Do state insurance mandates alter ICSI utilization?

BACKGROUND: Assisted reproductive technology (ART) insurance mandates resulted in improved access to infertility treatments like intracytoplasmic sperm injection (ICSI). Our objective was to examine whether ART insurance mandates demonstrate an increased association with ICSI use. METHODS: In this retrospective cohort study, clinic-specific data for 2000-2016 from the Centers for Disease Control (CDC) were grouped by state and subgrouped by the presence and extent of ART state insurance mandates. Mandated (n = 8) and non-mandated (n = 22) states were compared for ICSI use and male factor (MF) infertility in fresh non-donor ART cycles with a transfer in women < 35 years. Clinical pregnancy (CPR), live birth (LBR) rates, preimplantation genetic testing (PGT), elective single-embryo transfer (eSET) and twin birth rates per clinic were evaluated utilizing Welch's t-test. Pearson correlation was used to measure the strength of association between MF and ICSI; ICSI and CPR, and ICSI and LBR over time. Results were considered statistically significant at a p-value of < 0.05, with Bonferroni correction used for multiple comparisons. RESULTS: From 2000 to 2016, ICSI use per clinic increased in both mandated and non-mandated states. ICSI use per clinic in non-mandated states was significantly greater from 2011 to 2016 (p < 0.05, all years) than in mandated states. Clinics in mandated states had less MF (30.5 ± 15% vs 36.7 ± 15%; p < 0.001), lower CPR (39.8 ± 4% vs 43.4 ± 4%; p = 0.02) and lower LBR (33.9 ± 3.5% vs 37.9 ± 3.5%; p < 0.05). PGT rates were not significantly different. ICSI use in non-mandated states correlated with MF rates (r = 0.524, p = 0.03). A significant correlation between ICSI and CPR (r = 0.8, p < 0.001) and LBR (r = 0.7, p < 0.001) was noted in mandated states only. eSET rates were greater and twin rates were lower in mandated compared with non-mandated states. CONCLUSIONS: There was greater use of ICSI per clinic in non-mandated states, which correlated with an increased frequency of MF. In mandated states, lower ICSI rates per clinic were accompanied by a positive correlation with CPR and LBR, as well as a trend for greater eSET rates and lower twin rates, suggesting that state mandates for ART coverage may encourage more selective utilization of laboratory resources.

Preconception leptin levels and pregnancy outcomes: A prospective cohort study.

OBJECTIVE: Obesity has become a major, worldwide public health issue and is associated with a greater risk of adverse pregnancy outcomes. Leptin, a hormone produced by adipocytes, is elevated in individuals with obesity and may mediate the association between obesity and pregnancy outcomes. Though leptin levels during pregnancy have been associated with pregnancy outcomes, less is understood regarding preconception levels. Therefore, the objective of this study was to evaluate associations between preconception leptin levels and adverse pregnancy outcomes. METHODS: This was a prospective cohort study nested within a large randomized controlled trial conducted at four medical centres in the United States. A total of 1078 women completed the parent study; this analysis involved women who became pregnant during that study (n = 776). Patients were healthy women, ages 18 to 40, attempting to conceive, with 1 to 2 prior pregnancy losses. Participants were followed for less than or equal to 6 cycles while trying to conceive and throughout pregnancy if they conceived. Preconception leptin concentrations were measured in serum collected at baseline then categorized by tertiles (using the lowest as reference group). Weighted log-binomial regression estimated risk ratios (RR) and 95% confidence intervals (CIs) for pregnancy loss, preterm delivery (PTD), gestational diabetes (GDM), and hypertensive disorders in pregnancy, adjusting for age, waist-to-hip ratio (WHR), and body mass index (BMI). RESULTS: The mean (SD) BMI in this cohort was 25.4 ± 6.0. GDM (RR 18.37; 95% CI, 2.39-141.55) and hypertensive disorders of pregnancy (RR 2.35; 95% CI, 1.20-4.61) risks were higher among women in the high tertile after adjusting for age and WHR. The associated risk persisted when adjusting for BMI for GDM but was attenuated for hypertensive disorders in pregnancy. Leptin levels were not associated with risk of pregnancy loss or PTD. CONCLUSIONS: Women with higher baseline preconception leptin levels had a higher likelihood of experiencing some adverse pregnancy outcomes including GDM and hypertensive disorders of pregnancy. These findings warrant further evaluation, especially in light of the association between leptin and obesity.

