Surgical Considerations in the Management of Adolescent Endometriosis-An Expert Commentary.

Given the complexities and controversies that exist in diagnosing adult endometriosis, as well as optimizing medical and surgical management, it is not surprising that there is even more ambiguity and inconsistency in the optimal surgical care of endometriosis in the adolescent. This collaborative commentary aimed to provide evidence-based recommendations optimizing the role of surgical interventions for endometriosis in the adolescent patient with input from experts in minimally invasive gynecologic surgery, pediatric and adolescent gynecology, and infertility/reproductive medicine.

Ultra-low-dose and very-low-dose Lupron downregulation protocols for poor responders based on POSEIDON group 3 and 4 classifications.

PURPOSE: The objective of this study was to assess if very-low-dose Lupron (VLDL) and ultra-low-dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other "poor responder" stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). METHODS: A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). RESULTS: The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. CONCLUSION: Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Association between serum estradiol level on day of progesterone start and outcomes from frozen blastocyst transfer cycles utilizing oral estradiol.

PURPOSE: Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol. METHODS: This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI. RESULTS: Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups. CONCLUSION: High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer.

The cost-effectiveness of preimplantation genetic testing for aneuploidy in the United States: an analysis of cost and birth outcomes from 158,665 in vitro fertilization cycles.

BACKGROUND: A controversial and unresolved question in reproductive medicine is the utility of preimplantation genetic testing for aneuploidy as an adjunct to in vitro fertilization. Infertility is prevalent, but its treatment is notoriously expensive and typically not covered by insurance. Therefore, cost-effectiveness is critical to consider in this context. OBJECTIVE: This study aimed to analyze the cost-effectiveness of preimplantation genetic testing for aneuploidy for the treatment of infertility in the United States. STUDY DESIGN: As reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, a national data registry, in vitro fertilization cycles occurring between 2014 and 2016 in the United States were analyzed. A probabilistic decision tree was developed using empirical outputs to simulate the events and outcomes associated with in vitro fertilization with and without preimplantation genetic testing for aneuploidy. The treatment strategies were (1) in vitro fertilization with intended preimplantation genetic testing for aneuploidy and (2) in vitro fertilization with transfers of untested embryos. Patients progressed through the treatment model until they achieved a live birth or 12 months after ovarian stimulation. Clinical costs related to both treatment strategies were extracted from the literature and considered from both the patient and payer perspectives. Outcome metrics included incremental cost (measured in 2018 US dollars), live birth outcomes, incremental cost-effectiveness ratio, and incremental cost per live birth between treatment strategies. RESULTS: The study population included 114,157 first fresh in vitro fertilization stimulations and 44,508 linked frozen embryo transfer cycles. Of the fresh stimulations, 16.2% intended preimplantation genetic testing for aneuploidy and 83.8% did not. In patients younger than 35 years old, preimplantation genetic testing for aneuploidy was associated with worse clinical outcomes and higher costs. At age 35 years and older, preimplantation genetic testing for aneuploidy led to more cumulative births but was associated with higher costs from both perspectives. From a patient perspective, the incremental cost per live birth favored the no preimplantation genetic testing for aneuploidy strategy from the <35 years age group to the 38 years age group and beginning at age 39 years favored preimplantation genetic testing for aneuploidy. From a payer perspective, the incremental cost per live birth favored preimplantation genetic testing for aneuploidy regardless of patient age. CONCLUSION: The cost-effectiveness of preimplantation genetic testing for aneuploidy is dependent on patient age and perspective. From an economic perspective, routine preimplantation genetic testing for aneuploidy should not be universally adopted; however, it may be cost-effective in certain scenarios.

Chronic opioid use and complication risks in women with endometriosis: A cohort study in US administrative claims.

