ABCC4 is a PGE2 efflux transporter in the ovarian follicle: A mediator of ovulation and a potential non-hormonal contraceptive target.

The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in cultured human GCs is mediated by ABCC4 thus regulating its extracellular concentration. The ABCC4 inhibitor probenecid demonstrated effective blocking of ovulation and affects key ovulatory genes in female mice in vivo. We postulate that the reduction in PGE2 efflux caused by the inhibition of ABCC4 activity in GCs decreases the extracellular concentration of PGE2 and its ovulatory effect. Treatment of female mice with low dose of probenecid as well as with the PTGS inhibitor indomethacin or Meloxicam synergistically blocks ovulation. These results support the hypothesis that ABCC4 has an important role in ovulation and might be a potential target for non-hormonal contraception, especially in combination with PGE2 synthesis inhibitors. These findings may fill the gap in understanding the role of ABCC4 in PGE2 signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment and control of fertility.

An artificial intelligence-based approach for selecting the optimal day for triggering in antagonist protocol cycles.

RESEARCH QUESTION: Can a machine-learning model suggest an optimal trigger day (or days), analysing three consecutive days, to maximize the number of total and mature (metaphase II [MII]) oocytes retrieved during an antagonist protocol cycle? DESIGN: This retrospective cohort study included 9622 antagonist cycles between 2018 and 2022. The dataset was divided into training, validation and test sets. An XGBoost machine-learning algorithm, based on the cycles' data, suggested optimal trigger days for maximizing the number of MII oocytes retrieved by considering the MII predictions, prediction errors and outlier detection results. Evaluation of the algorithm was conducted using a test dataset including three quality groups: 'Freeze-all oocytes', 'Fertilize-all' and 'ICSI-only' cycles. The model suggested 1, 2 or 3 days as trigger options, depending on the difference in potential outcomes. The suggested days were compared with the actual trigger day chosen by the physician and were labelled 'concordant' or 'discordant' in terms of agreement. RESULTS: In the 'freeze-all' test-set, the concordant group showed an average increase of 4.8 oocytes and 3.4 MII oocytes. In the 'ICSI-only' test set there was an average increase of 3.8 MII oocytes and 1.1 embryos, and in the 'fertilize-all' test set an average increase of 3.6 oocytes and 0.9 embryos was observed (P < 0.001 for all parameters in all groups). CONCLUSIONS: Utilizing a machine-learning model for determining the optimal trigger days may improve antagonist protocol cycle outcomes across all age groups in freeze-all or fresh transfer cycles. Implementation of these models may more accurately predict the number of oocytes retrieved, thus optimizing physicians' decisions, balancing workloads and creating more standardized, yet patient-specific, protocols.

Intrauterine insemination timing models-LH can only take you so far.

RESEARCH QUESTION: Can an optimal LH threshold algorithm accurately predict timing of ovulation for natural cycle-intrauterine insemination (NC-IUI)? DESIGN: A retrospective cohort study (2018-2022) including 2467 natural cycles. Ovulation timing for these cycles was determined using a previously developed AI model. Two LH thresholds, low and high, were determined in the LH algorithm. Being below the low threshold meant that ovulation is likely to occur in ≥ 4 days, suggesting another daily blood test. Between the two thresholds meant that ovulation was likely in 2-3 days, suggesting IUI the next day. Above the high threshold meant that ovulation will likely occur tomorrow, suggesting performing IUI on the same day. RESULTS: The optimal LH model with a high threshold of 40 mIU/ml and a low threshold of 11 mIU/ml succeeded in correctly predicting timing for IUI (day - 1, - 2 relative to ovulation) in 75.4% (95%CI 75.3-75.4). In 23.1% (95%CI 23.0-23.2), the algorithm predicted "error," suggesting performing insemination when in fact it would have been performed on a non-optimal day (0 or - 3). A previously described 3-hormone-based (LH, estradiol, progesterone) AI model performed significantly better in all parameters (93.6% success rate, 4.3 "error" rate). CONCLUSIONS: An LH threshold model, representing common practice, evaluating all possible high and low LH threshold combinations, was successful in accurately scheduling timing for IUI in only 75% of cases. Integrating all three hormones as performed in the AI model may have an advantage in accurately predicting the optimal time for IUI, over the use of LH only.