Preconception Leptin and Fecundability, Pregnancy, and Live Birth Among Women With a History of Pregnancy Loss.

CONTEXT: With the increase of obesity, it is imperative to understand the neuroendocrine mechanisms, including the neuroendocrine hormone leptin, by which obese or overweight women are at increased risk for subfertility and infertility. OBJECTIVE: The objective was to examine associations between preconception serum leptin concentrations, fecundability, pregnancy, and live birth. DESIGN: Secondary analysis of a prospective cohort among women with prior pregnancy losses. SETTING: The study was conducted at four US medical centers (2006 to 2012). INTERVENTION: Not available. MATERIALS AND METHODS: Preconception serum leptin concentrations were measured at baseline, and women were followed for up to six menstrual cycles, and throughout pregnancy if they conceived. Discrete Cox proportional hazard regression models were used to assess fecundability odds ratios (FORs) and log-binomial regression to estimate risk ratios (RRs) for pregnancy and live birth. Models were adjusted for age, physical activity, treatment arm, and adiposity, either by measured waist-to-hip ratio or body mass index (BMI). RESULTS: High leptin concentrations were associated with decreased fecundability (FOR 0.72, 95% CI 0.58, 0.90), reduced risk of pregnancy (RR 0.87, 95% CI 0.78, 0.96) and live birth (RR 0.76, 95% CI 0.65, 0.89) comparing the upper to the lower tertile. However, adjustment for BMI in lieu of waist-to-hip ratio nullified observed associations. CONCLUSIONS: In women with a history of pregnancy loss, relations between higher preconception leptin and fecundability were attenuated after adjustment for BMI, although not after adjustment for other markers of adiposity. Leptin may serve as a complementary marker of adiposity for assessment of obesity and reproductive outcomes.

Does elevated progesterone on day of oocyte maturation play a role in the racial disparities in IVF outcomes?

The aim of this study was to evaluate if premature progesterone elevation on the last day of assisted reproduction technique stimulation contributes to racial disparities in IVF outcome. A total of 3289 assisted reproduction technique cycles were evaluated in Latino, Asian, African American, and white women. Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%), but was similar to Latino women (40.7%). In all racial groups, progesterone was negatively associated with live birth and the negative effect of progesterone persisted when adjusting for confounders. Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. Progesterone > 1.5 ng/ml occurred in only 10.6% of cycles in white women compared with 18.0% in Latino and 20.2% in Asian women. Progesterone > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino, 5.9% in Asian and 4.4% in African American women. The increased prevalence of premature elevated progesterone persisted when controlling for IVF stimulation parameters. In conclusion, premature progesterone elevation had a negative effect on live birth in all racial groups studied. The prevalence of elevated progesterone was higher in racial minorities.

Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study.

BACKGROUND: Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. OBJECTIVES: We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. DESIGN: Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. RESULTS: The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. CONCLUSION: Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.

Subclinical Hypothyroidism and Thyroid Autoimmunity Are Not Associated With Fecundity, Pregnancy Loss, or Live Birth.

CONTEXT: Prior studies examining associations between subclinical hypothyroidism and antithyroid antibodies with early pregnancy loss and live birth suggest mixed results and time to pregnancy (TTP) has not been studied in this patient population. OBJECTIVE: This study sought to examine associations of prepregnancy TSH concentrations and thyroid autoimmunity with TTP, pregnancy loss, and live birth among women with proven fecundity and a history of pregnancy loss. DESIGN AND SETTING: This was a prospective cohort study from a large, randomized controlled trial that took place at four medical centers in the United States. PATIENTS OR OTHER PARTICIPANTS: Healthy women, ages 18-40 y, who were actively attempting to conceive and had one or two prior pregnancy losses and no history of infertility were eligible for the study. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURE: TTP, pregnancy loss, and live birth. RESULTS: Women with TSH ≥ 2.5 mIU/L did not have an increased risk of pregnancy loss (risk ratio, 1.07; 95% confidence interval [CI], 0.81-1.41) or a decrease in live birth rate (risk ratio, 0.97; 95% CI, 0.88-1.07) or TTP (fecundability odds ratio, 1.09; 95% CI, 0.90-1.31) compared with women with TSH <2.5 mIU/L after adjustment for age and body mass index. Similar findings were observed for women with thyroid autoimmunity and after additional adjustment for treatment assignment. CONCLUSIONS: Among healthy fecund women with a history pregnancy loss, TSH levels ≥ 2.5 mIU/L or the presence of antithyroid antibodies were not associated with fecundity, pregnancy loss, or live birth. Thus, women with subclinical hypothyroidism or thyroid autoimmunity can be reassured that their chances of conceiving and achieving a live birth are likely unaffected by marginal thyroid dysfunction.

