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OBJECTIVE: To study if stress, as measured by salivary alpha-amylase and cortisol, negatively impacts male fertility, as measured by semen parameters, pregnancy and live birth rates. DESIGN: Prospective, cohort study of men enrolled in the Males, Antioxidants, and Infertility (MOXI) Trial. MATERIALS AND METHODS: 112 infertile men provided first morning salivary and semen samples at baseline. Salivary samples were analyzed for alpha-amylase and cortisol. Couples attempted to conceive naturally (months 1-3) and with clomiphene citrate/intrauterine insemination (months 4-6). The association between stress related biomarkers and semen parameters including DNA fragmentation were assessed using linear regression models adjusting for male age. Salivary levels were dichotomized at the 80(th) percentile. Pregnancy/live birth rates in couples in the upper quintile were compared to remaining subjects using chi-square testing. RESULTS: Salivary levels of alpha-amylase were not associated with semen parameters or DNA fragmentation. Salivary cortisol levels were not correlated with DNA fragmentation or normal morphology. For every 1-unit increase in salivary cortisol, total sperm count increased by 13.9million (95%CI: 2.5, 25.3) and total motile sperm count increased by 9.9million (95%CI: 3.2-16.6). Couple pregnancy rates and live birth rates did not differ for males in the highest quintile of alpha-amylase (27% and 28%, p=0.96; 23% and 21%, p=0.87) or cortisol (40% and 26%, p=0.22; 35% and 19%, p=0.12), compared to males with lower values. CONCLUSION: Physiologic measures of high stress may not harm but actually improve semen parameters among men with male-factor infertility. TRIAL REGISTRATION NUMBER: NCT02421887

Objective To evaluate the relationship between semen regurgitation and intrauterine insemination (IUI) outcomes. We hypothesized that clinical pregnancy rates and live birth rates would be reduced when regurgitation occurred. Design Retrospective cohort study. Setting A university-based reproductive endocrinology and infertility clinic. Patient(s) Retrospective review of 1,957 IUI cycles performed on 660 patients between July 2007 and May 2012. Intervention(s) None. Main Outcome Measure(s) The primary outcome was live birth. Secondary outcomes were positive serum pregnancy result and clinical pregnancy. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a cluster-weighted generalized estimating equations method to estimate modified Poisson regression models with robust standard errors to account for multiple IUI cycles in the same patient. Result(s) Live birth rates were similar in IUI cycles with and without regurgitation (6.3% vs. 6.8%, respectively, RR = 0.82, 95% CI [0.53–1.26]). Clinical pregnancy rates in the presence or absence of regurgitation were 10.5% vs. 10.0% (RR = 0.99, 95% CI [0.73–1.35]). Positive serum pregnancy tests after IUI did not differ by regurgitation status (15.0% vs. 15.4%, RR = 0.97, 95% CI [0.75–1.24]). Results were unchanged when adjusted for covariates (age, race and ethnicity, body mass index, duration of infertility, medication, infertility diagnosis, total motile count, and method of sperm preparation). Conclusion(s) The presence of regurgitation during the IUI procedure is not related to pregnancy outcome.

Diagnostic evaluation for infertility in women should be conducted in a systematic, expeditious, and cost-effective manner to identify all the relevant factors with an initial emphasis on the least invasive methods for detecting the most common causes of infertility. The purpose of this committee opinion is to provide a critical review of the current methods and procedures for the evaluation of in fertile women, and it replaces the document of the same name, last published in 2015 (Fertil Steril 2015;103:e44-50). This guidance is intended for any provider evaluating women for infertility.

PURPOSE: The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. METHODS: This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon’s rank-sum test and linear regression models. RESULTS: At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. CONCLUSIONS: Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02301-2.

Context Sleep plays important roles in metabolic and reproductive function, and polycystic ovary syndrome (PCOS) is associated with sleep disturbances, including increased prevalence of obstructive sleep apnea. Objective We sought to evaluate sleep parameters in infertile women with PCOS compared with women with unexplained infertility (UI) and identify risk factors for disturbed sleep. Methods At private and academic ambulatory gynecology and infertility practices, we evaluated a prospective cohort of women diagnosed with PCOS or UI from 2 randomized clinical trials. We included 1603 infertile women enrolled in 2 concurrent randomized clinical trials. The main outcome measures were self-reported sleep measures. Results Sleep duration 88 cm (P = .003), and current smoking (P = .012) were associated with habitual snoring. Clinical depression score (P Conclusion Infertile women with PCOS more commonly report sleep disturbances than those with UI. Markers of insulin resistance are associated with previous diagnosis of OSA, habitual snoring, and short sleep duration. The presence of clinical symptoms of OSA or short sleep duration does not affect fertility treatment response.