The Fer tyrosine kinase protects sperm from spontaneous acrosome reaction.

The physiological acrosome reaction occurs after mammalian spermatozoa undergo a process called capacitation in the female reproductive tract. Only acrosome reacted spermatozoon can penetrate the egg zona-pellucida and fertilize the egg. Sperm also contain several mechanisms that protect it from undergoing spontaneous acrosome reaction (sAR), a process that can occur in sperm before reaching proximity to the egg and that abrogates fertilization. We previously showed that calmodulin-kinase II (CaMKII) and phospholipase D (PLD) are involved in preventing sAR through two distinct pathways that enhance F-actin formation during capacitation. Here, we describe a novel additional pathway involving the tyrosine kinase Fer in a mechanism that also prevents sAR by enhancing actin polymerization during sperm capacitation. We further show that protein-kinase A (PKA) and the tyrosine-kinase Src, as well as PLD, direct Fer phosphorylation/activation. Activated Fer inhibits the Ser/Thr phosphatase PP1, thereby leading to CaMKII activation, actin polymerization, and sAR inhibition.

Treatment safety of ART cycles with extremely high oestradiol concentrations using GnRH agonist trigger.

RESEARCH QUESTION: Are IVF treatments with extremely high peak oestradiol levels and gonadotrophin releasing hormone (GnRH) agonist trigger associated with higher complication rates? DESIGN: A retrospective cohort study including patients from two large medical centres treated between 2019 and 2021. A study group with extremely high peak oestradiol levels (≥20,000 pmol/l on the day of ovarian stimulation, or ≥15,000 pmol/l on the previous day) and a control group with normal range oestradiol levels (3000-12000 pmol/l) that received GnRH agonist triggering. Patients were surveyed about complaints and medical care related to ovum retrieval and medical files were reviewed. Major complication rates and the need for medical assistance were compared. RESULTS: Several differences between the study and control group were observed because of the study design: mean age was 33.01 ± 5.14 versus 34.57 ± 4.52 (P < 0.001), mean peak oestradiol levels was 26645.34 ± 8592.57 pmol/l versus 7229.75 ± 2329.20 pmol/l (P < 0.001), and mean number of oocytes were 27.55 ± 13.46 versus 11.67 ± 5.76 (P < 0.001) for the study and control group, respectively. Major complications and hospitalization rates were similar between the study and control groups (three [1.25%] versus one [0.48%]; P = 0.62 and three [1.25%] versus two [0.96%]; P = 1.0, respectively). Thirty-six patients (15.1%) in the study group and 11 (5.3%) in the control group sought medical care after retrieval, mostly due to abdominal pain, without the need for further workup or hospitalization (P < 0.001). CONCLUSIONS: Extremely high oestradiol levels were not associated with thromboembolic events, higher major complication or hospitalization rates, and therefore may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results.

IVF under COVID-19: treatment outcomes of fresh ART cycles.

