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. ((C) 2019 by American Society for Reproductive Medicine.)

Objective: To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. Design: Secondary analysis of randomized trials. Setting: Multicenter fertility trial sites. Patient(s): A total of 900 women with UI and 750 women with PCOS. Main Outcome Measure(s): Live birth. Intervention(s): Weight assessment at enrollment and start of up to 4-5 cycles of clomiphene, letrozole, or gonadotropins and intrauterine insemination for women with UI and clomiphene or letrozole with regular intercourse for women with PCOS. Result(s): Weight data were available for 856 women with UI and 697 women with PCOS. Mean weight change was -0.2 +/- 0.3 kg among women with UI and +2.2 +/- 0.2 kg among women with PCOS and did not differ based on treatment allocation. There were 115 women with PCOS (16.4%) who gained >= 3 kg. Increased body mass index and three or more cycles were associated with weight gain in women with PCOS. There was no difference in live birth rate among women with PCOS and >= 3 kg weight gain and women with PCOS who did not gain weight. Conclusion(s): Women with PCOS gained an average of 2.2 kg regardless of the medication received, whereas women with UI experienced no short-term weight change during ovulation induction. Weight gain in women with PCOS was not associated with live birth rate. ((C) 2020 by American Society for Reproductive Medicine.)

STUDY QUESTION Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER Patient 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 KNOWN We 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, DURATION This 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, METHODS AMIGOS 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 CHANCE After 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 CAUTION This 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 FINDINGS Most 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 NUMBER n/a.

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: A total of 868 couples with unexplained infertility (n=2,459 cycles). Interventions: OS-IUI treatment cycles (n= 2,459) as part of the AMIGOS clinical trial. Main Outcome Measures: Live birth rates; 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 human chorionic gonadotropin administration in cycles with a live birth was significantly greater than in those without. Compared to the referent EMT group of 9 to 12 mm, the unadjusted RR for live birth for the EMT groups of <= 5 and 6-8 were 0.48 and 0.92, respectively. The test for trend indicated evidence of decreasing LBR with decreasing EMT. After adjustment for ovarian stimulation medication, a linear trend was no longer supported. Stratified analyses revealed no differences in associations by treatment group. Conclusions: In OS-IUl 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 EMT, even those of <= 5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium. (C) 2020 by American Society for Reproductive Medicine.

Objective: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. Design: Prospective cohort study. Setting: U.S. academic health centers. Patient(s): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). Intervention(s): Longitudinal annual follow-up from birth to age 3. Main Outcome Measure(s): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. Result(s): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. Conclusion(s): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates. (C) 2020 by American Society for Reproductive Medicine.

BACKGROUNDPolycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine.OBJECTIVE AND RATIONALEWe aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics.SEARCH METHODSWe searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs.OUTCOMESIPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06).WIDER IMPLICATIONSIn women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

Objective: To determine whether men with unexplained infertility and low total T (TT) have abnormal spermatogenesis and lower fecundity. Design: Secondary analysis of the prospective, randomized, multicenter clinical trial, Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). Setting: Infertility clinics. Patient(s): Nine hundred couples with unexplained infertility enrolled in AMIGOS. Semen analysis with an ejaculate of at least 5 million total motile sperm was required for enrollment. For inclusion in this secondary analysis, a fasting TT was required. Intervention(s): None. Main Outcome Measure(s): Logistic regression, adjusted for age and body mass index, assessed the association between low TT (defined as <264 ng/dL), semen parameters, and pregnancy outcome. Result(s): Seven hundred eighty-one men (mean age, 34.2 +/- 5.7 years) with a median (interquartile range) TT of 411 (318-520) ng/dL were included. Men with TT <264 ng/dL were less likely to have normal (>= 4% strict Kruger) morphology (unadjusted odds ratio [OR], 0.56; 95% confidence interval [CI], 0.34, 0.92; adjusted OR, 0.59; 95% CI, 0.35, 0.99). There was no association between low TT and semen volume < 1.5 mL, sperm concentration < 15 x 10(6)/mL, or motility < 40%. Among couples whose male partner had low TT, 21 (18.8%) had a live birth, compared with 184 (27.5%) live births in couples with a male partner having TT > 264 ng/dL. The odds of live birth decreased by 40% in couples whose male partner had low TT (unadjusted OR, 0.60; 95% CI, 0.36, 1.00; adjusted OR, 0.65; 95% CI, 0.38, 1.12). Conclusion(s): In couples with unexplained infertility, low TT in the male partner was associated with abnormal sperm morphology and lower live birth rates. ((C) 2019 by American Society for Reproductive Medicine.)