BACKGROUND: Women with endometriosis are prescribed opioids for pain relief but may be vulnerable to chronic opioid use given their comorbidity profile. METHODS: A cohort study was conducted in the Clinformatics™ DataMart database between 2006 and 2017 comparing women aged 18-50 years with endometriosis (N = 36 373) to those without (N = 2 172 936) in terms of risk of chronic opioid use, opioid dependence diagnosis, and opioid overdose. Chronic opioid use was defined as ≥120 days' supply dispensed or ≥10 fills of an opioid during any 365-day interval. Among women with endometriosis, we evaluated factors associated with higher risk of chronic opioid use and quantified the risk of complications associated with the use of opioids. RESULTS: Women with endometriosis were at greater risk for chronic opioid use (OR: 3.76; 95%CI: 3.57-3.96), dependence (OR: 2.73, 95%CI: 2.38-3.13) and overdose (OR: 4.34, 95%CI: 3.06-6.15) compared to women without. Chronic users displayed dose escalation and increase in days supplied over time, as well as co-prescribing with benzodiazepines and sedatives. Approximately 34% of chronic users developed constipation, 20% experienced falls, and 8% reported dizziness. Among endometriosis patients, women in younger age groups, those with other comorbidities associated with pain symptoms, as well as those with depression or anxiety were at a higher risk of developing chronic opioid use. CONCLUSIONS: Women with endometriosis had a four times greater risk of chronic opioid use compared to women without. Multimorbidity among these patients was associated with the elevated risk of chronic opioid use and should be taken into account during treatment selection.

Self-reported barriers to accessing infertility care: patient perspectives from urban gynecology clinics.

PURPOSE: (1) To test the hypothesis that under-represented minority women, including Hispanic/Latina and African American or Black women, will be more likely to report greater socioeconomic and cultural barriers to infertility care compared with white women. (2) To identify gaps in knowledge that can guide future educational interventions. METHODS: A cross-sectional survey was completed by 242 women, ages 18-44, at five gynecology clinics in the greater Boston, Massachusetts area from February 27, 2018, to February 25, 2019. RESULTS: Of the respondents, 61.4% identified as Hispanic/Latina, 24.5% as white, and 6.6% as Black or African American. Cost was the most commonly reported barrier to care (62.8%) regardless of race/ethnicity or insurance status. Only 8.9% of participants were aware of personal insurance coverage for infertility treatment. Compared with white patients, Hispanic/Latina patients were less likely to know if their own insurance covered infertility treatment: 14.3% vs 6.8%; aRR 0.36 (95% CI 0.17-0.74), after adjusting for a personal history of infertility. CONCLUSION: Cost was the most commonly reported barrier to care. Most women were unaware of their insurance coverage despite the state insurance mandate to cover infertility treatment in Massachusetts. Education and outreach will be instrumental in helping address disparities in access to care.

The effect of endometriosis on the antimüllerian hormone level in the infertile population.

PURPOSE: To determine whether the presence of endometriosis in infertile women without prior ovarian surgery influences markers of ovarian reserve, AMH and FSH. METHODS: A retrospective cohort study included three groups of women who presented for IVF treatment at our tertiary care center from 04/27/2015 to 05/31/2017: women with endometriosis and prior ovarian surgery (EnSx), women with endometriosis without prior ovarian surgery (En), and women with a primary diagnosis of male factor infertility (MF; reference group). RESULTS: There were 671 patients that met inclusion criteria (78 EnSx, 60 En, and 533 MF). Compared to the MF group (3.6 ± 3.0), a lower mean AMH level (ng/mL) was observed in the EnSx group (2.5 ± 2.5; aß - 1.21; 95% CI [- 1.79, -0.62]) and in the En group (2.5 ± 2.2; aß - 1.11; 95% CI [- 1.68, - 0.54]). Both endometriosis groups had a statistically significantly higher proportion of patients with an AMH < 1 (EnSx, 24.4%; OR, 2.39 [95% CI, 1.31, 4.36]; En, 28.3%; OR, 2.67 [95% CI, 1.41, 5.08]) compared to the MF group (13.9%). The mean baseline FSH level (lU/L) was statistically significantly higher in both endometriosis groups (EnSx, 8.6 ± 4.3; ß, 1.37 [95% CI, 0.39, 2.34]; En, 8.4 ± 3.7; ß, 0.96 [95% CI, 0.04, 1.87]) compared to the MF group (7.3 ± 2.2). CONCLUSIONS: Among infertility patients with endometriosis, with and without a history of ovarian surgery, ovarian reserve markers were worse (lower AMH and higher FSH) and a higher proportion had decreased ovarian reserve as measured by AMH compared to women with MF.