Complications and Safety of Preconception Low-Dose Aspirin Among Women With Prior Pregnancy Losses.

OBJECTIVE: To evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007-2011). METHODS: Evaluation of the safety of low-dose aspirin in the participants and their fetuses was a planned secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, a multicenter, block-randomized, double-blind, placebo-controlled trial investigating the effect of low-dose aspirin on the incidence of live birth. Women aged 18-40 years with a history of one to two pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for up to six menstrual cycles or through gestation if they became pregnant. Emergency care visits and possible aspirin-related symptoms were assessed at each study follow-up using standardized safety interviews. In addition, complications for both the participant and her fetus or neonate were captured prospectively using case report forms, interviews conducted during pregnancy and postpartum, and medical records. RESULTS: The proportion of women with at least one possible aspirin-related symptom during the trial was similar between treatment arms (456 [74%] low-dose aspirin compared with 447 [73%] placebo, P=.65) as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin compared with 99 [16%] placebo, P=.76). Maternal complications were evenly distributed by treatment arm with the exception of vaginal bleeding, which was more commonly reported in the low-dose aspirin arm (22% compared with 17%, P=.02). The distribution of fetal and neonatal complications-which included three stillbirths, three neonatal deaths, and 10 neonates with birth defect(s)-was similar between treatment arms. CONCLUSION: Although rare but serious complications resulting from low-dose aspirin cannot be ruled out, preconception low-dose aspirin appears to be well tolerated by women trying to conceive, women who become pregnant, and by their fetuses and neonates.

Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait.

OBJECTIVE: To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date. METHODS: In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18-40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy. RESULTS: Couples with a 0-3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30-2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates. CONCLUSION: Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss.

Dietary fat intake and reproductive hormone concentrations and ovulation in regularly menstruating women.

BACKGROUND: Emerging evidence suggests potential links between some dietary fatty acids and improved fertility, because specific fatty acids may affect prostaglandin synthesis and steroidogenesis. OBJECTIVE: The objective of this exploratory study was to evaluate associations between total and specific types of dietary fat intake and 1) hormone concentrations and 2) the risk of sporadic anovulation in a cohort of 259 regularly menstruating women in the BioCycle Study. DESIGN: Endogenous reproductive hormones were measured up to 8 times/cycle for up to 2 cycles, with visits scheduled with the use of fertility monitors. Dietary intake was assessed with up to four 24-h recalls/cycle. Linear mixed models and generalized linear models were used to evaluate the associations between dietary fatty acids and both reproductive hormone concentrations and ovulatory status. All models were adjusted for total energy intake, age, body mass index, and race. RESULTS: Relative to the lowest levels of percentage of energy from total fat, the highest tertile was associated with increased total and free testosterone concentrations (total: percentage change of 4.0%; 95% CI: 0.7%, 7.3%; free: percentage change of 4.1%; 95% CI: 0.5%, 7.7%). In particular, the percentage of energy from polyunsaturated fatty acids (PUFAs) in the highest tertile was associated with increases in total and free testosterone (total: percentage change of 3.7%; 95% CI: 0.6%, 6.8%; free: percentage change of 4.0%; 95% CI: 0.5%, 7.5%). The PUFA docosapentaenoic acid (22:5n-3) was not significantly associated with testosterone concentrations (P-trend = 0.86 in energy substitution models) but was associated with increased progesterone and a reduced risk of anovulation (highest tertile compared with the lowest tertile: RR: 0.42; 95% CI: 0.18, 0.95). Fat intakes were not associated with other reproductive hormone concentrations. CONCLUSIONS: These results indicate that total fat intake, and PUFA intake in particular, is associated with very small increases in testosterone concentrations in healthy women and that increased docosapentaenoic acid was associated with a lower risk of anovulation.

Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss.

STUDY QUESTION: What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses? SUMMARY ANSWER: Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses. WHAT IS KNOWN ALREADY: LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses. STUDY DESIGN, SIZE, DURATION: The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses. PARTICIPANTS, SETTING, METHODS: Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach. MAIN RESULTS AND THE ROLE OF CHANCE: Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26). LIMITATIONS, REASONS FOR CAUTION: Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered at ClinicalTrials.gov #NCT00467363. TRIAL REGISTRATION DATE: 27 April 2007. DATE OF FIRST PATIENT'S ENROLLMENT: 15 June 2007.

Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women.

BACKGROUND: Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. OBJECTIVE: The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. METHODS: The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and ß-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. RESULTS: Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). CONCLUSIONS: These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.

Antimüllerian hormone and pregnancy loss from the Effects of Aspirin in Gestation and Reproduction trial.

OBJECTIVE: To evaluate if antimüllerian hormone (AMH) is associated with pregnancy loss. DESIGN: Prospective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin. SETTING: Not applicable. PATIENT(S): Women (n = 1,228) were of ages 18-40 years with a history of one to two pregnancy losses and were actively attempting pregnancy without fertility treatment. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Pregnancy loss. RESULT(S): Relative risks (and 95% confidence interval [CIs]) of human chorionic gonadotropin (hCG)-detected and clinical pregnancy loss were assessed with the use of log binomial models with robust variance and inverse probability weights adjusted for age, race, body mass index, income, trial treatment assignment, parity, number of previous losses, and time since most recent loss. AMH levels were defined as: low (<1.00 ng/mL; n = 124), normal (referent; 1.00-3.5 ng/mL; n = 595), and high (>3.5 ng/mL; n = 483). Of the 1,202 women with baseline AMH data, 19 (17.3%) with low AMH experienced a clinical loss, compared with 61 (11.4%) with normal AMH and 50 (11.8%) with high AMH levels. Low or high AMH levels, compared with normal AMH, were not associated with clinical loss. Results for hCG-detected pregnancy loss mirrored those of clinical loss. CONCLUSION(S): AMH values were not associated with hCG-detected or clinical pregnancy loss in unassisted conceptions in women with a history of one to two previous losses. Our data do not support routine AMH testing for prediction of pregnancy loss. CLINICAL TRIAL REGISTRATION NUMBER: NCT00467363.

Gynecologic health and disease in relation to the microbiome of the female reproductive tract.

It is well established that the vagina is colonized by bacteria that serve important roles in homeostasis. Imbalances in the proportion of bacteria may lead to a predisposition to infection or reproductive complications. Molecular-based approaches demonstrated a greater degree of microbial diversity both within and between women than previously recognized. The vaginal microbiome may fluctuate during various states of health, such as during the menstrual cycle or after menopause, and there may be differences in the vaginal microbiome between women of different ethnicities. Furthermore, the specific composition of the vaginal microbiome may influence the predisposition to dysbiosis and the transmission of sexually transmitted infections. An understanding of the diversity of the vaginal microbial environment during states of health is essential for the identification of risk factors for disease and the development of appropriate treatment.

Is Anti-Müllerian Hormone Associated With Fecundability? Findings From the EAGeR Trial.

OBJECTIVE: The objective of the study was to evaluate whether anti-Müllerian hormone (AMH) is associated with fecundability among women with proven fecundity and a history of pregnancy loss. DESIGN: This was a prospective cohort study within a multicenter, block-randomized, double-blind, placebo-controlled clinical trial ( clinicaltrials.gov , number NCT00467363). SETTING: The study was conducted at four US medical centers (2006-2012). PARTICIPANTS: Participating women were aged 18-40 years, with a history of one to two pregnancy losses who were actively attempting pregnancy. MAIN OUTCOME MEASURES: Time to human chorionic gonadotropin detected and clinical pregnancy were assessed using Cox proportional hazard regression models to estimate fecundability odds ratios (fecundability odds ratios with 95% confidence interval [CI]) adjusted for age, race, body mass index, income, low-dose aspirin treatment, parity, number of previous losses, and time since most recent loss. Analyses examined by preconception AMH levels: low (<1.00 ng/mL, n = 124); normal (referent 1.00-3.5 ng/mL, n = 595); and high (>3.5 ng/mL, n = 483). RESULTS: Of the 1202 women with baseline AMH levels, 82 women with low AMH (66.1%) achieved an human chorionic gonadotropin detected pregnancy, compared with 383 with normal AMH (65.2%) and 315 with high AMH level (65.2%). Low or high AMH levels relative to normal AMH (referent) were not associated with fecundability (low AMH: fecundability odds ratios 1.13, 95% CI 0.85-1.49; high AMH: FOR 1.04, 95% CI 0.87-1.24). CONCLUSIONS: Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women.