ObjectiveTo determine the reproducibility of the World Health Organization Fifth Edition (WHO5) strict grading methodology by comparing the percentage of morphologically normal sperm (PNS) recorded by the core laboratory with results obtained at the fertility centers participating in a multisite clinical trial.DesignSecondary cohort analysis of data from the Males, Antioxidants, and Infertility trial.SettingFertility centers.PatientsSemen values of 171 men participating in a multicenter, double-blind, randomized, placebo-controlled trial evaluating the effect of antioxidants on male fertility.InterventionsNot applicable.Main outcome measuresStrict morphology expressed as PNS as determined at each fertility center and the core central laboratory for the same semen sample.ResultsNo correlation was found in the PNS values for the same semen sample between the core laboratory and fertility center laboratories either as a group or by individual site. Interobserver agreement was similarly low (κ = 0.05 and 0.15) between the core and fertility laboratories as a group for strict morphology, categorized by the WHO5 lower reference limits of 4% and 0, respectively. Moderate agreement was found between the core and 2 individual fertility laboratories for the cutoff value of 0 (κ = 0.42 and 0.57). The remainder of the comparisons demonstrated poor to fair agreement.ConclusionsStrict morphology grading using the WHO5 methodology demonstrated overall poor reproducibility among a cohort of experienced fertility laboratories. This lack of correlation and agreement in the PNS values calls into question the reproducibility, and thereby the potential applicability, of sperm strict morphology testing.

Sexually transmitted infections are of major concern to reproductive specialists. Heading the list are human immunodeficiency virus types 1 and 2 and hepatitis B and C viruses. These pathogens, which may cause incurable chronic infections, can be transmitted through assisted reproductive technologies and from infected mothers to the fetus or newborn. This document replaces the document of the same name last published in 2013 (Fertil Steril 2013;99:340-6).

STUDY QUESTIONAre intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility?SUMMARY ANSWERPatient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success.WHAT IS ALREADY KNOWNWe previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome.STUDY DESIGN, SIZE, DURATIONThis was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSAMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate.MAIN RESULTS AND THE ROLE OF CHANCEAfter adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16–0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1–20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31–3.33)). However, live births did occur with TMC ≤ 1 million (5.1%).LIMITATIONS, REASONS FOR CAUTIONThis investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI.WIDER IMPLICATIONS OF THE FINDINGSMost factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI.STUDY FUNDING/COMPETING INTEREST(S)Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work.TRIAL REGISTRATION NUMBERn/a

Objective To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. Design Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. Setting Multicenter university-based clinical practices. Patient(s) Nine hundred couples with unexplained infertility were included. Women were 18–40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. Intervention(s) None. Main Outcome Measure(s) The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. Result(s) When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. Conclusion(s) In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. Clinical Trial Registration Number NCT 01044862.

