCG levels following methotrexate therapy is associated with lower treatment success rates in ectopic pregnancy patients.

OBJECTIVE: To determine the association between early increase in the serum hCG levels (days 0-4) and treatment success rates following methotrexate therapy in ectopic pregnancy patients. STUDY DESIGN: A level II-2 case-control study of involving 140 patients treated with methotrexate for ectopic pregnancy at the gynecology department in a tertiary care hospital. RESULTS: A logistic regression model for the "failure of treatment" was fitted with serum hCG levels change between day 0 and day 4, patient age, pregnancy age at day-0, and day-0 ß-hCG level as predictors. The logistic regression analysis indicated that having more than 50% increase in the ß-hCG levels between days 0 and 4 significantly (P = 0.011) increases the risk of MTX treatment failure. CONCLUSION: The results of this study indicate that >50% increase in ß-hCG levels between days 0 and 4 significantly increases the risk of methotrexate treatment failure. This novel information could assist patients and physicians in making decisions regarding ectopic pregnancy treatment.

The expected cumulative incidence of live birth for patients starting IVF treatment at age 41 years or older.

RESEARCH QUESTION: What is the cumulative incidence of live birth (CILB) for high-order consecutive IVF cycles, and which factors are associated with live birth in women aged ≥41 years using autologous oocytes? DESIGN: A retrospective cohort study including 146 patients aged 41 years to <44 years who started their first IVF cycle attempt using autologous oocytes, between January 2006 and December 2013. RESULTS: After 13 IVF cycles, CILB reached up to 33.6%. After six IVF cycles, 42 (28.8%) women delivered a live infant (85.7% of the total live birth). Mean live birth rate per cycle declined with age at the initial cycle (8% at 41 years; 5.8% at 42 years; and 4.1% at 43 years). Multivariable modified Poisson regression models identified patient's age (RR for 41 years versus 43 years: 0.47; 95% CI 0.25 to 0.87; P = 0.01), smoking status (RR 0.21; 95% CI 0.05 to 0.08; P = 0.02), and mean number of fertilized oocytes (RR 1.23; 95% CI 1.08 to 1.39; P < 0.01) as factors significantly associated with the probability of a live birth. CONCLUSIONS: Multiple repeat IVF cycles in women aged 41-44 years offers a reasonable long-term success rate. After six cycles of treatment, about 29% of women of advanced reproductive age using autologous oocytes expected to achieve a live birth. This information might assist in fertility counselling and managing patients' expectations by adjusting the appropriate treatment strategy and number of IVF cycle attempts, especially in countries in which egg donation is prohibited or when multiple repeated IVF cycles attempts are financially affordable.

Sonographic Signs of Adenomyosis Are Prevalent in Women Undergoing Surgery for Endometriosis and May Suggest a Higher Risk of Infertility.

OBJECTIVES: To determine the prevalence of ultrasound features suggestive of adenomyosis in women undergoing surgery for endometriosis compared with a control group of healthy women without endometriosis. METHODS: Retrospective case-control study comparing women with intractable pain or infertility, who underwent transvaginal ultrasound and subsequent laparoscopic surgery, with a control group of healthy women without a previous history of endometriosis. A diagnosis of adenomyosis on TVUS was made based on asymmetrical myometrial thickening, linear striations, myometrial cysts, hyperechoic islands, irregular endometrial-myometrial junction, parallel shadowing, and localized adenomyomas and analyzed for one sign and for three or more signs. RESULTS: The study and control groups included 94 and 60 women, respectively. In the study group, women were younger and had more dysmenorrhea and infertility symptoms. The presence of any sonographic feature of adenomyosis, as well as three or more signs, was found to be more prevalent in the study group, which persisted after controlling for age, for all features but linear striations. Women in the study group who had five or more sonographic features of adenomyosis had more than a threefold risk of suffering from infertility (OR = 3.19, p = 0.015, 95% CI; 1.25-8.17). There was no association with disease severity at surgery. CONCLUSIONS: Sonographic features of adenomyosis are more prevalent in women undergoing surgery for endometriosis compared to healthy controls. Women with more than five features had an increased risk of infertility.

The Clinical Significance of Endocannabinoids in Endometriosis Pain Management.

Introduction: Patients with endometriosis often suffer from diffuse and poorly localized severe pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. Better pain management is therefore of urgent need. Methods: Among the various candidates, the endocannabinoid system (ECS) has recently emerged as a relevant pharmacological target for the management of endometriosis-related pain. A computerized literature search was performed to identify relevant studies combining the keywords "endometriosis," "endocannabinoid," "cannabinoid receptor," "THC," and "pain mechanisms." Conclusions: This review describes the multiple and complex pain mechanisms associated with endometriosis. Current data and theories concerning the link between the ECS and pain management for endometriosis patients are presented. Finally, we will discuss which aspects of endometriosis-associated pain can be targeted by modulation of the ECS.

Laparoscopic Findings Associated with Bladder Endometriosis Are Correlated with Disease Severity.

STUDY OBJECTIVE: Bladder involvement is rare in endometriosis. The prevalence is estimated to be ∼1% in patients with endometriosis. However, this figure seems to be an underestimation. The diagnosis of bladder endometriosis might be missed during laparoscopy. The aim of this study was to determine an intraoperative visual score of pelvic lesions that help the surgeon suspect bladder endometriosis. Design, Design Classification: A retrospective analysis was performed on the intraoperative photographs and videos of 69 patients with histological confirmation of bladder endometriosis. SETTING: A tertiary referral center. PATIENTS: Sixty-nine patients with bladder endometriosis were operated on in our center over a 9-year period. INTERVENTIONS: Evaluation and analysis of intraoperative laparoscopic findings. MAIN RESULTS: We found three subtypes of laparoscopic findings that can assist with diagnosing bladder endometriosis. The most prominent sign was named "kissing round ligaments" (Type K), in which the right and left round ligaments appear closer to each other than usual or even touching one another. This sign is strongly associated with full-thickness invasion of the bladder. Other laparoscopic findings that indicated bladder endometriosis were anatomical distortion (Type A) and proximal occlusion of the tubes (Type B). We further define a scoring system for the lesion that correlates with the severity of the bladder endometriosis from superficial lesions to full thickness. CONCLUSION: Bladder endometriosis is a rare condition and often remains undiagnosed. Indeed, even during surgery, bladder endometriosis can be missed if the operator is not aware of the suggestive signs. Operative laparoscopic findings may help the surgeon to diagnose bladder endometriosis, and these signs correlate with the severity of the disease.

Religion and family planning.

Religion is embedded in the culture of all societies. It influences matters of morality, ideology and decision making, which concern every human being at some point in their life. Although the different religions often lack a united view on matters such contraception and abortion, there is sometimes some dogmatic overlap when general religious principles are subject to the influence of local customs. Immigration and population flow add further complexities to societal views on reproductive issues. For example, present day Europe has recently faced a dramatic increase in refugee influx, which raises questions about the health care of immigrants and the effects of cultural and religious differences on reproductive health. Religious beliefs on family planning in, for example, Christianity, Judaism, Islam and Hinduism have grown from different backgrounds and perspectives. Understanding these differences may result in more culturally competent delivery of care by health care providers. This paper presents the teachings of the most widespread religions in Europe with regard to contraception and reproduction.

Fertility outcome of laparoscopic treatment in patients with severe endometriosis and repeated in vitro fertilization failures.

OBJECTIVE: To evaluate fertility outcomes in infertile women with severe endometriosis (The revised American Fertility Society classification [AFS] 3-4) and repeated IVF failures, who underwent surgery due to exacerbation of endometriosis-related symptoms. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): All women who failed IVF treatment before surgery and who underwent laparoscopic surgery for severe endometriosis between January 2006 and December 2014. INTERVENTION(S): All patients were operated by highly skilled surgeons specializing in laparoscopic surgery for advanced endometriosis. Only patients with evidence of endometriosis in the pathology specimens were included in this study. MAIN OUTCOME MEASURE(S): Delivery rate after surgery. RESULT(S): Seventy-eight women were included in the present study. All women were diagnosed with severe endometriosis during surgery (AFS 3-4) and all women had experienced failed IVF treatments before surgery. All women were symptomatic before their surgery. After surgical treatment 33 women (42.3%) delivered. Three women (9%) conceived spontaneously and all other women conceived after IVF treatment. Women who delivered were younger (32.5 [±4.1] years vs. 35.5 [±3.8] years), were less often diagnosed with diminished ovarian reserve before surgery (6% vs. 28.8%), and were more often diagnosed with normal uterine anatomy (by preoperative transvaginal ultrasound and during operation). In addition, performing salpingectomy during surgery was associated with a trend of improvement in delivery rates after surgery (70% in women who delivered vs. 51% in women who failed to deliver). CONCLUSION(S): Symptomatic women with severe endometriosis and repeated IVF implantation failures may benefit from extensive laparoscopic surgery when performed by an experienced multidisciplinary surgical team to improve IVF outcome.