Objective: To study whether there is a difference in the prevalence of non-cavity-distorting uterine fibroids between infertile patients with polycystic ovary syndrome (PCOS) and those with unexplained infertility (UI). Design: A secondary analysis of data from three randomized clinical trials. Setting: Academic health centers. Patient(s): A total of 2,249 patients with normal uterine cavities. Interventions(s): None. Main Outcome Measure(s): The presence or absence of non-cavity-distorting fibroids. Result(s): Compared with women with UI, those with PCOS were younger, had a higher body mass index, and were more likely to be Hispanic or African American, with a lower percentage of previous conception and live birth, a higher percentage of current smokers, a lower percentage of current alcohol users, and higher total testosterone, fasting insulin, and homeostasis-model-assessment insulin resistance. The prevalence of women with non-cavity-distorting uterine fibroids was lower in women with PCOS than in those with UI (6.7% vs. 12.4%); this result held after patients were divided into Black and non-Black or into three different body mass index groups. After adjustment for all the other variables in the final model, patients with PCOS had a significantly lower prevalence of fibroids than those with UI (odds ratio 0.54). No differences in the prevalence of non-cavity-distorting fibroids with any dimensions >= 4 cm or the volume of the largest fibroid was found between the two groups. Conclusion(s): A lower prevalence of non-cavity-distorting uterine fibroids was found in infertile women with PCOS than in those with UI. ((C) 2019 by American Society for Reproductive Medicine.)

Context:Women with polycystic ovary syndrome (PCOS) have increased risk for pregnancy complications, possibly related to pre-existing obesity and excessive gestational weight gain (GWG). Objectives:To assess the contributions of diagnosis and preconception weight on GWG and perinatal outcomes. Research Design and Methods:Prospective cohort study of singleton pregnancies in PCOS (n = 164) and ovulatory controls (n = 176) from infertility treatment. Main Outcome Measures:GWG, birthweight, pregnancy complications. Results:From preconception baseline, normal-weight women with PCOS gained 2.3 pounds more during the first trimester (95% CI, 0.3 to 4.3; P = 0.02), and by the end of the second trimester, 4.2 pounds more than controls (95% CI, 0.7 to 7.7; P = 0.02). Women who were overweight with PCOS gained significantly more weight than did controls by the end of the second trimester (5.2 pounds; 95% CI, 0.2 to 10.2; P = 0.04), whereas women with obesity and PCOS and control women had similar weight gain throughout pregnancy. Within normal-weight, overweight, and obese groups, prevalence of pre-eclampsia and gestational diabetes did not differ between the PCOS and control groups, nor was there a difference in birthweight. Preconception body mass index (BMI) was significantly associated with GWG; for every 1-kg/m2 increase in preconception BMI, GWG decreased by 0.62 pounds (95% CI, -0.85 to -0.40; P < 0.001). Conclusions:Women with PCOS who are of normal weight or are overweight before conception experience more GWG than do ovulatory controls. Within normal-weight, overweight, and obese groups, rates of perinatal complications do not significantly differ between women with PCOS and controls. Preconception BMI is the strongest predictor of GWG.

Objective: To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments. Design: Cohort study. Setting: Clinics. Patient(s): Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility). Intervention(s): Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score R10 was used to define currently active MD. Main Outcome Measure(s): Primary outcome: live birth. Secondary outcomes: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS). Result(s): Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception. Conclusion(s): Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant. (C) 2018 by American Society for Reproductive Medicine.

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.

PURPOSEWe sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction.MATERIALS AND METHODSThis study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity.RESULTSA total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77).CONCLUSIONSIn men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

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.

To compare saline infusion sonohysterography (SIS) versus hysterosalpingogram (HSG) for confirmation of tubal patency.

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. (C)2017 by American Society for Reproductive Medicine.