Author(s): Rios, Julie S; Coward, R Matthew; Hansen, Karl R; Barnhart, Kurt T; Cedars, Marcelle I; Legro, Richard S; Diamond, Michael P; Krawetz, Stephen A; Usadi, Rebecca; Baker, Valerie L; Sun, Fangbai; Wild, Robert; Smith, James F; Santoro, Nanette; Zhang, Heping; Steiner, Anne Z | Abstract: ObjectiveTo examine the factors associated with increased deoxyribonucleic acid fragmentation index (DFI), evaluate the pregnancy outcomes of men with increased DFI, and compare three independent DFI assays.DesignSecondary analysis.SettingNine US-based fertility centers.PatientsInfertile men (N = 147) with sperm concentration ≤15 × 106/mL, motility ≤40%, or normal morphology ≤4% were enrolled. The female partners were ovulatory, ≤40 years old, and had documented tubal patency.InterventionsAt a baseline visit, the men provided a semen sample. The couples attempted conception without assistance for 3 months and with ovarian stimulation and intrauterine insemination in the subsequent 3 months.Main outcome measuresThe DFI was analyzed using the sperm chromatin structure assay (SCSA) with increased DFI defined as g30%. The predictors of increased DFI were determined by a multivariable linear regression model. The pregnancy outcomes were compared using the χ2 test. The independent DFI assays (SCSA, deoxynucleotidyl transferase-mediated dUTP nick end labeling, and Comet) were compared with Pearson and Spearman correlations.ResultsThe 19% of men with increased DFI were older (36.0 vs. 33.0 years) and had lower total sperm motility (38.2% ± 20.5% vs. 45.2% ± 15.6%). Increased male age was found to be a significant predictor of DFI (0.75, 95% confidence interval [0.06, 1.45]). Increased DFI was not associated with conception or live birth. There was a modest correlation of the deoxynucleotidyl transferase-mediated dUTP nick end labeling assay with the SCSA (r = 0.34) and Comet assay (r = 0.19).ConclusionsOlder age was associated with increased DFI among infertile men. The DFI assays were only weakly correlated, indicating a standard definition of DFI is needed to truly interrogate how sperm deoxyribonucleic acid fragmentation impacts male fertility.

Importance Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of −12%. Results Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, −8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration ClinicalTrials.gov Identifier:NCT02152696

Background Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. Methods and findings In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (−6.6 ± 5.4% versus −0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. Conclusions A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. Trial registration ClinicalTrials.gov NCT02432209., Richard Legro and colleagues investigate the impact of a preconception weight loss intervention on healthy live birth rates in women with obesity and unexplained infertility., Author summary Why was this study done? Obesity in women is associated with an increased time to pregnancy, pregnancy loss, and many pregnancy complications. Consequently, women who are obese and infertile are recommended to lose weight prior to conception to increase their chance for a healthy baby. There are few data from prospective trials to support this recommendation. What did the researchers do and find? In this study, we conducted an open-label, randomized controlled trial examining the effects of an intensive preconception intervention designed to lose weight acutely compared to a standard intervention designed to maintain weight consisting of exercise alone for 16 weeks prior to initiating routine infertility treatment in women with unexplained infertility in the US. We found that our intensive intervention resulted in about 7% weight loss in the intensive group versus no significant weight loss in the standard group. After the preconception intervention, both groups received 3 cycles of routine infertility treatment for both groups. There were no significant differences in cumulative pregnancy or live birth rates between groups. The small number of pregnancies reduced the statistical power for examining differences in the rate of pregnancy complications between groups. What do these findings mean? Our study supports other studies that have found no improved live birth or healthy live birth rates in women who were obese or overweight who participated in a preconception weight loss intervention prior to starting infertility therapy. Further research will be needed to investigate potential harms and benefits of weight loss interventions that did not reach statistical significance in the present trial. There is not strong evidence to recommend weight loss prior to conception in women who are obese with unexplained infertility.

To estimate the probability of clinical or multiple pregnancy during ovulation induction (OI)/ovarian stimulation (OS).Secondary analysis of two multicenter randomized clinical trials (combined).Multicenter.A total of 750 women with polycystic ovary syndrome and 900 women with unexplained infertility.Ovulation induction/OS with either timed intercourse (polycystic ovary syndrome) or intrauterine insemination.Clinical and multiple pregnancy rates/cycle, cumulative pregnancy rates. Age, body mass index, parity, diagnosis, medication, markers of ovarian reserve, and ovarian response were considered in multivariable regression models for clinical, multiple, and cumulative pregnancy rates. Receiver operating characteristic curves were created for clinical and multiple pregnancy rates.Younger patient and partner age, treatment type, lower body mass index, and medication dose were all associated with clinical pregnancy. Variables associated with multiple pregnancy included the abovementioned variables (except age), in addition to diagnosis, parity, higher antral follicle count, antimüllerian hormone levels, and ovarian response. Gonadotropin use was associated with multiple pregnancy, with progressively increasing odds ratios (cycles 1-4). Receiver operating characteristic curves indicated the model's predictive power to be fair for clinical pregnancy (areas under the curve [95% confidence interval {CI}]: 0.78 [0.75-0.81] for cycle 1 and 0.70 [0.64-0.75] for cycle 4) and good-to-excellent for multiple pregnancy (areas under the curve [95% CI]: 0.78 [0.72-0.84] for cycle 1 and 0.86 [0.78-0.93] for cycle 4). Partner age, lower medication dose, parity, antimüllerian hormone levels, and diagnosis were associated with cumulative pregnancy rates.Using the majority of the factors known to predict the outcome of OI/OS cycles, we constructed an easy-to-use formula that may predict individualized chances of clinical and multiple pregnancy for commonly used fertility treatments (https://pregnancyprediction.medicine.yale.edu/CalDirect.html).Assessing Multiple Intrauterine Gestations after Ovulation Stimulation NCT01044862; PPCOSII NCT00719186.