Why do couples discontinue unlimited free IVF treatments?

Worldwide, IVF is often discontinued before a live birth is achieved due to high costs. Even when partial financial coverage is provided, often medical providers advise treatment discontinuation. In Israel, unlimited IVF is offered free of charge for a couples' first two children. Our objective was to assess the reasons couples discontinue IVF treatments before achieving two children in a completely unlimited cost-free environment. This cohort study included all primary infertile women, <35 years, referred for their first IVF cycle to Sheba IVF unit between 2001 and 2002. Patients were followed until February 2012. Those who ceased treatments for 12 months were interviewed to assess the main reason they ceased treatments. Of the 134 couples included, only 46 ceased IVF treatments without achieving two children, after performing an average of 6.2 IVF cycles to achieve their first birth. The reasons given were: lost hope of success (13), psychological burden (18), divorce (6), medical staff recommendation (5), bureaucratic difficulties (3) and general medical condition (1). The main reasons for "drop out" in our cost-free environment were as follows: psychological burden and lost hope of success. Due to high availability of treatments, medical staff recommendation was a less significant factor in our study.

Influence of structured counseling on women's selection of hormonal contraception in Israel: results of the CHOICE study.

BACKGROUND: The multinational CHOICE (Contraceptive Health Research Of Informed Choice Experience) study evaluated the effects of structured counseling on women's contraceptive decisions, their reasons for making those decisions, and their perceptions of combined hormonal contraceptive (CHC) methods in eleven countries. The aim of this paper to present data from the 1,802 women participating in Israel's CHOICE program. METHODS: Women (aged 17-40 years) who consulted their health care providers about contraception and who would consider a CHC method qualified to participate. After indicating their intended CHC method, the women received counseling about the daily pill, weekly patch, and monthly vaginal ring. After counseling, the women completed a questionnaire about their contraceptive decisions. RESULTS: Before counseling, 67%, 6%, and 5% of women (mean age 27 years) intended to use the pill, patch, or ring, respectively. Counseling significantly influenced the women's CHC choice, with 56%, 12%, and 23% of women selecting the pill, patch, or ring (P<0.0001 for all contraceptive methods versus before counseling). Logistic regression analysis suggested that age significantly increased the probability of switching from the pill to the ring. CONCLUSION: Although the pill was the most popular choice overall, counseling appeared to influence Israeli women's contraceptive decisions, with significantly more women selecting the patch. More than four times as many women selected the ring after counseling than before counseling.

Pelvic inflammatory disease in women with endometriosis is more severe than in those without.

AIMS: To determine the incidence and severity of acute pelvic inflammatory disease (PID) or tubo-ovarian abscess (TOA) in hospitalised women with and without a history of endometriosis. METHODS: Retrospective analysis of hospital records retrieved for all women hospitalised with PID or TOA between January 2008 and December 2011 in a tertiary referral centre. Women were compared with regard to a history of endometriosis for demographic, clinical and fertility data. RESULTS: 26 (15%) of the 174 women hospitalised due to PID or TOA were excluded because of age older than 45 years, leaving 148 for analysis. The mean age was 35.7 ± 9.3 years and mean duration of hospitalisation was 5.9 ± 3.7 days. The women were divided into two groups: Group 1 with endometriosis (n = 21) and Group 2 without endometriosis (n = 127). Women in Group 1 as compared with Group 2 were significantly more likely to have undergone a fertility procedure prior to being admitted to the hospital with PID (9/27 (45%) vs 22/121 (17%), P < 0.001); particularly in vitro fertilisation (IVF) (7/ 27 (33%) vs 12/121 (9%), P < 0.006); Women in Group 1 more frequently experienced a severe and complicated course involving longer duration of hospitalisation (8.8 ± 4.7 vs 4.4 ± 2.3 days, P < 0.0001) and antibiotic treatment failure (10/27 (48%) vs 8/121 (6%), P < 0.0001). CONCLUSIONS: Pelvic inflammatory disease in women with endometriosis is more severe and refractory to antibiotic treatment, often requiring surgical intervention. It is likely that endometriosis is a risk factor for the development of severe PID, particularly after IVF treatment.