Context: The impact of vitamin D deficiency on the success of ovarian stimulation according to underlying infertility diagnosis has not been investigated. Objective: To evaluate the relationship between vitamin D deficiency and reproductive outcomes after ovarian stimulation in women with either polycystic ovary syndrome (PCOS) or unexplained infertility. Design: Retrospective cohort study. Setting: Analysis of randomized controlled trial (RCT) data. Participants: Participants from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) RCT (n = 607); participants from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) RCT of unexplained infertility (n = 647). Interventions: Serum 25(OH)D levels measured in banked sera. Main Outcome Measures: Primary: live birth; secondary: ovulation (PPCOS II), pregnancy, and early pregnancy loss. Results: In PPCOS II, subjects with vitamin D deficiency [25(OH)D < 20 ng/mL or 50 nmol/L] were less likely to ovulate (adjusted OR, 0.82; 95% CI, 0.68 to 0.99; P = 0.04) and experienced a 40% lower chance of live birth (adjusted OR, 0.63; 95% CI, 0.41 to 0.98; P = 0.04) than those not deficient. In AMIGOS, no significant association between vitamin D deficiency and live birth was noted. In pregnant subjects from both studies, vitamin D deficiency was associated with elevated risk of early pregnancy loss (OR, 1.6; 95% CI, 1.0 to 2.6; P = 0.05). Conclusions: In this investigation of women pursuing ovarian stimulation, the association between vitamin D deficiency and diminished live birth relied on carrying the diagnosis of PCOS and was not observed in unexplained infertility. Given the generally modest success of ovarian stimulation, addressing vitamin D deficiency may prove an important treatment adjunct for many infertile women.

Objective: To investigate the association of non-cavity-distorting uterine fibroids and pregnancy outcomes after ovarian stimulation intrauterine insemination (OS-IUI) in couples with unexplained infertility.Design: Secondary analysis from a prospective, randomized, multicenter clinical trial investigating fertility outcomes after OS-IUI.Setting: Reproductive Medicine Network clinical sites.Patient(s): Nine hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial.Intervention(s): Participants were randomized to one of three arms (clomiphene citrate, letrozole, or gonadotropins), and treatment was continued for up to four cycles or until pregnancy was achieved.Main Outcomes Measure(s): Conception (serum hCG increase), clinical pregnancy (fetal cardiac activity), and live birth rates.Result(s): A total of 102/900 participants (11.3%) had at least one documented fibroid and a normal uterine cavity. Women with fibroids were older, more likely to be African American, had a greater uterine volume, lower serum antimiillerian hormone levels, and fewer antral follicles than women without fibroids. In conception cycles, clinical pregnancy rates were significantly lower in participants with fibroids than in those without uterine fibroids. Pregnancy loss before 12 weeks was more likely in African American women with fibroids compared with non-African American women with fibroids. There was no difference in conception and live birth rates in subjects with and without fibroids.Conclusion(s): No differences were observed in conception and live birth rates in women with non-cavity-distorting fibroids and those without fibroids. These findings provide reassurance that pregnancy success is not impacted in couples with non-cavity-distorting fibroids undergoing OS-IUI for unexplained infertility.

Systematic reviews and some recent studies have suggested that anxiety plays a role in reducing chances of becoming pregnant1, although the literature is not yet settled. The primary goal of this study was to further explore trait anxiety as a predictor of fertility treatment outcome in patients seeking treatment at an academic reproductive clinic serving a rural population in the northeastern United States. This is a prospective cross-sectional study. Anxiety symptomology was assessed through self-report using the Brief Symptom Inventory (BSI) subscales Phobic Anxiety (PA, e.g., "Feeling uneasy in crowds, such as shopping or at a movie"), Anxiety (A, e.g., "Feeling tense or keyed up"), and Obsessive-Compulsive (OC, e.g., "Having to check and double-check what you do"). Fertility treatments are defined as ovulation induction and IVF. Fertility treatment outcomes (i.e., positive pregnancy test at two weeks following intervention) were obtained through medical chart review. Thirty-three women were recruited and assessed during their first appointment to the clinic. After controlling for age, body mass index (BMI), and insurance coverage for reproductive care, anxiety symptomology significantly predicted fertility treatment outcomes. This model explained a significant proportion of variance in outcomes, R2 = .42, F(2 , 26) = 3.17, p =.018. All three anxiety subscales - PA (β = -.75, p = .001); A (β = .79, p = .01); OC (β = -.47, p = .05) had a negative predictive value for a successful treatment. More broad analyses of clusters of symptomology underlying anxiety disorders, demonstrate that an increase in anxiety symptoms, specifically phobic and obsessive-compulsive symptomology, is related to a decrease in pregnancy rates following fertility treatment. Results of this study further support the body of research that trait anxiety plays a predictive role in the outcome of fertility treatment and suggest that identifying and treating anxiety in patients undergoing fertility treatment could improve outcomes. In addition to improving fertility treatment outcomes, early screening and intervention for anxiety could also benefit more long term outcomes such as maternal well-being and birth outcomes.

In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes.