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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., Competing Interests: Declaration of interests M.Y. has nothing to disclose. A.L. is a shareholder and board member of FertilAI LTD. M.B. is a shareholder and board member of FertilAI LTD. R.H. is a shareholder and board member of FertilAI LTD. S.R. is an employee of FertilAI LTD. E.M. is a shareholder and board member of FertilAI LTD. A.H. is a shareholder and board member of FertilAI LTD., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

There have been concerns on the potential overuse of in vitro fertilization (IVF) in view of the lack of evidence on effectiveness in certain populations, potential short and long-term safety risks, and economic considerations. On the other hand, the use of alternatives to IVF seems to be underappreciated in clinical practice as well as research. In this review, we summarized the up-to-date evidence on the effectiveness, safety as well as cost-effectiveness of different alternatives to IVF, including expectant management, intrauterine insemination, tubal flushing, in vitro maturation as well as intravaginal culture. We also discussed the trend of IVF use over the last decade and the available tiers of service because of intravaginal culture, and revisited the roles of different alternatives to IVF in modern reproductive medicine from both clinical and research perspectives., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability., Design: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort., Setting: Four US reproductive endocrinology and infertility care study centers, 2013-2017., Patient(s): Couples (n = 2,369) seeking fertility consultations at 4 US infertility care study centers., Intervention(s): Semen volume, pH, sperm viability, morphology, progressive and total motility, concentration, count, and total and progressive motile count assessed at baseline and at 2, 4, and 6 months after enrollment., Main Outcome Measure(s): Log-binomial models stratified by fertility treatment received (in vitro fertilization [IVF], intrauterine insemination [IUI], ovulation induction [OI], or no treatment) estimated risk differences (RDs) between semen parameter quartiles and live birth and accounted for multiple semen assessments per person. We accounted for abstinence time, the biological interdependence of semen parameters, and potential selection bias because of loss to follow-up., Result(s): Among couples using OI only or no treatment, 39% had a live birth, and relative to the highest quartile, the lowest quartiles of morphology (RD, -19 [95% CI, -23 to -15] per 100 couples), motility (RD, -13 [95% CI, -17 to -9]), concentration (RD, -22 [95% CI, -26 to -19]), and total motile count (RD, -18 [95% CI, -22 to -14]) were associated with fewer live births. For IUI, 26% had a live birth, and the lowest quartiles of volume (RD, -6 [95% CI, -11 to -0.4]), concentration (RD, -6 [95% CI, -11 to -0.1]), count (RD, -10 [95% CI, -15 to -4]), and total motile count (RD, -7 [95% CI, -13 to -1]) were associated with fewer live births. For IVF, 61% had a live birth, and only morphology (Q1 RD, -7 [95% CI, -14 to 0.2]; Q2 RD, -10 [95% CI, -17 to -2.2]) was associated with live birth., Conclusion(s): Semen parameters are critical in couples undergoing OI/IUI. Only low morphology was important for live birth after IVF. Although data supporting the use of semen parameters are fragmented across differing populations, current findings are generalizable across the range of male fertility and couple fertility treatments, providing evidence about which semen parameters are most relevant in which settings., Clinical Trial Registration Number: NCT#01857310., (Published by Elsevier Inc.)

Objective: To compare clinical and ongoing pregnancy after natural cycle (NC) intrauterine insemination (IUI) versus ovarian stimulation (OS) IUI in ovulatory women undergoing therapeutic donor insemination (TDI)., Design: Retrospective cohort., Setting: Single infertility center., Patient(s): A total of 76,643 IUI cycles in patients treated with intrauterine insemination were examined. Women undergoing TDI in the absence of diagnosed female factor infertility were included., Intervention(s): NC TDI or OS TDI with either clomiphene citrate or letrozole., Main Outcome Measure(s): Clinical and ongoing pregnancies were analyzed by generalized estimating equations adjusting for age, body mass index, total motile sperm at time of insemination and cycle number. Ongoing multiple gestations were examined as a secondary outcome., Result(s): Six thousand one hundred ninety-two TDI cycles from 2,343 patients (711 patients without repeated IUI cycles) met inclusion criteria and were available for analysis (3,837 NC and 2,355 OS). There was no difference in mean age between the two groups (NC, 34.2 years vs. OS, 34.3 years). Probability of clinical and ongoing pregnancy was higher in the OS cohort compared with the NC cohort (OS, 22.4% vs. NC, 18.7% and OS, 15.4% vs. NC, 14.9%, respectively). However, OS significantly increased ongoing multiple gestations (OS, 10.8% vs. NC, 2.4%)., Conclusion(s): Ovarian stimulation in TDI cycles resulted in a <4% increase in clinical and <1% increase in ongoing pregnancy, and more than fourfold increase in ongoing multiple gestations. Natural cycle IUI should be considered as a first-line treatment for ovulatory women who need donor insemination., (Published by Elsevier Inc.)