Is the wrong question being asked in infertility research?

A persistent finding is that assisted reproductive technology (ART) is associated with compromised birth outcomes, including higher risks for prematurity, low birthweight, and congenital malformations, even among singletons. Over the past decade, our research group, the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART), has evaluated pregnancy and birth outcomes among three groups of women, those women treated with ART, those with indicators of subfertility but without ART treatment, and fertile women. We have also explored the influence of infertility-related diagnoses on outcomes for women and infants. Over the course of our research, we have changed our perspective from an original focus on ART treatment parameters as the primary cause of excess morbidity to one centered instead on the underlying infertility-related diagnoses. This paper summarizes the research findings from our group that support this change in focus for infertility-based research from a primary emphasis on ART treatment to greater attention to the contribution of preexisting pathology underlying the infertility and suggests directions for future analyses.

Deep infiltrating endometriosis of the bowel wall: the comet sign.

The purpose of this study was to evaluate the appearance of deep infiltrating endometriosis of the bowel wall in the cul-de-sac and determine the characteristic appearance of these lesions. We searched our database between January 1, 2011, and December 31, 2013, for all patients who had sonographic findings of suspected deep infiltrating endometriosis of the bowel with obliteration of the cul-de-sac. The medical record of each patient was examined retrospectively for evidence of surgical confirmation of disease. The sonographic appearance, shape, and size of the bowel wall lesions were evaluated to develop criteria for deep infiltrating endometriosis of the rectosigmoid and cul-de-sac. The search of our database revealed 35 patients with sonographic findings of pelvic bowel wall endometriosis associated with obliteration of the cul-de-sac. Ten of these patients had surgical confirmation of bowel wall endometriosis after the scan, and another 4 patients had surgical evidence of endometriosis from prior surgery. All of the patients who underwent surgery subsequent to sonography had confirmation of their bowel wall infiltrative endometriosis. Sonographically, the bowel lesions were solid, focal, and tubular with slightly irregular margins and in most cases a thinner section or a "tail" at one end, resembling a comet. This study confirms that bowel wall implants have a very characteristic appearance, and extending the transvaginal examination to include an evaluation of the rectosigmoid seeking these bowel lesions is valuable, especially in any patient presenting with a history of pelvic pain.

The development of endometriosis in a murine model is dependent on the presence of dendritic cells.

Endometriosis is a common condition associated with pelvic pain and infertility. This study group has previously shown that supplementation of dendritic cells led to enhancement of endometriosis lesion growth and angiogenesis. This study determined whether endometriosis is dependent on the presence of endogenous dendritic cells. Surgical induction of endometriosis was performed in CD11c⁺ DTR/GFP transgenic (Tg) female mice in which dendritic cells were ablated upon injection of diphtheria toxin (DT). Mice were allocated into four groups (n=5 each): group I, wild-type mice treated with vehicle; group II, wild-type mice treated with DT; group III, Tg mice treated with DT; and group IV, Tg mice treated with vehicle. After 10 days, mice were killed and endometriosis lesions were analysed by flow cytometry. DT treatment led to ablation of dendritic cells in spleens and endometriosis lesions in Tg mice while no ablation was observed in controls. Corresponding to dendritic cell ablation, endometriosis lesions in group III were ∼5-fold smaller than in the control groups (ANOVA P<0.0001). This study suggests that endometriosis development is dependent on the presence of endogenous dendritic cells. Therapies designed to inhibit dendritic cell infiltration as possible treatments for endometriosis warrant further study.

The effect of father's age in fertile, subfertile, and assisted reproductive technology pregnancies: a population based cohort study.