Background Obesity is common in women with polycystic ovary syndrome. polycystic ovary syndrome and obesity are associated with reduced fertility. The effect of metabolic syndrome on the success of infertility treatment and pregnancy outcomes in women with polycystic ovary syndrome undergoing ovulation induction has not been investigated. Objective The objectives of this study were to determine the associations of metabolic syndrome on the rate of live birth after ovulation induction and pregnancy complications in obese women with polycystic ovary syndrome and determine whether there is a difference in outcomes concerning specific medications used for ovulation induction. Study Design This prospective cohort analysis used data collected from participants in the Pregnancy in Polycystic Ovary Syndrome II clinical trial conducted by the Reproductive Medicine Network. In the Pregnancy in Polycystic Ovary Syndrome II trial, 750 women with polycystic ovary syndrome and infertility were randomized to either clomiphene citrate or letrozole for ovulation induction for 1 to 5 cycles or until pregnancy occurred. Cox regression and modified Poisson regression, chi-square test, and Student t test or Wilcoxon test were used in this study. Outcomes of interest were rates of live birth and clinical pregnancy and pregnancy complications. Having metabolic syndrome was defined by the presence of at least 3 of 5 cardiometabolic risk factors (waist circumference of >88 cm, low high-density lipoprotein cholesterol of 100 mg/dL). In addition, we used a continuous metabolic syndrome z score. Body mass index categories were defined as normal (body mass index of 35 kg/m2). Results As illustrated in the Table , early pregnancy losses showed no difference by metabolic syndrome. Fewer women achieved a clinical pregnancy (20.5% vs 29.7%; P=.007) or had a live birth (16.5% vs 27%; P=.001) in the presence of metabolic syndrome. Early pregnancy losses showed no difference by metabolic syndrome status. However, at least 1 pregnancy complication occurred more often with metabolic syndrome: 61.9% (26 of 42 cases) with metabolic syndrome vs 44.4% (59 of 133 cases) (P=.05) without metabolic syndrome. Gestational diabetes mellitus (35.7% vs 18.2%; P=.02) and macrosomia (21.4% vs 8.3%; P=.02) were more common in the presence of metabolic syndrome. After adjustment for other potential confounders, the rate ratio for live births for a 1-unit change in the metabolic syndrome z score was 0.89 (95% confidence interval, 0.79–1.00; P=.04) for those whose body mass index was 25 to 35 kg/m2. For the very high body mass index subgroup (>35 kg/m2), the independent effects of metabolic syndrome from obesity were harder to discern. The rate of live birth was higher with the use of letrozole, although metabolic syndrome had a different detrimental effect concerning the medication given. The overall incidence of pregnancy complications was high (approximately 49%) in the Pregnancy in Polycystic Ovary Syndrome II trial and the 2 medications. Letrozole was associated with more obstetrical complications in the presence of metabolic syndrome, and clomiphene was associated with a lower rate of live birth rate when metabolic syndrome was present. Conclusion Metabolic syndrome is a risk factor that lowers the rate of live birth after ovulation for women with polycystic ovary syndrome, independent of obesity, and it is particularly associated with a lower rate of live birth for women using clomiphene compared with women using letrozole. In addition, metabolic syndrome is a risk factor for pregnancy complications for women with obesity using letrozole. Furthermore, having metabolic syndrome is a risk factor for gestational diabetes mellitus and macrosomia.