Objective: To determine whether body mass index (BMI) affects intrauterine insemination treatment success., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): A total of 3,217 intrauterine insemination treatment cycles in 1,306 patients., Intervention(s): None., Main Outcome Measure(s): Primary outcome was live birth rate stratified by BMI. Secondary outcomes included rates of clinical pregnancy (defined as an intrauterine pregnancy with a heartbeat present on ultrasound), multiple gestation, biochemical pregnancy, missed abortion, ectopic, and spontaneous abortion., Result(s): Women with BMI 25 to 29.99 kg/m 2 or ≥30 kg/m 2 were equally likely to have a live birth as women of normal BMI. Women with BMI ≥30 kg/m 2 did have a higher likelihood of biochemical pregnancy than women with normal BMI., Conclusion(s): A BMI between 25 and 29.99 kg/m 2 or ≥30 kg/m 2 does not appear to have a negative effect on live birth after intrauterine insemination. Obesity may be associated with a higher risk of biochemical pregnancy after intrauterine insemination., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate whether superovulation improves fecundity in women undergoing therapeutic donor insemination (TDI)., Design: Retrospective cohort study., Setting: University-affiliated fertility clinic., Patient(s): Healthy women aged 23-45 years with no history of or risk factors for infertility who underwent 152 medicated and 104 unmedicated TDI cycles from 2013 to 2018., Intervention: Unmedicated TDI versus use of medication in a TDI cycle (clomiphene citrate or letrozole)., Main Outcome Measure(s): Cumulative probability of pregnancy in six TDI cycles., Result(s): In adjusted all-cycle analysis, medicated TDI cycles were less likely to result in pregnancy compared with unmedicated cycles. The incidence of twins was 23% in the medicated group and 0% in the unmedicated group. Medicated cycles were less likely to result in pregnancy in women younger than 40 years or with an antimüllerian hormone (AMH) level >1.2. After three cycles not resulting in pregnancy, the only women who conceived were those who crossed over from an unmedicated to a medicated cycle (12% vs. 0%)., Conclusion(s): Patients undergoing unmedicated TDI cycles had higher fecundity and no incidence of twin gestations. Older women, those with low AMH, and those who fail to conceive after three unmedicated cycles may benefit from medication., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study the influence of human papillomavirus (HPV) virions present in different sperm fractions of male partners of women undergoing IUI on fertility outcome., Design: Prospective noninterventional multicenter study., Setting: Inpatient hospital fertility centers., Patient(s): Seven hundred thirty-two infertile couples undergoing 1,753 IUI cycles with capacitated sperm., Intervention(s): None., Main Outcome Measure(s): Biochemical and clinical pregnancy rate in IUI cycles with HPV-positive or HPV-negative semen., Result(s): Five hundred seventy-three infertile couples undergoing 1,362 IUI cycles were enrolled. Work-up of the 1,362 sperm samples that were used for IUI generated 3,444 separate sperm fractions. Each of the sperm fractions was tested with quantitative polymerase chain reaction for 18 different HPV types (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, and 68). HPV prevalence in sperm was 12.5%/IUI cycle. When infectious HPV virions were detected in sperm, a significant decrease in clinical pregnancies was observed when compared with HPV-negative cycles (2.9% vs. 11.1 %/cycle). Above a ratio of 0.66 HPV virions/spermatozoon no pregnancies occurred (sensitivity 100%, specificity 32.5%)., Conclusion(s): Women inseminated with HPV-positive sperm had 4 times fewer clinical pregnancies compared with women who had HPV-negative partners. Detection of HPV virions in sperm is associated with a negative IUI outcome and should be part of routine examination and counseling of infertile couples., European Clinical Trials Database Number: 2017-004791-56., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This paper discusses the variety of effective sperm selection techniques that have been developed for use in assisted reproductive technologies. Available methods for isolating the competent sperm in an ejaculate are outlined, as well as techniques for selecting single sperm for use in intracytoplasmic sperm injection procedures. Case-specific methods for selecting the most competent sperm are discussed, with reference to the potential causes of male factor infertility and guidance for the embryologist based on the issues present for each couple seeking treatment., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To determine the best practices of intrauterine insemination with the partner's fresh sperm., Design: Prospective multicenter observational study., Setting: Assisted reproduction technology (ART) centers., Patient(s): Seven