PURPOSE: To compare ages of mothers and of fathers at delivery in couples who are fertile, subfertile, and subfertile treated with assisted reproductive technology (ART) and to characterize birth outcomes in the ART population according to paternal age. METHODS: Live birth deliveries in Massachusetts between July, 2004 and December, 2008 were identified from vital records and categorized by maternal fertility status and treatment as ART, subfertile or fertile. The ART births were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database to obtain cycle-specific treatment data. Parental ages were obtained from birth certificates. Age of mothers and fathers were compared using ANOVA for continuous measures and χ (2) for categories. Risks of prematurity (<37 weeks), low birthweight (<2,500 g), and low birthweight z-score (small for gestatational age, SGA) were modeled using logistic regression by categories of paternal age as adjusted odds ratios and 95 % CI. RESULTS: The study population included 9,092 ART, 6,238 subfertile, and 318,816 fertile deliveries. Paternal ages in the ART and subfertile groups were similar and differed significantly from those of the fertile group. Maternal age in the ART and subfertile groups averaged 5-6 years older than their fertile counterparts and fathers averaged 4-5 years older with twice as many being older than 37. The risks for prematurity, low birthweight and SGA did not increase with increasing paternal age. CONCLUSIONS: Fathers in ART- treated and subfertile couples are older than in their fertile counterparts. Older paternal age was not assoicated with increased risk for prematurity, low birthweight, or SGA.

Perceptions among infertile couples of lifestyle behaviors and in vitro fertilization (IVF) success.

PURPOSE: To assess how patients perceive various lifestyle behaviors impact IVF success. METHODS: Cross-sectional study of heterosexual, English-speaking couples (n = 138) who completed web-based surveys during IVF treatment cycle. Perceived impact of lifestyle choices assessed by multivariable logistic regression and p-value tests for linear trend (Pt). RESULT(S): During the IVF cycle, most patients consider it helpful for women to exercise (76 %), avoid stress (87 %) and limit activity after embryo transfer (92 %). The majority of patients (62 %) consider rigorous exercise (4+ h/week) helpful and nearly one-third (32 %) perceive benefit to complete bed rest after transfer. Overall, couples with a sex-specific infertility diagnosis are more likely to consider partner's lifestyle choices impactful: male-factor couples are more likely to consider it helpful for men to limit cellular phone use (OR:2.73,CI:1.06-7.04) and diminished ovarian reserve couples are more likely to consider it helpful for women to limit exposure to plastics (OR:2.38,CI:1.03-5.51). Patients at higher levels of education (Pt < 0.01) and income (P(t) < 0.01) are less likely to consider lifestyle impactful. CONCLUSION(S): Patient perceptions of the impact of lifestyle factors on IVF success vary by sex, infertility diagnosis and socioeconomic factors. Despite counseling to the contrary, many patients perceive benefit to rigorous exercise during the IVF cycle and complete bedrest following transfer. Results provide insight into patient beliefs and highlight opportunities to improve patient education, alleviate patient anxieties and potentially improve IVF outcomes.

Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use.

Introduction: Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods: The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2-ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results: In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67-0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion: The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.

Amniocytes can serve a dual function as a source of iPS cells and feeder layers.

Clinical barriers to stem-cell therapy include the need for efficient derivation of histocompatible stem cells and the zoonotic risk inherent to human stem-cell xenoculture on mouse feeder cells. We describe a system for efficiently deriving induced pluripotent stem (iPS) cells from human and mouse amniocytes, and for maintaining the pluripotency of these iPS cells on mitotically inactivated feeder layers prepared from the same amniocytes. Both cellular components of this system are thus autologous to a single donor. Moreover, the use of human feeder cells reduces the risk of zoonosis. Generation of iPS cells using retroviral vectors from short- or long-term cultured human and mouse amniocytes using four factors, or two factors in mouse, occurs in 5-7 days with 0.5% efficiency. This efficiency is greater than that reported for mouse and human fibroblasts using similar viral infection approaches, and does not appear to result from selective reprogramming of Oct4(+) or c-Kit(+) amniocyte subpopulations. Derivation of amniocyte-derived iPS (AdiPS) cell colonies, which express pluripotency markers and exhibit appropriate microarray expression and DNA methylation properties, was facilitated by live immunostaining. AdiPS cells also generate embryoid bodies in vitro and teratomas in vivo. Furthermore, mouse and human amniocytes can serve as feeder layers for iPS cells and for mouse and human embryonic stem (ES) cells. Thus, human amniocytes provide an efficient source of autologous iPS cells and, as feeder cells, can also maintain iPS and ES cell pluripotency without the safety concerns associated with xenoculture.