STUDY QUESTION: Does prior severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in women undergoing fertility treatments affect the outcomes of fresh ART cycles? SUMMARY ANSWER: SARS-CoV-2 infection does not affect fresh ART treatment outcomes, except for a possible long-term negative effect on oocyte yield (>180 days postinfection). WHAT IS KNOWN ALREADY: A single previous study suggested no evidence that a history of asymptomatic or mild SARS-CoV-2 infection in females caused impairment of fresh ART treatment outcomes. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study, including all SARS-CoV-2 infected women who underwent fresh ART cycles within a year from infection (the first cycle postinfection), between October 2020 and June 2021, matched to non-diagnosed controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from two large IVF units in Israel who were infected with SARS-CoV-2 and later underwent fresh ART cycles were matched by age to non-diagnosed, non-vaccinated controls. Demographics, cycle characteristics and cycle outcomes, including oocyte yield, maturation rate, fertilization rate, number of frozen embryos per cycle and clinical pregnancy rates, were compared between groups. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and twenty-one infected patients and 121 controls who underwent fresh ART cycles were included. Oocyte yield (12.50 versus 11.29; P = 0.169) and mature oocyte rate (78% versus 82%; P = 0.144) in all fresh cycles were similar between groups, as were fertilization rates, number of frozen embryos per cycle and clinical pregnancy rates (43% versus 40%; P = 0.737) in fresh cycles with an embryo transfer. In a logistic regression model, SARS-CoV-2 infection more than 180 days prior to retrieval had a negative effect on oocyte yield (P = 0.018, Slope = -4.08, 95% CI -7.41 to -0.75), although the sample size was small. LIMITATIONS, REASONS FOR CAUTION: A retrospective study with data that was not uniformly generated under a study protocol, no antibody testing for the control group. WIDER IMPLICATIONS OF THE FINDINGS: The study findings suggest that SARS-CoV-2 infection does not affect treatment outcomes, including oocyte yield, fertilization and maturation rate, number of good quality embryos and clinical pregnancy rates, in fresh ART cycles, except for a possible long-term negative effect on oocyte yield when retrieval occurs >180 days post-SARS-CoV-2 infection. Further studies are warranted to support these findings. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: 0010-21-HMC, 0094-21-ASF.

The impact of past COVID-19 infection on pregnancy rates in frozen embryo transfer cycles.

PURPOSE: To study the effect of SARS-CoV-2 infection on pregnancy rates in frozen embryo transfer (FET) cycles. METHODS: A retrospective cohort study including women under the age of 42 with documented SARS-CoV-2 infection up to 1 year prior to treatment, undergoing FET cycles in the first half of 2021, with transfer of embryos generated prior to the infection. Controls were SARS-CoV-2 non-diagnosed, non-vaccinated women matched by age, number, and day of embryo transfer. Demographic and cycle characteristics and outcomes were compared. RESULTS: Forty-one recovered women and 41 controls were included. Pregnancy rates were 29% and 49% respectively (p = 0.070). Stratification by time from SARS-CoV-2 infection to transfer into ≤ 60 and > 60 days revealed a difference in pregnancy rates, with women in the COVID group having lower pregnancy rates if infected in proximity to the transfer (21% vs. 55%; p = 0.006). In a logistic regression model, infection was a significant variable (p = 0.05, OR 0.325, 95% CI 0.106-0.998). Logistic regression applied on the subgroup of women infected in proximity to the transfer further strengthened the univariate results, with COVID-19 remaining a significant parameter (p = 0.005, OR 0.072, 95% CI 0.012-0.450). CONCLUSIONS: In FET cycles of patients with past SARS-CoV-2 infection, in which oocytes were retrieved prior to infection, decreased pregnancy rates were observed, specifically in patients who recovered less than 60 days prior to embryo transfer. Pending further studies, in cases of FET cycles with limited number of embryos, postponing embryo transfer for at least 60 days following recovery from COVID-19 might be considered when feasible.

Lower Sperm Exposure among Participants Undergoing Intrauterine Insemination Associated with Increased Incidence of Gestational Hypertensive Disorders.