OBJECTIVE: To study the association of endometrial thickness (EMT) with live birth rates (LBR) in ovarian stimulation with intrauterine insemination (OS-IUI) treatments for unexplained infertility DESIGN: Prospective cohort analysis of the Reproductive Medicine Network’s Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial SETTING: multicenter randomized controlled trial PATIENTS: 868 couples with unexplained infertility (n=2459 cycles) INTERVENTIONS: OS-IUI treatment cycles (n = 2,459) as part of the AMIGOS clinical trial MAIN OUTCOME MEASURES: Live birth rates (LBR); unadjusted and adjusted risk ratios (RR) for live birth by EMT category calculated using generalized estimating equations. RESULTS: The overall mean EMT on day of hCG administration in cycles with a live birth (9.5 mm, 95% CI 9.1–9.8) was significantly greater than in those without (8.9, 8.8–9.1; p=0.004). Compared to the referent EMT group of 9–12 mm, the unadjusted RR for live birth for the EMT groups of ≤5 and 6–8 were 0.48 (95% CI 0.22–1.03) and 0.92 (0.69–1.23), respectively. The test for trend indicated evidence of decreasing LBR with decreasing EMT (p=0.03). After adjustment for ovarian stimulation medication, a linear trend was no longer supported (p=0.41). Stratified analyses revealed no differences in associations by treatment group. CONCLUSIONS: In OS-IUI for unexplained infertility, higher LBR are observed with increasing EMT; however, EMT is not significantly associated with LBR when adjusted for OS treatment type. Appreciable LBR are seen at all EMTs, even those of ≤5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium. TRIAL REGISTRATION: clinicaltrials.gov NCT01044862

Ovarian reserve is defined as the number of oocytes remaining in the ovary, or oocyte quantity (oocyte number). Markers of ovarian reserve include hormone levels and sonographically measured features of the ovaries. These markers can be useful as predictors of oocyte yield following controlled ovarian stimulation and oocyte retrieval. However, they are poor predictors of reproductive potential independently from age. This document replaces the document of the same name last published in 2012 (Fertil Steril 2012;98:1407–15).

We hypothesized that weight loss with an intensive preconception lifestyle (IL) intervention of caloric restriction with meal replacements, daily orlistat and increased physical activity in women with obesity and unexplained infertility (UI) was more likely to result in Good Birth Outcome than a standard lifestyle modification (SL) with increased physical activity alone. The 16 week period of lifestyle modification was followed by an open label empiric infertility treatment regimen of 3 cycles of ovarian stimulation with clomiphene, ovulation triggering with hCG and intrauterine insemination. We randomized 379 obese women 18-40y with UI (regular menses, normal ovarian reserve, patent reproductive tract and normal male factor). A Good Birth Outcome (GBO) was the primary outcome, defined as a live birth of an infant born at ≥37wks with a birthweight between 2500-4000g and no major congenital anomaly. Key secondary outcomes were live birth, pregnancy loss and pregnancy complication rates. The study had 80% power and an alpha of 0.05 to detect an absolute 15% difference in GBO. An Intention-to-Treat analysis was used. Both groups (SL N=191, IL N =188) were well matched at baseline(e.g. weight (kg), mean ± SD, SL:107±21, IL: 108 ±23). Women in the IL arm lost significantly more weight preconception than SL (SL -0.3±3.4 vs IL -7.3±6.6 kg, P5% weight vs 6.5% in SL group(P

