Lower Pregnancy and Live Birth Rates with Vaginal Endometrin Plus Intramuscular Progesterone Every Third Day Versus Intramuscular Progesterone Alone in Programmed Frozen Embryo Transfers: A Retrospective Case-control Study.

This study aimed to determine whether the use of vaginal Endometrin plus intramuscular progesterone on every third day (VIM) in programmed frozen embryo transfer (FET) is associated with lower pregnancy and live birth rates compared to daily intramuscular progesterone (IM). FET data from a single program were collected between November 2018 and December 2021. A total of 903 FETs were analyzed, including 504 FETs in the IM group, and 399 FETs in the VIM group. Inclusion criteria were women undergoing FETs with either 50 mg daily IM progesterone only (control) or 200 mg Endometrin twice daily plus 50 mg IM progesterone on every third day, with the transfer of a single day 5 or 6 frozen embryo. There were no significant differences in patient age at time of FETs, BMI, endometrial thickness, blastocyst quality, or infertility diagnosis between the groups. The VIM had significantly lower positive hCG and clinical pregnancy rates compared to the IM (60.2% vs 72.0% and 40.6% vs 56.7%, respectively, P = 0.0002 and P < 0.0001). The live birth rate was 36.1% in the VIM, compared to 49.4% in the IM (P < 0.0001). These findings also remained significant when excluding FETs with donor egg (35.9% vs 50.1%, P < 0.0001). This study demonstrated that VIM in FET cycles yields significantly lower pregnancy and live birth rates compared to IM along. IM progesterone alone may be preferable to combined Endometrin and IM progesterone in patients undergoing programmed frozen embryo transfers.

Association of the human semen DNA virome with successful in vitro fertilization.

OBJECTIVE: To comprehensively characterize the DNA virome in semen samples collected for in vitro fertilization (IVF). DESIGN: A descriptive clinical study. SETTING: Single academic fertility center. PATIENT(S): Twenty-four male partners from couples undergoing IVF. INTERVENTION(S): Couples were randomized to receive 1 g of azithromycin (standard of care) or no azithromycin at the time of baseline IVF assessment. Semen samples were collected at the time of the female partners' egg retrieval, and 100 µL of the sample was used for the virome analysis. MAIN OUTCOME MEASURE(S): Detection of viruses by ViroCap enrichment of viral nucleic acid and sequencing. Association between the virome, semen parameters, and pregnancy outcomes. RESULT(S): We detected viruses in 58% of the participants. Viruses included polyomaviruses, papillomaviruses, herpesviruses, and anelloviruses. Viromes detected in semen had little overlap with the viromes detected in vaginal samples from their female partners collected at the time of embryo transfer, which were analyzed in a previous study. A lower viral diversity in semen samples was positively associated with pregnancy (Hodges-Lehmann estimate of difference, 1; 95% confidence interval, 2-0.00003). There was no association between viral diversity and sperm concentration, motility, or fertilization rates. CONCLUSION(S): This comprehensive characterization of the DNA virome in semen reveals an association between virome diversity and pregnancy in couples undergoing IVF. However, no association was found with specific semen parameters or fertilization rates, suggesting that viral exposure may negatively affect pregnancy after fertilization. Future studies should be undertaken to evaluate the associations between the semen virome with IVF outcomes in larger cohorts.

Dietary patterns are associated with improved ovarian reserve in overweight and obese women: a cross-sectional study of the Lifestyle and Ovarian Reserve (LORe) cohort.