hundred and seven patients entering the program, regardless of age or cause of infertility., Intervention(s): Intrauterine insemination by standard procedures., Main Outcome Measure(s): Effect of patient characteristics (duration of infertility, indications, age, parity, body mass index, semen parameters) as well as IUI parameters on delivery rates per couple or per attempt., Result(s): The overall live birth rate was 11.4% per cycle, varying from 8.4% to 17.6% between centers. The main differences in practice that had a statistically significant impact on the delivery rate were the use of gonadotropin-releasing hormone (GnRH) antagonists (15.2% with versus 9.4% without) and the number of mature recruited follicles (9.4% for one versus 15.2% for two)., Conclusion(s): Our results indicate that the use of GnRH antagonists has a positive effect on the delivery rate, especially in the multifollicular stimulations that are required when women are older than 27 years., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the value of sperm parameters to predict an ongoing pregnancy outcome in couples treated with intrauterine insemination (IUI), during a methodologically stable period of time., Design: Retrospective, observational study with logistic regression analyses., Setting: University hospital., Patient(s): A total of 1,166 couples visiting the fertility laboratory for their first IUI episode, including 4,251 IUI cycles., Intervention(s): None., Main Outcome Measure(s): Sperm morphology, total progressively motile sperm count (TPMSC), and number of inseminated progressively motile spermatozoa (NIPMS); odds ratios (ORs) of the sperm parameters after the first IUI cycle and the first finished IUI episode; discriminatory accuracy of the multivariable model., Result(s): None of the sperm parameters was of predictive value for pregnancy after the first IUI cycle. In the first finished IUI episode, a positive relationship was found for ≤4% of morphologically normal spermatozoa (OR 1.39) and a moderate NIPMS (5-10 million; OR 1.73). Low NIPMS showed a negative relation (≤1 million; OR 0.42). The TPMSC had no predictive value. The multivariable model (i.e., sperm morphology, NIPMS, female age, male age, and the number of cycles in the episode) had a moderate discriminatory accuracy (area under the curve 0.73)., Conclusion(s): Intrauterine insemination is especially relevant for couples with moderate male factor infertility (sperm morphology ≤4%, NIPMS 5-10 million). In the multivariable model, however, the predictive power of these sperm parameters is rather low., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between infertility and fertility treatments on subsequent risk of hypertension., Design: Cohort study., Setting: Not applicable., Patient(s): A total of 116,430 female nurses, followed from 1993 to June 2011, as part of the Nurses' Health Study II cohort., Intervention(s): None., Main Outcome Measure(s): Self-reported, physician-diagnosed hypertension., Result(s): Compared with women who have never reported infertility, infertile women were at no greater risk of hypertension (multivariable adjusted relative risk (RR) = 1.01, with 95% confidence interval [CI] [0.94-1.07]). Infertility due to tubal disease was associated with a higher risk of hypertension (RR = 1.15 [1.01-1.31]), but no other diagnoses were associated with hypertension risk, compared with women who did not report infertility (ovulatory disorder: RR = 1.03 [0.94-1.13]; cervical: RR = 0.88 [0.70-1.10]; male factor: RR = 1.05 [0.95-1.15]; other reason: RR = 1.02 [0.94-1.11]; reason not found: RR = 1.02 [0.95-1.10]). Infertile women collectively had 5,070 cases of hypertension. No clear pattern between use of fertility treatment and hypertension was found among infertile women (clomiphene citrate: RR = 0.97 [0.90-1.04]; gonadotropin alone: RR = 0.97 [0.87-1.08]; intrauterine insemination: RR = 0.86 [0.71-1.03]; in vitro fertilization: RR = 0.86 [0.73-1.01])., Conclusion(s): Among this relatively young cohort of women, no apparent increase occurred in hypertension risk among infertile women, or among women who had undergone fertility treatment previously., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the continuation of in vitro fertilization (IVF) with the conversion to intrauterine insemination (IUI) in cases of suboptimal ovarian response in Bologna-criteria poor responders., Design: Retrospective and multicenter comparative study., Setting: Three academic fertility centers and a fertility private clinic., Patient(s): Analysis of 7,176 initiated IVF cycles from January 2010 to January 2013. The 461 cycles with poor ovarian response (fewer than three follicles ≥16 mm at hCG trigger) in patients with poor response according to the Bologna criteria were included., Intervention(s): Decision to pursue IVF (n = 184), convert to IUI (n = 141), or cancel cycle (n = 136) when only one or two follicles were