STUDY QUESTION What are the psychosocial and financial issues experienced among families with children 2–12 years of age conceived by ART? SUMMARY ANSWER Our results suggest that families with children, 2–12 years of age, conceived via ART are doing well, although impacts were identified on parents of twins and higher-order multiples. WHAT IS KNOWN ALREADY Multiple births have been associated with higher morbidity and mortality of children, as well as financial costs to families and society. STUDY DESIGN, SIZE, DURATION This study was an assessment of familial response to birth of singletons, twins and higher order multiples at child’s ages of 2–12. PARTICIPANTS/MATERIALS, SETTING, METHODS Semi-structured interviews and surveys were conducted with mothers (n = 348) and fathers (n = 338) of singletons, twins and higher-order multiple gestations who received fertility services. MAIN RESULTS AND THE ROLE OF CHANCE No significant differences were observed between the groups in domains of primary caregiving or parental separation/divorce. Impacts were identified on parent’s ability to maintain employment. The revised 15-item scores of the Impact on Family Scale were significantly lower, reflecting more negative impacts, among families with twins (beta = −2.6, 95% confidence interval (CI), −4.7, −0.5, P = 0.014) and multiples (beta = −7.4, 95% CI, −10.4, −4.5, P LIMITATIONS, REASONS FOR CAUTION The study was limited to families who received fertility treatment and constitutes a population that was well educated and had higher incomes. Additionally, interview data was self-reported. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) U10 HD39005 (to M.P.D.), U10 HD077680 (to K.R.H.), U10 HD077844 (to A.Z.), U10 HD077841 (to M.C.), U10 HD38992 (to R.S.L.), U10 HD27049 (to C.C.), U10 HD055925 (to H.Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or NIH. Dr Virginia Miller—no conflicts; Dr Michael P. Diamond—NIH Funding, AbbVie, Bayer and ObsEva Funding; Board of Directors and Stockholder for Advanced Reproductive Care; Dr Karl R. Hansen—Yale University/Reproductive Medicine Network/NICHD, Roche Diagnostics and Ferring International Pharmascience Center US funding; Dr Anne Steiner—NIH Funding; Dr Marcelle I. Cedars—no conflicts; Dr Richard Legro—consultant for Ogeda, Millendo, Kindex and Bayer; Ferring and Astra Zeneca funding; Dr Stephen A. Krawetz—no conflicts; Dr Christos Coutifaris—NIH Funding; Dr Hao Huang—no conflicts; Dr Nanette Santoro—no conflicts; Dr Heping Zhang—NIH Funding. TRIAL REGISTRATION NUMBER N/A

Objective Pregnancy of unknown location (PUL) is not a diagnosis but a transient state used to classify a woman when she has a positive pregnancy test without definitive evidence of an intra-uterine or extra-uterine pregnancy on transvaginal ultrasonography. Management of a persisting PUL varies substantially, including expectant or active management. Active management can include uterine cavity evacuation or systemic administration of methotrexate. To date, no consensus has been reached on whether either management strategy is superior or non-inferior to the other. Design Randomized controlled trial. Setting Academic medical centers. Patients We plan to randomize 276 persisting PUL-diagnosed women who are 18 years or older from Reproductive Medicine Network clinics and additional interested sites, all patients will be followed for 2 years for fertility and patient satisfaction outcomes. Interventions Randomization will be 1:1:1 ratio between expectant management, uterine evacuation and empiric use of methotrexate. After randomization to initial management plan, all patients will be followed by their clinicians until resolution of the PUL. The clinician will determine whether there is a change in management, based on clinical symptoms, and/or serial human chorionic gonadotropin (hCG) concentrations and/or additional ultrasonography. Main outcome The primary outcome measure in each of the 3 treatment arms is the uneventful clinical resolution of a persistent PUL without change from the initial management strategy. Secondary outcome measures include: number of ruptured ectopic pregnancies, number and type of re-interventions (additional methotrexate injections or surgical procedures), treatment complications, adverse events, number of visits, time to resolution, patient satisfaction, and future fertility. Conclusion This multicenter randomized controlled trial will provide guidance for evidence-based management for women who have persisting pregnancy of unknown location.

Encounters for infertility care are opportunities to assess and update immunization status. Women of reproductive age are often unaware of their need for immunization, their own immunization status, and the potentially serious consequences of preventable disease on pregnancy outcome. The purpose of this ASRM Practice Committee document is to summarize current recommendations regarding vaccinations for women of reproductive age. This document replaces the ASRM Practice Committee document titled, "Vaccination guidelines for female infertility patients," last published in 2013 (Fertil Steril 2013;99:337-9).

It is the responsibility of the clinician to assess for the presence of erectile dysfunction, ejaculatory dysfunction, or diminished libido related to hypoandrogenism among men presenting with a primary complaint of infertility. Referral to a reproductive urologist or other appropriate specialist with requisite expertise in the evaluation and treatment of such conditions is often warranted.

Approximately 21% of women of reproductive age and 22% of men of reproductive age in the United States smoke cigarettes. Substantial harmful effects of cigarette smoke on fecundity and reproduction have become apparent but are not generally appreciated. This committee opinion reviews the potential deleterious effects of smoking on conception, ovarian follicular dynamics, sperm parameters, gamete mutations, early pregnancy, and assisted reproductive technology (ART) outcomes. It also reviews the current status of smoking cessation strategies. This document replaces the 2012 ASRM Practice Committee document of the same name (Fertil Steril 2012;98:1400-6).