BACKGROUND: Growing evidence suggests that adherence to certain dietary patterns is associated with improved fecundity and reproductive outcomes in the general population and infertile couples assisted reproductive treatments. The objective of this study was to assess if dietary patterns are associated with ovarian reserve in reproductive age women without a history of infertility. METHODS: This was a cross-sectional study of 185 women in the Lifestyle and Ovarian Reserve (LORe) cohort. Women aged 18-44 without a history of infertility were recruited from the local community at an academic medical center. Subjects completed validated food frequency and physical activity questionnaires to assess patterns over the year prior to presentation. Dietary patterns including a Western (including meat, refined carbohydrates, high-calorie drinks), prudent (including fruits, vegetables, olive oil and nuts), fertility (lower intake of trans fat with higher intake of monounsaturated fatty acids, increased intake of plant based protein, high-fat dairy, lower glycemic load carbohydrates and supplemental iron) and profertility diet (PFD) (characterize by whole grains, soy and seafood, low pesticide residue produce, supplemental folic acid, B12 and vitamin D) were identified through principal component analysis. Main outcome measures were serum antimullerian hormone concentration (AMH) (ng/mL) and antral follicle count (AFC) obtained by transvaginal ultrasound. RESULTS: After stratifying by BMI, adjusting for age, smoking and physical activity, dietary patterns were not associated with ovarian reserve in normal weight women. Increased adherence to a profertility diet in overweight and obese women (BMI ≥ 25 kg/m2) was associated with a significantly higher AMH. Women in the third and fourth quartiles of PFD adherence had a mean AMH concentration of 1.45 ng/mL (95%CI 0.33-2.56, p = 0.01) and 1.67 ng/mL (95%CI 0.60-2.74, p = 0.003) higher than women in the lowest quartile respectively. The highest adherence to PFD was also associated with a higher AFC in women with a BMI ≥ 25 kg/m2 (ß = 7.8, 95%CI 0.003-15.34, p < 0.05). Other common dietary patterns were not significantly associated with ovarian reserve. CONCLUSIONS: Increased adherence to a profertility diet is associated with improved markers of ovarian reserve in overweight and obese women. These findings provide novel insight on potential modifiable lifestyle factors associated with ovarian reserve.

Association of vaginal bacterial communities and reproductive outcomes with prophylactic antibiotic exposure in a subfertile population undergoing in vitro fertilization: a prospective exploratory study.

OBJECTIVE: To determine whether prophylactic azithromycin is associated with the vaginal bacterial microbiome and clinical outcomes in subfertile women undergoing in vitro fertilization (IVF). DESIGN: Prospective exploratory cohort study. SETTING: Single academic fertility center. PATIENTS: Subfertile women aged 18-43 years undergoing their first IVF cycle and fresh embryo transfer. INTERVENTION: Primary exposure to prophylactic azithromycin (1 g orally) once at baseline. MAIN OUTCOME MEASURES: The primary outcome was the effect of azithromycin on the vaginal microbiome compared with a no-azithromycin group at 3 time points throughout the IVF cycle (baseline, retrieval, and embryo transfer). The secondary outcomes were associations of vaginal bacterial communities with clinical outcomes. RESULTS: A planned a priori exploratory cohort of 27 subjects (12 in the azithromycin treatment group and 15 in the no-azithromycin group) contributed 79 vaginal swabs for the analysis as part of an ongoing randomized, controlled noninferiority trial. No specific taxa were associated with azithromycin or pregnancy at any time point. Azithromycin did not affect alpha diversity or community stability. Although there were trends of a lower bacterial load and higher percentage of Lactobacillus species in the azithromycin group at the time of transfer, these were not statistically significant. In women who did not become pregnant, the percentage of Lactobacillus species was lower (P = .048; Hodges-Lehmann estimate of difference, 0.41; 95% confidence interval, 0.08-0.65) and the change in community composition over time was higher. The percentage of Lactobacillus species at baseline was not predictive of the percentage of Lactobacillus species at the time of embryo transfer. CONCLUSIONS: Prophylactic azithromycin at baseline is not associated with changes in vaginal bacterial communities. Bacterial community features at the time of embryo transfer are associated with pregnancy. Bacterial community structures at baseline are not predictive of those at the time of embryo transfer. CLINICAL TRIAL REGISTRATION NUMBER: NCT03386227.

Dietary Patterns, Physical Activity, and Socioeconomic Associations in a Midwestern Cohort of Healthy Reproductive-Age Women.

OBJECTIVE: To characterize dietary patterns and physical activity in a diverse cohort of Midwestern reproductive-age women and to determine associations between these lifestyle factors, socioeconomic factors, and obesity. METHODS: In this cross-sectional study, 185 women completed validated food frequency and physical activity questionnaires. Dietary patterns were identified through principal component analysis. Sociodemographic characteristics associated with dietary pattern adherence and physical activity participation were identified through linear regression. Associations between lifestyle factors and obesity were assessed through logistic regression. RESULTS: Two dietary patterns were identified: a "Prudent" pattern characterized by consumption of fruits, vegetables, olive oil, and nuts and a "Western" pattern including meat, refined carbohydrates, and high-calorie drinks. African-American women and women without a college degree were more likely to adhere to the Western dietary pattern than other women. Women in areas with higher socioeconomic deprivation had lower levels of physical activity, especially leisure-time exercise. Women who completed college participated in more leisure-time exercise and had less physically demanding occupations. Obesity was associated with increasing adherence to the Western dietary pattern in a dose-dependent fashion (aOR range 2.68-4.33, 95% CI range 0.69-16.61) but was not associated with adherence to the Prudent pattern (aOR range 0.46-1.06, 95% CI range 0.13-3.41). Increased physical activity was associated with reduced odds of obesity (aOR range 0.28-0.30, 95% CI range 0.10-0.93). CONCLUSIONS FOR PRACTICE: This study highlights dietary and physical activity patterns associated with obesity in reproductive-age women. Lifestyle interventions focused on minimizing consumption of the Western diet and increasing physical activity may provide an opportunity to reduce obesity among reproductive-age women.

Self-Administered Questionnaire to Screen for Polycystic Ovarian Syndrome.

Background: Polycystic ovary syndrome (PCOS) is a common yet underdiagnosed endocrinopathy with potentially serious sequelae. A screening questionnaire for PCOS can improve early identification and diagnosis. Objective: The purpose of this study was to test the utility of a self-administered questionnaire to help identify women at risk for PCOS. Study Design: We recruited women ages 18-50 with and without PCOS as defined by modified Rotterdam criteria to complete a self-administered survey of common PCOS signs and symptoms. The survey included questions regarding menstrual cycle characteristics and hyperandrogenism as measured by images from the Ferriman-Gallwey (FG) scoring system, and by report of depilatory practices. Results: Fifty-one women with PCOS and 50 women without PCOS participated in this study. Many study participants were current users of hormonal contraceptives making it difficult to discern menstrual cycle characteristics. Hirsutism, defined by a modification of the FG score of ≥3 from the upper lip and abdomen based on self-assessments, provided a sensitivity of 76% and specificity of 70%, whereas report of any depilatory practices provided a sensitivity of 71% and specificity of 74%. The combined sensitivity of these measures was 93% with a specificity of 52%. In multivariate logistic regression, women who used depilatory techniques had an adjusted odds ratio (aOR) of PCOS of 6.6 (95% confidence interval [CI] 2.5-17.3, p = 0.0002). Those with obesity had similar aOR of PCOS (aOR 6.7, 95% CI 2.5-17.9, p = 0.0001). Addition of other variables did not improve model fit and the net sensitivity and specificity of these two variables did not improve those of depilatory practices and hirsutism. Conclusions: Self-report of depilatory practices or hirsutism is sensitive for identifying women with PCOS. Given the prevalence of PCOS in reproductive-age women and the potentially serious health sequelae, it would be worthwhile to include questions about terminal hair growth and depilatory practices when providing general medical care to reproductive-age women to determine if further testing and screening for PCOS are indicated. This tool may also be helpful in populations where complete diagnostic evaluation may not be feasible.

Correction to: Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

The original version of this article unfortunately contained mistakes. The complete list of corrections is given below.

Letrozole Compared With Clomiphene Citrate for Unexplained Infertility: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the clinical effectiveness, as determined by positive pregnancy test, of letrozole compared with clomiphene citrate for ovarian stimulation in patients with unexplained infertility. DATA SOURCES: We conducted a systematic review and meta-analysis of data from electronic databases including Ovid-MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and ClinicalTrials.gov. METHODS: We searched for concepts of unexplained infertility, letrozole, clomiphene citrate, and clinical outcomes including pregnancy and live birth. Studies were included if they were randomized controlled trials (RCTs) comparing clomiphene citrate with letrozole in patients with unexplained infertility. Eight RCTs including 2,647 patients with unexplained infertility were included. Primary outcome was positive pregnancy test per patient. Secondary outcomes included positive pregnancy test per cycle, clinical pregnancy, live birth, spontaneous miscarriage, twin gestation, mean serum estradiol (E2), endometrial thickness, and number of dominant follicles. The Cochrane Q test and Higgin's I were used to assess heterogeneity. Random effects models were used to obtain pooled relative risks (RR) and 95% CIs. TABULATION, INTEGRATION, AND RESULTS: In analysis per patient, there was no significant difference in positive pregnancy test between patients treated with letrozole compared with clomiphene citrate (24% vs 23%, pooled RR 1.08, 95% CI 0.85-1.36). Significant heterogeneity was noted between studies (I=60.8%). There were no significant differences in clinical pregnancy (pooled RR 1.15, 95% CI 0.71-1.85), live birth (pooled RR 0.94, 95% CI 0.83-1.08), spontaneous miscarriage (pooled RR 0.92, 95% CI 0.61-1.38), or twin gestation (pooled RR 0.81, 95% CI 0.39-1.68). Mean serum E2 was significantly lower in the letrozole group than in the clomiphene citrate group. CONCLUSION: Although limited by heterogeneity, studies of ovarian stimulation in women with unexplained infertility show no difference in clinical outcomes between letrozole and clomiphene citrate.

Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

PURPOSE: Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population. METHODS: Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth. RESULTS: One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07). CONCLUSIONS: EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population.

Ultrasound-guided follicle aspiration at time of laparotomy in a patient with Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE: To demonstrate a unique case of direct ultrasound-guided follicle aspiration at time of a laparotomy in a patient with Mayer-Rokitansky-Küster-Hauser Syndrome. DESIGN: Video presentation. SETTING: Academic fertility center PATIENT(S): A 32-year-old gravida 0 with Mayer-Rokitansky-Küster-Hauser Syndrome and bilateral ovarian masses presented as a fertility preservation consult from gynecologic oncology due to the possibility of bilateral oophorectomy. Due to the appearance and size of the left ovary oncology planned to perform an exploratory laparotomy and left oophorectomy, with possible right oophorectomy. The patient and her partner desired embryo cryopreservation with plans for future use in a gestational carrier. She had previously undergone vaginal dilator therapy, however her ovaries were inaccessible transvaginally due to their cephalad location and small caliber of the vaginal pouch. The plan was made to proceed with controlled ovarian stimulation and concurrent ultrasound-guided follicle aspiration of the right ovary at the time of laparotomy following left oophorectomy. INTERVENTION(S): Ultrasound-guided follicle aspiration in vivo at time of laparotomy. MAIN OUTCOME MEASURE(S): Successful controlled ovarian stimulation, oocyte retrieval and embryo cryopreservation. RESULT(S): The patient underwent a long agonist protocol and received a total of 2,525 units of gonadotropin with a peak estradiol of 3,264 pg/ml. She required a total of 9 days of stimulation. The normal right ovary responded as expected, and the left ovary remained unchanged. Following laparotomy and left oophorectomy, direct application of the transvaginal ultrasound probe was used to aspirate all visible follicles on the right side in vivo. Twenty-four oocytes were retrieved, 15 were mature and 5 blastocysts were cryopreserved. Final pathology of left ovary returned as serous cystadenoma. The right ovary was examined by gynecologic oncology prior to and following retrieval and was thought to be normal and remained in situ. CONCLUSION(S): Although the approach described here is not feasible in most cases, this video demonstrates a unique and successful fertility preservation technique by direct ultrasound-guided follicle aspiration in vivo at the time of laparotomy in a Mayer-Rokitansky-Küster-Hauser Syndrome patient and to our knowledge, is the first description of its kind. This retrieval would have otherwise been limited by lack of access transvaginally and limited visualization transabdominally. This combined approach should be considered in future patients with müllerian anomalies and similar complicating factors necessitating laparotomy.

Ovarian hyperstimulation syndrome management strategies: where are we going?

Ovarian hyperstimulation syndrome (OHSS) is one of the most frequent, serious and potentially lethal iatrogenic complications of controlled ovarian stimulation. Despite extensive research, the exact pathogenesis of this syndrome remains less clear, but there appears to be a relationship of increased vascular permeability mediated by HCG and other downstream mediators. Adequate experience with ovulation induction therapy and identifying patients with known risk factors are essential in preventing OHSS. As this is a completely iatrogenic disease numerous strategies have been investigated to help decrease the risk of OHSS and their effects on pregnancy and live birth rate. What follows is a review of the common strategies apply today to minimize risk of OHSS in patients undergoing assisted reproductive technologies.

The association between fatty acid index and in vitro fertilization outcomes.

PURPOSE: Fatty acids have been shown to play an important role in oocyte competence and early implantation of the embryo. Our hypothesis-generating study sought to determine if individual fatty acids expressed as a percentage of total erythrocyte fatty acids are associated with embryo quality and other in vitro fertilization (IVF) outcomes. METHODS: This was a prospective cohort study at an academic fertility center. Sixty women undergoing their first IVF cycle were recruited. Serum measurements of 22 fatty acids were obtained. We calculated each fatty acid as a percentage of total fatty acids, defined as the index for that individual fatty acid. RESULTS: Omega-3 index had no correlation with IVF outcomes. A negative correlation was found between the trans fatty acid index, elaidic acid (EA), and IVF outcomes, including fertilization rate (r = - 0.261, p = 0.04), blastocyst conversion rate (r = - 0.41, p = 0.001), and number of usable blastocysts and embryos (r = - 0.411, p = 0.001). There was no correlation between EA index and number of oocytes retrieved, embryo grade, or clinical pregnancy. No consistent correlations were observed with the additional fatty acids analyzed. CONCLUSIONS: No correlation was observed between omega-3 index and IVF outcomes. Elevated erythrocyte EA index, the major trans fatty acid commonly consumed in hydrogenated oils, margarine, and fried foods, was negatively correlated with number of usable blastocysts and embryos, blastocyst conversion, and fertilization rate. Our findings suggest preliminary evidence that trans fat may be negatively associated with IVF outcomes.

A History of Developments to Improve in vitro Fertilization.

Methods of in vitro fertilization (IVF) have advanced dramatically since the first IVF baby was born in 1978. Originally yielding single-digit success rates, IVF is now successful in nearly 50% of cases in which the woman is younger than 35 years. Here, we describe the improvements in laboratory techniques and advances in our abilities to manipulate reproductive physiology that have facilitated this improvement. Additionally, we describe efforts to ensure safety standards in this competitive field.

Levonorgestrel Intrauterine Device Placement in a Premenopausal Breast Cancer Patient with a Bicornuate Uterus.

Young women with breast cancer face contraceptive challenges. Data are limited and conflicting on the use of the levonorgestrel intrauterine device (LNG-IUD) in this patient population. A 32-year-old nulligravid woman with a history of breast cancer on tamoxifen presented with new-onset vaginal bleeding. Further workup revealed a previously undiagnosed bicornuate uterus. She underwent hysteroscopy, dilation and curettage, and LNG-IUD placement in each uterine horn. Postoperative follow-up confirmed retention and proper placement of both IUDs. Pathology from the dilation and curettage was benign, and the abnormal uterine bleeding abated. LNG-IUD placement in a young patient with a personal history of breast cancer on tamoxifen and a bicornuate uterus is a safe and feasible alternative for contraception.

Clinical significance of inadequate endometrial biopsies prior to hysterectomy.

OBJECTIVE: To evaluate preoperative clinical risk factors associated with significant uterine histopathologic abnormalities in final hysterectomy specimens in patients with inadequate preoperative endometrial biopsies. STUDY DESIGN: This is an institutional review board-approved, retrospective cohort analysis of 469 consecutive patients who underwent preoperative endometrial biopsies with subsequent hysterectomy from January 1, 2005, to December 31, 2009, at the University of Louisville Medical Center. We analyzed risk factors for inadequate biopsy and for final diagnosis of endometrial pathology (defined as endometrial hyperplasia or uterine cancer). RESULTS: Of the 469 preoperative endometrial biopsies reviewed, 26.2% (123/469) were inadequate (IBx) and 73.8% (346/469) were adequate and benign. IBx on endometrial biopsies was associated with a greater risk of having significant uterine histopathologic abnormalities on final hysterectomy specimens (6.5% vs. 2.3%, RR 2.8 [95% CI 1.1-7.3], p = 0.04). CONCLUSION: Although inadequate endometrial biopsies are a common finding, they can be associated with significant uterine histopathologic abnormalities on final hysterectomy specimens.