Surgery versus pharmacological treatment for endometriosis.

The two major consequences of endometriosis are pain and infertility. Despite numerous studies and proposed guidelines, some aspects of the treatment for these complications are still under debate or lack convincing evidence that favors one approach over the other. Future studies will hopefully present new evidence in regard to the optimal treatment for each indication and suggest innovative pharmacotherapy following improved understanding of the pathophysiology of endometriosis. Until then, individualization of the treatment according to the specific indication, taking into consideration the benefits versus the risks for the patient and the tolerability profile, remains the most appropriate approach.

Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study.

OBJECTIVE: To evaluate the efficacy and safety of 3 months of vaginal mifepristone treatment on leiomyoma volume and related symptoms. DESIGN: Prospective, open-label, two tertiary centers, phase II clinical trial. SETTING: Two tertiary medical centers in Israel. PATIENT(S): Thirty-three enrolled women, ages 30-53 years, diagnosed with symptomatic uterine fibroids. INTERVENTION(S): Patients received 10 mg mifepristone vaginally daily for 3 months. MAIN OUTCOME MEASURE(S): Reduction in uterine leiomyoma volume. Improvement in symptoms related to uterine fibroids was assessed with the use of the "Uterine Fibroid Symptoms Quality of Life Questionnaire" (UFS-QoL). The number of bleeding days, safety, and tolerability were secondary measures. RESULT(S): Mifepristone treatment significantly reduced leiomyoma volume from 135.3 ± 22.9 cc at enrollment to 101.2 ± 22.4 cc after 3 months of treatment. The UFS-QoL Score significantly decreased from 20.7 ± 0.7 at enrollment to 14.0 ± 0.8 after 3 months of treatment. The number of bleeding days significantly decreased by 3.5 days. Endometrial biopsies showed no evidence of endometrial hyperplasia or cellular atypia. There were no major side effects during the course of the study, and treatment was well tolerated. CONCLUSION(S): Vaginal mifepristone may offer an effective treatment option for women with symptomatic uterine leiomyoma and can improve the patients' quality of life. CLINICAL TRIAL REGISTRATION NUMBER: NCT00881140.

What is the quality of information on social oocyte cryopreservation provided by websites of Society for Assisted Reproductive Technology member fertility clinics?

OBJECTIVE: To evaluate adequacy and adherence to American Society for Reproductive Medicine (ASRM) guidelines of internet information provided by Society for Assisted Reproductive Technology (SART)-affiliated clinics regarding social oocyte cryopreservation (SOC). DESIGN: Systematic evaluation of websites of all SART member fertility clinics. SETTING: The internet. PATIENT(S): None. INTERVENTION(S): All websites offering SOC services were scored using a 0-13 scale, based on 10 questions designed to assess website quality and adherence to the ASRM/SART guidelines. The websites were analyzed independently by two authors. Whenever disagreement occurred, a third investigator determined the score. MAIN OUTCOME MEASURE(S): Scores defined website quality as excellent, ≥9; moderate, 5-8; or poor, ≤4 points. RESULT(S): Of the 387 clinics registered as SART members, 200 offered oocyte cryopreservation services for either medical or social reasons; 147 of these advertised SOC. The average website scores of those clinics offering SOC was 3.4 ± 2.1 (range, 2-11) points. There was no significant difference in scores between private versus academic clinics or clinics performing more or less than 500 cycles per year. CONCLUSION(S): The majority of the websites do not follow the SART/ASRM guidelines for SOC, indicating that there is a need to improve the type and quality of information provided on SOC by SART member websites.