Study question Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? Summary answer AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. What is known already Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. Study design, size, duration A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. Participants/materials, setting, methods Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. Main results and the role of chance Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). Limitations, reasons for caution Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. Wider implications of the findings Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. Study funding/competing interest(s) Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. Trial registration number Clinical Trials.gov number: NCT01044862.

Context Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. Objective To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Design and setting Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Participants Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Main outcome measures Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Results Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). Conclusions During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

The purpose of this document is to review the current methods of diagnosis and evaluation for men with azoospermia.

BACKGROUND: No research exists on American Indian pregnancy rates following infertility treatment. Most racial/ethnic fertility research has focused on pregnancy following in vitro fertilization, with only rare studies looking at intrauterine insemination (IUI). The objective of our study was to compare fecundability following IUI by race/ethnicity, with a special focus on American Indians. METHODS: This was a retrospective analysis of subjects undergoing IUI July 2007—May 2012 at a university-based infertility clinic. The primary outcome was positive pregnancy test, with a secondary outcome of ongoing pregnancy/delivery (OP/D). We calculated risk ratios (RR) and 95% confidence intervals (CI) using cluster-weighted generalized estimating equations method to estimate modified Poisson regression models with robust standard errors to account for multiple IUI cycles in the same patient. RESULTS: A total of 663 females (median age 32) undergoing 2007 IUI cycles were included in the analysis. Pregnancy rates overall were 15% per IUI cycle. OP/D rates overall were 10% per IUI cycle. The American Indian patients had significantly lower pregnancy (RR 0.34, 95%CI 0.16–0.72) and OP/D rates (RR 0.33, 95%CI 0.12–0.87) compared to non-Hispanic whites when patient and cycle characteristics were controlled. Pregnancy and OP/D rates for blacks, Asians and Hispanics did not differ from non-Hispanic whites. CONCLUSIONS: Our finding of lower IUI treatment success among American Indian patients is novel, as no published studies of assisted reproductive technology or other fertility treatments have examined this subgroup separately. Further investigation of patient and clinical factors that may mediate racial/ethnic disparities in fertility treatment outcomes is warranted.

Objective To determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility. Design Multicenter, double-blind, randomized, placebo-controlled trial with an internal pilot study. Setting Nine fertility centers in the United States from December 2015 to December 2018. Patient(s) Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency. Intervention(s) Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l -carnitine, 20 mg of zinc, 1,000 μg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6. Main Outcome Measure(s) Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment. Result(s) In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median −4.0 [interquartile range−12.0, 5.7] million/mL) and placebo group (+2.4 [−9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%. Conclusion(s) Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates. Clinical Trial Registration Number NCT02421887

OBJECTIVE: To study whether preconceptual thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) antibodies are associated with poor reproductive outcomes in infertile women. DESIGN: Secondary analysis of data from two multicenter, randomized, controlled trials conducted by the Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Multivariable logistic regression analyses were performed to assess the association between preconceptual TSH levels and anti-TPO antibodies. SETTING: Not applicable. PATIENT(S): Serum samples from 1,468 infertile women were utilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception, clinical pregnancy, miscarriage, and live birth rates were calculated. RESULT(S): Conception, clinical pregnancy, miscarriage, and live birth rates did not differ between patients with TSH ≥2.5 mIU/L vs. TSH < 2.5 mIU/L. Women with anti-TPO antibodies had similar conception rates (33.3% vs. 36.3%) but higher miscarriage rates (43.9% vs. 25.3%) and lower live birth rates (17.1% vs. 25.4%) than those without anti-TPO antibodies. Adjusted, multivariable logistic regression models confirmed elevated odds of miscarriage (odds ratio 2.17, 95% confidence interval 1.12-4.22) and lower odds of live birth (oddr ratio 0.58, 95% confidence interval 0.35-0.96) in patients with anti-TPO antibodies. CONCLUSION(S): In infertile women, preconceptional TSH ≥2.5 mIU/L is not associated with adverse reproductive outcomes; however, anti-TPO antibodies are associated with increased risk of miscarriage and decreased probability of live birth. CLINICAL TRIAL REGISTRATION NUMBER: PPCOS II NCT00719186; AMIGOS NCT01044862.