Prenatal food allergen exposures and odds of childhood peanut, tree nut, or sesame seed sensitization.

BACKGROUND: The prevalence of peanut (PN) and tree nut (TN) allergy in children has tripled in the past decade. Prenatal exposures, including maternal diet and medications, may account for some of this increase. In the United States, progesterone for luteal support in assisted reproduction is commonly formulated in PN or sesame seed (SS) oil. OBJECTIVE: To determine whether prenatal exposure to PN or SS oil as progesterone in oil increases the child's odds of PN, TN, or SS allergy. METHODS: Parents of 1,272 children evaluated by allergists from May 2005 through October 2009 completed questionnaires on conception, prenatal exposures, dietary history, and allergic history, with review of the child's medical record and skin prick and specific IgE test results. Odds ratios and 95% confidence intervals were calculated using multivariable adjusted logistic regression models. RESULTS: Children of mothers with a history of infertility, in vitro fertilization, or use of progesterone in oil did not have increased odds of PN, TN, and/or SS sensitization. Maternal consumption of TNs during first 2 trimesters was associated with 60% higher odds of having a PN/TN/SS-sensitized child (95% confidence interval 1.01-2.51), with similarly increased odds with maternal SS ingestion. Odds of PN/TN/SS sensitization were doubled in children with asthma or environmental allergies. CONCLUSION: Neither maternal infertility nor exposure to PN or SS oils through progesterone support during assisted reproduction treatment was associated with increased odds of PN/TN/SS sensitization in the child. However, maternal ingestion of TNs and SS during pregnancy was associated with increased odds of PN/TN/SS sensitization in the child.

In vitro fertilization outcomes and alcohol consumption in at-risk drinkers: the effects of a randomized intervention.

BACKGROUND AND OBJECTIVES: Women's use of alcohol in pregnancy is associated with an increased risk of fetal loss and birth defects. Also, alcohol use in women decreases the success of infertility treatment, such as in vitro fertilization (IVF). Our goal was to determine if there were differences in IVF outcomes and alcohol use parameters among at-risk drinkers randomized to a brief intervention (BI) versus assessment only (AO). METHODS: We conducted a randomized controlled trial to determine the effect of BI or AO among at-risk drinkers on IVF. We studied 37 women (AO = 21; BI = 16). RESULTS: While the BI group had a significantly greater decrease in the number of drinks/drinking day compared to the AO group (p = .04), there were no differences in the likelihood of implantation failure, chemical pregnancy, spontaneous abortion, preterm birth, or live birth. CONCLUSIONS: BI and AO contributed to a decrease in alcohol use and did not demonstrate differences in IVF outcomes. A larger study may confirm these preliminary findings. SCIENTIFIC SIGNIFICANCE: Our results will assist care providers in treating alcohol use in pregnancy in an effective way, such that IVF cycles and the chance of pregnancy are optimized.

Predictors of twin live birth following cryopreserved double embryo transfer on day 3.

PURPOSE: To determine embryo and cycle-specific parameters associated with twin live birth in day 3 cryopreserved double embryo transfer (DET) cycles, and to propose a new prediction model for external validation. METHODS: All cycles with autologous or donor cryopreserved DET of day 3 embryos from 2002 to 2011 at a single academic institution with a singleton or twin live birth were included (n = 207). Patient characteristics, post-thaw embryo morphology and freeze-thaw parameters were compared between patients with a single and twin live birth. RESULTS: Demographic characteristics were similar, except that patients delivering twins were younger at age of cryopreserved embryo transfer (CET), fewer were parous and more were anovulatory. Duration of embryo storage, time in culture post-thaw, endometrial thickness and use of assisted hatching were comparable. Six predictors of twin delivery were identified: patient age <35 year at CET, intact survival of the lead embryo, resumption of mitosis, 7-8 viable cells in the non-lead embryo, transfer of a lead embryo with ≥7 cells and a sum of ≥14 viable cells in the two transferred embryos. Regression modeling predicted a step-wise increase in the probability of twins with addition of each predictor; with all six present, the risk of twins was predicted to be 53 % and with none present, the risk decreased to 6 %. CONCLUSIONS: The six identified variables associated with twin live birth following day 3 cryopreserved DET have been applied to derive a prediction model for estimating the risk of twin delivery. External validation of the model is required prior to clinical application.