BACKGROUND: Gestational hypertensive (GH) disorders remain a major obstetric problem. OBJECTIVES: To evaluate the incidence of gestational hypertensive disorders among participants undergoing intrauterine insemination (IUI) after exposure to various levels of sperm from sperm donation (SD). METHODS: A retrospective case-control study was conducted at a single tertiary medical center between 2011 and 2019. Participants conceived via IUI using SD from a single sperm bank and had a successful singleton birth. Group 1 conceived during 1-2 cycles of IUI from the same sperm donor; whereas Group 2 after 3+ cycles. RESULTS: Overall 171 patients (Group 1 = 81, Group 2 = 90) met inclusion criteria. Participants showed no differences in age, chronic medical conditions, or history of pregnancy complications. The groups differed in gravidity and parity. The factors positively associated with Group 1 included either preeclampsia or GH (11 [13.5%] vs. 1 [1.1%], P = 0.001) and GH alone (8 [9.9%] vs. 1 [1.1%], P = 0.014). Newborns from Group 1 had a statistically significant lower birth weight than those from Group 2 (3003 grams ± 564.21 vs. 3173 grams ± 502.59, P = 0.039). GH was more prevalent in Group 1 (P = 0.008) than a control group of 45,278 participants who conceived spontaneously. No significant differences were observed between Group 2 and the control group. CONCLUSIONS: The incidence of GH and preeclampsia in participants was higher among those exposed to 1-2 cycles than those exposed to 3+ cycles of IUI.

Postpartum visits in the gynecological emergency room: How can we improve?

BACKGROUND: The attendance to the gynecological-emergency-room (GER) of women only a few weeks following previous discharge after birth comprises a medical as well as social problem. The objective of the study was to characterize the postpartum women that attended the GER, and depict the leading etiologies and risk-factors that lead them to attend the GER, and to examine correlations between their medical findings at discharge and the reasons for their attendance to the hospital. METHODS: All women that attended the GER between 01/01/2016 and 30/09/2016 during 6 weeks after birth were included. The variables assessed were: medical history, mode of birth, maternal complications of birth, diagnosis at the GER, treatment received and readmission. RESULTS: There were 446 visits of 413 women (5.6% of all deliveries). Most were generally healthy after their first normal vaginal birth with no complications during or following birth. 38.7% had a cesarean birth (p < 0.001). The most common causes of the visits were fever (30.3%), problems in episiotomy or surgical scar (26.6%) and abdominal pain (25.7%). Women with hypertensive disorders during birth had significantly more hypertensive problems in the GER. Diabetic women suffered statistically more from hypertensive disorder in the GER. 33.2% were examined and found healthy. Seventy-two women (1% of all deliveries) were hospitalized, most of them due to infection. Only 7.5% were referred to the GER due to bleeding. CONCLUSIONS: Postpartum women are at risk of morbidities, especially following cesarean sections and in women with hypertensive disorders of during pregnancy. Scheduled visits to high-risk women to attend outpatient clinic sooner are recommended.

The Impact of Sperm and Egg Donation on the Risk of Pregnancy Complications.

OBJECTIVE: The aim of this study was to evaluate obstetric outcomes in relation to the extent of donor sperm exposure with and without egg donation. MATERIALS AND METHODS: This is a retrospective cohort study in a single tertiary care center. All women with a singleton pregnancy who conceived following sperm donation (SD) were included. Obstetrics and neonatal outcomes for pregnancies following single SD were compared with pregnancies following repeat SD from the same donor. In a secondary analysis, we compared pregnancy outcomes among three modes of assisted reproductive technology (intrauterine insemination [IUI-SD], in vitro fertilization [IVF-SD], and IVF sperm + egg donation [IVF-SD + ED]). RESULTS: A total of 706 pregnant women met the inclusion criteria, 243 (34.4%) following the first SD and 463 (65.6%) following repeat donations. Compared with repeat SDs, single donation was not associated with higher rates of preterm delivery (12.8 vs. 12.7%, respectively, p = 0.99), preeclampsia (7.0 vs. 6.9%, p = 0.999), and intrauterine growth restriction (4.1 vs. 3.9%, p = 0.88). Pregnancies following IVF-SD + ED had increased risk for preeclampsia (adjusted odds ratio [AOR], 3.1; 95% confidence interval [CI], 1.5-6.6), preterm labor (AOR, 2.4; 95% CI, 1.1-5.4), and cesarean section (AOR, 2.1; 95% CI, 1.0-4.3) compared with IUI-SD and IVF-SD. CONCLUSION: The extent of donor sperm exposure did not correlate with obstetrics complications, but double gamete donation was associated with increased risk for preeclampsia, preterm labor, and cesarean section.

Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes?

PURPOSE: To determine the rate of obstetric and neonatal complications associated with intrahepatic cholestasis of pregnancy in twin versus singleton gestations. METHODS: A retrospective cohort study including patients diagnosed with intrahepatic cholestasis of pregnancy at a single tertiary center between 2011 and 2016. Women were allocated into two groups: twin pregnancies (n = 56) and singleton pregnancies (n = 186). Obstetric and neonatal outcomes were compared between the two groups. RESULTS: Intrahepatic cholestasis of pregnancy was diagnosed earlier in gestation in twin compared to singleton pregnancies (33.1 ± 2.8 vs. 35.1 ± 3.0 weeks, respectively; adjusted P < 0.001). Maternal serum levels of fasting total bile acids were significantly higher in twin pregnancies compared to singletons [27 (IQR 16-44) vs. 16 (IQR 10-26) µmol/L, respectively; P = 0.01]. None of the pregnancies in our cohort was complicated by fetal death. Apgar score at 5 min and umbilical artery and vein PH at delivery were comparable between the two groups. CONCLUSIONS: Intrahepatic cholestasis of pregnancy in twin pregnancies appears to be more severe compared to singletons, as reflected by an earlier presentation and higher levels of maternal serum total bile acids. Large prospective studies are required to customize a management strategy specific for women with twin pregnancies and intrahepatic cholestasis of pregnancy.

Comparison of effects of thawing entire donor sperm vial vs. partial thawing (shaving) on sperm quality.

PURPOSE: Partial thawing of a vial of cryopreserved sperm (shaving) is sometimes applied as a measure to preserve sperm for further use, particularly in cases of very restricted sperm quantity. However, mechanical violence may disrupt the sperm-wall and lead to impaired in-vitro fertilization (IVF) outcomes. MATERIAL AND METHODS: In a retrospective case-control study at a tertiary, university-affiliated medical center, we compared the IVF/intracytoplasmic sperm injection (ICSI) outcomes of patients who used donor sperm following partial thawing (shaving) of the vial of cryopreserved sperm (n = 99) to a control group consisting of patients for whom the vial of sperm was completely thawed before use (n = 99). RESULTS: While no differences were observed in the rates of oocyte fertilization, the mean number of top-quality embryos (TQE) was significantly lower in the shaving group than in the complete thawing group (1.33 ± 0.17 vs. 1.87 ± 0.17, p < 0.02). Experimental analysis of aliquots from the same donors revealed significantly reduced motility in sperm samples that were shaved vs. fully thawed (6.5 vs. 37.1%, p < 0.001). CONCLUSIONS: In cases in which available cryopreserved sperm samples are limited, shaving of the vial without thawing can be used but with caution and only when absolutely necessary. Further, large prospective studies are needed to better clarify whether there is post-thawing sperm damage and to compare IVF outcomes after these two thawing methods.

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.

Is severe OHSS associated with adverse pregnancy outcomes? Evidence from a case-control study.

Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening complication of fertility treatment. This study evaluated pregnancy outcomes of women hospitalized for severe OHSS. A case-control study was performed of 125 women who were hospitalized due to severe OHSS compared with a control group, consisting of 156 women matched by age and aetiology of infertility, who conceived via IVF and did not develop OHSS. Among women with singleton pregnancies, patients with severe OHSS delivered significantly earlier (37.96 versus 39.11 weeks) and had smaller babies (2854 g versus 3142 g) compared with the matched controls. Similarly, rates of preterm delivery (<34 weeks of gestation: 8.9% versus 0%, P < 0.01; <37 weeks of gestation: 20.5% versus 5.1%, P < 0.01) were significantly increased among patients in the study group. There were no between-group differences in the rates of gestational diabetes, gestational hypertension and intrauterine growth restriction. In contrast, twin pregnancies following OHSS were not significantly different from matched control twins, with regard to the rates of delivery <34 weeks and <37 weeks of gestation, gestational diabetes, gestational hypertension and intrauterine growth restriction. In conclusion, severe OHSS at early gestation is associated with adverse pregnancy outcome only in singleton gestations.

Sperm preservation by electroejaculation in adolescent cancer patients.

BACKGROUND: The increasing prevalence of cancer survivors who are infertile due to gonadal failure highlights the importance of fertility preservation prior to gonadotoxic treatments. Adolescent cancer patients may not be mature enough to produce sperm by masturbation, leading to the use of alternative methods for obtaining sperm for cryopreservation. The aim of the current study was to evaluate the safety and efficacy of electroejaculation (EEJ) for cryopreservation among adolescent cancer patients. PROCEDURE: This retrospective cohort study included 45 adolescent (12-18 years old) cancer patients who underwent EEJ during 2002-2012 in an academic tertiary referral fertility center. Sperm cryopreservation, ejaculate parameters, and procedure complications were evaluated. RESULTS: EEJ was performed without documented complications. Sperm was successfully obtained in 30 (66.7%) patients. Retrieval failures included ejaculates without sperm in 8 patients (17.8%) and no ejaculate in 7 patients (15.5%). Cryopreserved ejaculates were characterized by severe asthenospermia, normal sperm concentration, and low volume. Retrieved sperm group was further divided to 19 motile sperm ejaculates with significantly higher volume, sperm concentration, and total count compared to 10 non-motile sperm patients. CONCLUSIONS: EEJ is a safe and feasible procedure for cryopreservation in adolescent cancer patients who are unable to masturbate. The wide diversity of EEJ outcome and ejaculate parameters may represent a continuum of pubertal changes in that population.

The effect of COVID-19 vaccination during IVF stimulation on cycle outcomes- a retrospective cohort study.

The effect of the mRNA-BNT162b2 vaccine administered prior to fertility treatments has been addressed in several studies, presenting reassuring results. Cycle outcomes of patients receiving the vaccine during the stimulation itself have not been previously described. This retrospective cohort study included patients who received mRNA-BNT162b2-vaccine during the stimulation of fresh IVF cycles, between January-September 2021, age matched to pre-stimulation vaccinated patients and to non-vaccinated patients. Demographics, cycle characteristics and cycle outcomes were compared between groups. A total of 132 in-treatment vaccinated patients (study group), 132 pre-treatment vaccinated and 132 non-vaccinated patients that underwent fresh IVF cycles were included. Mean time from vaccination to retrieval in the study group was 6.68 days (SD 3.74; range 0-12). Oocyte yield was similar between groups (9.35 versus10.22 and 10.05 respectively; p=0.491). A linear regression model demonstrated no effect of vaccination before or during the stimulation, on oocyte yield (p>0.999). Clinical pregnancy rates (30 % versus 30 % versus 28 %) and ongoing pregnancy rates (25 % for all groups) did not differ between groups. In a logistic regression model for clinical pregnancy rates, vaccine administration and timing of vaccination were not a significant factor. This is the first study reporting the outcome of the mRNA BNT162b2 vaccine administration during the IVF stimulation itself. The vaccine administration had no impact on fresh IVF treatment outcomes compared to pre-treatment vaccinated or non-vaccinated patients. This adds to the growing evidence of COVID-19 vaccine safety in relation to fertility treatments and enables more flexibility regarding timing of vaccine administration.