recruited., Main Outcome Measure(s): Live birth, ultrasound pregnancy, and early pregnancy rates were compared depending on whether they resulted from IVF or IUI and were stratified according to patient age and the number of mature follicles at trigger., Result(s): Live birth rates were significantly higher for IVF patients compared with IUI conversion when two follicles were present (11.6% IVF vs. 1.6% IUI), especially for patients <40 years of age (13.1% IVF vs. 2% in IUI). In case of a monofollicular recruitment, the pregnancy outcomes were similar., Conclusion(s): A therapeutic strategy could therefore be to pursue IVF for women demonstrating two follicles and to convert to IUI for cycles with only one follicle if the sperm and tubal parameters are favorable., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess procreative outcomes for HIV-positive men and women with seronegative partners., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Twenty-four studies with extractable data for HIV-serodiscordant couples undergoing intrauterine insemination (IUI) or in vitro fertilization (IVF)., Intervention(s): None., Primary Outcomes: HIV transmission to a seronegative partner and per cycle fecundability; secondary outcomes: analysis of multiple gestation rates, miscarriage rates, and cancellation rates., Result(s): For serodiscordant couples, HIV-positive men or women undergoing IUI and IVF treatment had a 17%, 30%, 14%, and 16% per cycle fecundability, respectively. Multiple gestation rates were 10%, 33%, 14%, and 29%, respectively. Miscarriage rates were 19%, 25%, 13%, and 20%, respectively. No HIV transmission was observed in 8,212 IUI and 1,254 IVF cycles, resulting in 95% confidence that the true rate is 4.5 transmissions per 10,000 IUI cycles or less., Conclusion(s): In serodiscordant couples, IUI and IVF seem effective and safe based on the literature. Evidence-based practice and social justice suggest that our field should increase access to care for HIV-serodiscordant couples., (Published by Elsevier Inc.)

Objective: To evaluate the use of fertility treatments among a large cohort of women in the United States., Design: Cohort study., Setting: Nurses' Health Study II., Patient(s): Ten thousand thirty-six women who reported having used fertility treatment on biennial questionnaires from 1993-2009., Intervention(s): None., Main Outcome Measure(s): Data on patterns of treatment modality were collected via self-report from validated mailed questionnaires. Information on clomiphene, gonadotropin injections alone, and gonadotropin injections as part of intrauterine insemination (IUI) and in vitro fertilization (IVF) was queried., Result(s): Most women who reported fertility treatment used clomiphene (94%), with a large majority reporting clomiphene as their only form of treatment (73%). Of women who reported treatment more advanced than clomiphene, 13% had used gonadotropin injections alone, 11% IUI treatment, and 11% IVF. Several subgroups were more likely to use multiple treatment modalities and to initiate treatment with gonadotropins rather than clomiphene, including women living in states with insurance coverage of fertility procedures, with higher household income, younger in age, who remained nulliparous at the study close, and treated after 2000., Conclusion(s): Results should be interpreted cautiously, but to our knowledge, this represents the first study of fertility treatment patterns in the United States and could inform public health planning., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of assisted reproductive technology (ART) treatments on the sex ratio of babies born., Design: Assessment of direct effects of assisted conception through retrospective data analysis on the progeny sex ratio of treated women in the United Kingdom., Setting: The study uses the anonymized register of the Human Fertilisation and Embryology Authority., Patient(s): A total of 106,066 babies of known gender born to 76,994 treated mothers and 85,511 treatment cycles between 2000 and 2010 in the United Kingdom., Intervention(s): Intrauterine insemination, IVF, or intracytoplasmic sperm injection (ICSI)., Main Outcome Measure(s): Sex ratio of babies born., Result(s): Intrauterine insemination, IVF, and ICSI lead to different sex ratios, highest after IVF (proportion male = mean 0.521 ± confidence interval 0.0056) and lowest under ICSI embryo transfer (0.493 ± 0.0031). In addition, for both ICSI and IVF, transferring embryos at a later stage (blastocyst) results in approximately 6% more males than after early cleavage-stage ET., Conclusion(s): Because the cumulative number of IVF babies born is increasing significantly in Britain and elsewhere, more research is needed into the causes of gender bias after ART and into the public health impact of such gender bias of offspring born observed on the rest of the population., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)