The clinical relevance of luteal phase progesterone support in true natural cycle cryopreserved blastocyst stage embryo transfers: a retrospective cohort study.

BACKGROUND: More than 67% of all embryos transferred in the United States involve frozen-thawed embryos. Progesterone supplementation is necessary in medicated cycles to luteinize the endometrium and prepare it for implantation, but little data is available to show if this is beneficial in true natural cycles. We evaluated the use of luteal phase progesterone supplementation for cryopreserved/warmed blastocyst transfers in true natural cycles not using an ovulatory trigger. METHODS: Retrospective cohort study in a single academic medical center. We studied the use of luteal phase progesterone supplementation in patients undergoing true natural cycle cryopreserved blastocyst embryo transfers. Our primary outcome measure was ongoing pregnancy rate, with other pregnancy outcomes being evaluated (i.e. implantation rate, miscarriage rate, ectopic rate, and multifetal gestation). Categorical data were analyzed utilizing Fisher's exact test and all binary variables were analyzed using log-binomial regression to produce a risk ratio. RESULTS: Two hundred twenty-nine patients were included in the analysis with 149 receiving luteal phase progesterone supplementation and 80 receiving no luteal phase support. Patient demographic and cycle characteristics, and embryo quality were similar between the two groups. No difference was seen in ongoing pregnancy rate (49.0% vs. 47.5%, p = 0.8738), clinical pregnancy rate (50.3% vs. 47.5%, p = 0.7483), positive HCG rate (62.4% vs. 57.5%, p = 0.5965), miscarriage/abortion rate (5.4% vs. 2.5%, p = 0.2622), ectopic pregnancy rate (0% vs. 1.3%, p = 0.3493), or multifetal gestations (7.4% vs. 3.8%, p = 0.3166). CONCLUSION(S): The addition of luteal phase progesterone support in true natural cycle cryopreserved blastocyst embryo transfers did not improve pregnancy outcomes and therefore the routine use in practice cannot be recommended based on this study, but the utilization should not be discouraged without further studies. CAPSULE: Progesterone supplementation as luteal phase support in true natural cycle cryopreserved blastocyst transfers does not improve ongoing pregnancies.

Nonhormonal therapy for endometriosis: a randomized, placebo-controlled, pilot study of cabergoline versus norethindrone acetate.

OBJECTIVE: To estimate the efficacy and safety of a novel nonhormonal therapeutic agent, cabergoline, compared with that of the standard clinical therapy, norethindrone acetate (NETA), for the treatment of endometriosis-associated pain in young women with endometriosis. DESIGN: Randomized, double-blind, placebo-controlled pilot study. SETTING: Tertiary care center. PATIENTS: Women (n = 9) with surgically confirmed endometriosis. INTERVENTIONS: A random, double-blind assignment to either NETA (5 mg/day) + placebo twice weekly or cabergoline (0.5 mg) twice weekly + placebo daily for 6 months. MAIN OUTCOME MEASURES: We collected the measures of pelvic pain and laboratory parameters every 3 months. RESULTS: We observed a decrease in pain scores and increase in pain relief in women randomized to receive cabergoline, who appeared to show similar or more improvements than women treated with NETA. The serum measures of vascular endothelial growth factor receptor 1 declined over 6 months in those who received cabergoline. Cabergoline was well tolerated, and no serious adverse events occurred. CONCLUSIONS: Safe, effective adjunct treatments are lacking for patients with endometriosis who do not respond to standard care. Because the growth of endometriosis requires angiogenesis, blood vessel growth is an attractive therapeutic target. This pilot study suggests that cabergoline, a vascular endothelial growth factor pathway inhibitor, is an effective therapeutic option for women with chronic pain due to endometriosis. Building upon this investigation, we will conduct larger, randomized trials of cabergoline, advancing research on the best treatments for endometriosis-particularly disease resistant to hormonal therapies. CLINICAL TRIAL REGISTRATION NUMBER: clinicaltrials.gov; registration number NCT02542410.