Prediction of ovulation: new insight into an old challenge.

Ultrasound monitoring and hormonal blood testing are considered by many as an accurate method to predict ovulation time. However, uniform and validated algorithms for predicting ovulation have yet to be defined. Daily hormonal tests and transvaginal ultrasounds were recorded to develop an algorithm for ovulation prediction. The rupture of the leading ovarian follicle was a marker for ovulation day. The model was validated retrospectively on natural cycles frozen embryo transfer cycles with documented ovulation. Circulating levels of LH or its relative variation failed, by themselves, to reliably predict ovulation. Any decrease in estrogen was 100% associated with ovulation emergence the same day or the next day. Progesterone levels > 2 nmol/L had low specificity to predict ovulation the next day (62.7%), yet its sensitivity was high (91.5%). A model for ovulation prediction, combining the three hormone levels and ultrasound was created with an accuracy of 95% to 100% depending on the combination of the hormone levels. Model validation showed correct ovulation prediction in 97% of these cycles. We present an accurate ovulation prediction algorithm. The algorithm is simple and user-friendly so both reproductive endocrinologists and general practitioners can use it to benefit their patients.

Artificial intelligence in the service of intrauterine insemination and timed intercourse in spontaneous cycles.

OBJECTIVE: To develop a machine learning model designed to predict the time of ovulation and optimal fertilization window for performing intrauterine insemination or timed intercourse (TI) in natural cycles. DESIGN: A retrospective cohort study. SETTING: A large in vitro fertilization unit. PATIENT(S): Patients who underwent 2,467 natural cycle-frozen embryo transfer cycles between 2018 and 2022. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prediction accuracy of the optimal day for performing insemination or TI. RESULT(S): The data set was split into a training set including 1,864 cycles and 2 test sets. In the test sets, ovulation was determined according to either expert opinion, with 2 independent fertility experts determining ovulation day ("expert") (496 cycles), or according to the disappearance of the leading follicle between 2 consecutive days' ultrasound examinations ("certain ovulation") (107 cycles). Two algorithms were trained: an NGBoost machine learning model estimating the probability of ovulation occurring on each cycle day and a treatment management algorithm using the learning model to determine an optimal insemination day or whether another blood test should be performed. The estradiol progesterone and luteinizing hormone levels on the last test performed were the most influential features used by the model. The mean numbers of tests were 2.78 and 2.85 for the "certain ovulation" and "expert" test sets, respectively. In the "expert" set, the algorithm correctly predicted ovulation and suggested day 1 or 2 for performing insemination in 92.9% of the cases. In 2.9%, the algorithm predicted a "miss," meaning that the last test day was already ovulation day or beyond, suggesting avoiding performing insemination. In 4.2%, the algorithm predicted an "error," suggesting performing insemination when in fact it would have been performed on a nonoptimal day (0 or -3). The "certain ovulation" set had similar results. CONCLUSION(S): To our knowledge, this is the first study to implement a machine learning model, on the basis of the blood tests only, for scheduling insemination or TI with high accuracy, attributed to the capability of the algorithm to integrate multiple factors and not rely solely on the luteinizing hormone surge. Introducing the capabilities of the model may improve the accuracy and efficiency of ovulation prediction and increase the chance of conception. CLINICAL TRIAL REGISTRATION NUMBER: HMC-0008-21.

Higher incidence of preeclampsia among participants undergoing in-vitro fertilization after fewer sperm exposures.