The purpose of this systematic review is to evaluate if uterine myomas impact the likelihood of pregnancy and pregnancy loss, and if myomectomy influences pregnancy outcomes in asymptomatic women. There is insufficient evidence to conclude that the presence of myomas reduces the likelihood of achieving pregnancy. However, there is fair evidence that myomectomy (open or laparoscopic) for cavity-distorting myomas (intramural or intramural with a submucosal component) improves pregnancy rates and reduces the risk of early pregnancy loss. There is fair evidence that hysteroscopic myomectomy for cavity-distorting myomas improves clinical pregnancy rates but insufficient evidence regarding the impact of this procedure on the likelihood of live birth or early pregnancy loss. In women with asymptomatic cavity-distorting myomas, myomectomy may be considered to optimize pregnancy outcomes.

A systematic review of the literature was conducted which examined each of the major steps of embryo transfer. Recommendations made for improving pregnancy rates are based on interventions demonstrated to be either beneficial or not beneficial.

Standardization improves performance and safety. A template for standardizing the embryo transfer procedure is presented here with 12 basic steps supported by published scientific literature and a survey of common practice of SART programs; it can be used by ART practices to model their own standard protocol.

Background: Women in early gestation without a pregnancy visualized on ultrasound and serial hCG values consistent with a nonviable gestation are at high risk for ectopic pregnancy. The goal of this trial was to determine if active management is superior to expectant management, and if two active management strategies are non-inferior. Methods: This multi-center study, 255 women with a persistent pregnancy of unknown location were randomized to expectant management or active management in a 1:2 ratio, and 1:1 within active management to a) uterine evacuation followed by methotrexate if needed or b) empiric methotrexate. The primary outcome was successful resolution of the pregnancy without change from initial strategy. Findings: Women treated with active management had a significantly higher percentage of successful resolution, Rate ratio 1·43 (1·04–1·96) intention to treat (ITT) and 1·64 (1·39–1·94) as treated (AT) and a lower rate of unscheduled surgery RR 0·43 (0·25-0·74) ITT and 0·24 (0·11-0·55) AT. Methotrexate was non-inferior to uterine evacuation (difference=6·6% (-8.4% to 21.6%) ITT. As treated, time to resolution was 8·1 days shorter after uterine evacuation compared to methotrexate. All strategies were safe and were rated with high acceptability and satisfaction. Women expressed a preference for expectant management with differential cross-over within this trial. Interpretation: A greater percentage of women achieved uneventful resolution with active management compared to expectant management with at least a 50% reduction in unscheduled interventions. Uterine evacuation resulted in a shorter time to resolution. Acceptability and safety of treatment were high for all strategies, but subjects expressed a preference for expectant management. Trial Registration: The trial was performed under IND #56407 and clinical trial registration number NCT02152696. Funding Statement: This work was supported by the National Institutes of Health (NIH)/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Declaration of Interests: Dr. Barnhart reports consulting fees to Swiss Precision Diagnostics and Bayer. Dr. Hansen reports research grants from Roche Diagnostics and Ferring outside of the submitted work. Dr. Diamond reports institutional grants/contracts from Bayer, ObsEva, and AbbVie; serving as a member of the Board of Directors and a stockholder of Advanced Reproductive Care; and serving as a Consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices. Dr. Steiner reports consulting fees from Seikagaku and Prima-Temp. Dr. Cedars reports research funding from Ferring Pharmaceuticals outside of the submitted work. Dr. Wild reports Ablacare PCOS, Amgen Repatha in Pg and Partners Mass General Menopause Reviews, outside of the submitted work. Dr Hoeger reports consultation to Bayer and Ablacare and research funding from Abbvie. Dr. Krawetz reports a research grant from Merck outside of the submitted work. Dr. Santoro reports consulting for Ansh Lab, and is a Scientific Advisor to Astellas and Menogenix, Inc. Ethics Approval Statement: The protocol was approved by a National Institutes of Health appointed advisory board and a data and safety monitoring board. The University of Pennsylvania served as single IRB (IRB # 815013).

This document provides guidance, background, and tips on how to recognize quality trials and focuses on evaluating the validity, importance, and relevance of clinical trial results. This document replaces the document of the same name, last published in 2008 (Fertil Steril® 2008;90:S114–20).