OBJECTIVE: Evaluation of preeclampsia (PE) incidence among participants undergoing in vitro fertilization (IVF) after various cycles of sperm donation (SD) via intrauterine inseminations (IUI) or IVF. STUDY DESIGN: A retrospective case-control study was conducted at a single tertiary medical center between 2011 and 2019 which included participants who conceived via IVF using SD from a single sperm bank and had a successful singleton birth at Sheba Medical Center. The study cohort was divided into two groups: Group 1 (participants who conceived via IVF after 0-1 cycles of IUI or IVF from the same sperm donor) and Group 2 (participants who conceived via IVF after 2 or more cycles of IUI or IVF from the same sperm donor). Baseline characteristics and pregnancy outcomes between the two groups were compared. In addition, a comparison between the study groups and a control of participants of the same age who conceived spontaneously and had a singleton birth at Sheba Medical Center during the same period with a record of up to two previous deliveries was done. RESULTS: A total of 228 participants conceived through IVF from SD and met the inclusion criteria. Of these, 110 were defined as Group 1 and 118 as Group 2. The participants showed no differences in their age, gravidity and parity, chronic medical conditions, or history of pregnancy complications. Preeclampsia was positively associated with Group 1 (9 [8.2%] vs. 2 [1.7%], P = 0.022). PE was observed to be more prevalent in Group 1 (P < 0.001) when compared to a control group of 45,278 participants who conceived spontaneously. No significant differences were observed in comparing Group 2 with the same control group. CONCLUSION: The incidence of PE was higher among participants who were exposed to 0-1 IUI or IVF cycles than in those who were exposed to 2 or more cycles of IUI or IVF from the same sperm donor. On comparing both groups with a control group, the incidence of PE was higher in participants who were exposed to 0-1 cycles, while there was no difference in participants exposed to 2 or more cycles. IMPLICATIONS STATEMENT: If there is a statistically significant increase in the incidence of PE when conception occurred following fewer sperm exposures, then there may be a correlation between these two. The reason for this is not entirely clear, but based on former literature, we hypothesize it may be related to the fact that repeated exposures to paternal antigens may alter the maternal immune response causing a better adaptation to the semi-allogenic nature of the fetus, its paternal half.

Spontaneous conceptions following successful ART are not associated with premature referral.

STUDY QUESTION: What is the rate of spontaneous live births after successful IVF treatment in a cost-free environment, and were couples who achieved a spontaneous live birth referred prematurely? SUMMARY ANSWER: Despite unlimited IVF treatments offered free of charge, the spontaneous live birth rate following successful IVF remained unchanged compared with that cited in previous literature. Couples were not referred prematurely to IVF before fully utilizing other less invasive treatments. WHAT IS KNOWN ALREADY: A significant number of infertile couples, who achieve their first live birth through assisted reproductive technology (ART), subsequently achieve a second live birth spontaneously. As IVF has become more widely available, it is used in less severe cases of infertility, perhaps explaining a rise in the subsequent spontaneous live birth rate after successful treatments. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study was performed at a university-based tertiary medical center. The study population included women aged <35 years, with primary infertility, referred for their first IVF treatment to the Sheba Medical Center IVF unit between 2001 and 2002 and followed up for 7 years. The primary outcome was spontaneous live birth rate following successful ART. Relevant data were obtained from the patient files and supplemented by a standardized telephone questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 171 couples who met the study inclusion criteria, 6 refused to participate in the questionnaire and 31 couples were lost to follow-up. Of the 134 couples who participated, 109 achieved a first live birth with ART. After achieving their first live birth with ART, seven couples who began using contraception or separated or divorced were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Of 102 couples who continued unprotected intercourse after successful ART, 22 subsequently achieved their second live birth spontaneously (21.6%). The women who achieved a second birth spontaneously were not referred earlier to IVF, and actually performed a higher number of ovulation induction cycles before initiating IVF, compared with women who did not conceive spontaneously. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective cohort study, and findings should be reaffirmed with a larger prospective randomized study comparing retreatment to achieve a second pregnancy with attempting to conceive spontaneously. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggests that young patients (<35 years), who previously conceived with IVF, without utilizing ICSI and with no known tubal pathology, should consider attempting to conceive spontaneously. STUDY FUNDING AND COMPETING INTEREST(S): No funding was obtained for this study and the authors have no competing interests.