Alcohol intake, reproductive hormones, and menstrual cycle function: a prospective cohort study.

BACKGROUND: Although habitual low-to-moderate alcohol intake has been linked with reduced all-cause mortality and morbidity, the effect of recent alcohol intake on female reproductive function has not been clearly established. OBJECTIVE: We assessed the relation between acute alcohol consumption, reproductive hormones, and markers of menstrual cycle dysfunction including sporadic anovulation, irregular cycle length, luteal phase deficiency, long menses, and heavy blood loss. DESIGN: A total of 259 healthy, premenopausal women from Western New York were followed for ≤2 menstrual cycles (2005-2007) and provided fasting blood specimens during ≤8 visits/cycle and four 24-h dietary recalls/cycle. Linear mixed models were used to estimate associations between previous day's alcohol intake and hormone concentrations, whereas Poisson regression was used to assess RR of cycle-average alcohol intake and menstrual cycle function. RESULTS: For every alcoholic drink consumed, the geometric mean total and free estradiol, total and free testosterone, and luteinizing hormone were higher by 5.26% (95% CI: 1.27%, 9.41%), 5.82% (95% CI: 1.81%, 9.99%), 1.56% (95% CI: 0.23%, 2.90%), 1.42% (95% CI: 0.02%, 2.84%), and 6.18% (95% CI: 2.02%, 10.52%), respectively, after adjustment for age, race, percentage of body fat, perceived stress, pain-medication use, sexual activity, caffeine, and sleep. Binge compared with nonbinge drinking (defined as reporting ≥4 compared with <4 drinks/d, respectively) was associated with 64.35% (95% CI: 18.09%, 128.71%) and 63.53% (95% CI: 17.41%, 127.73%) higher total and free estradiol. No statistically significant associations were shown between cycle-average alcohol intake and menstrual cycle function. CONCLUSION: Although recent moderate alcohol intake does not appear to have adverse short-term effects on menstrual cycle function, including sporadic anovulation, potential protective and deleterious long-term effects of alterations in reproductive hormones on other chronic diseases warrant additional investigation.

Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss.

BACKGROUND: Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA. METHODS: Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation. RESULTS: Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results. CONCLUSION: Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos. TRIAL REGISTRATION: ClinicalTrials.gov NCT00467363. FUNDING: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

Dietary Carbohydrate Intake Does Not Impact Insulin Resistance or Androgens in Healthy, Eumenorrheic Women.

CONTEXT: Diet is proposed to contribute to androgen-related reproductive dysfunction. OBJECTIVE: This study evaluated the association between dietary macronutrient intake, carbohydrate fraction intake, and overall diet quality on androgens and related hormones, including anti-Müllerian hormone (AMH) and insulin, in healthy, regularly menstruating women. DESIGN: This was a prospective cohort study from 2005 and 2007. SETTING: The study was conducted at the University at Buffalo, western New York State, USA. PARTICIPANTS: Participants were 259 eumenorrheic women without a self-reported history of infertility, polycystic ovary syndrome (PCOS), or other endocrine disorder. MAIN OUTCOME MEASURES: A 24-hour dietary recall was administered 4 times per menstrual cycle, and hormones were measured 5 to 8 times per cycle for 1 (n = 9) or 2 (n = 250) cycles per woman (n = 509 cycles). Associations between the dietary intake of carbohydrates (starch, sugar, sucrose, and fiber), macronutrients, overall diet quality and hormones (insulin, AMH, and total and free testosterone), as well as the relationship of dietary intake with occurrences of high total testosterone combined with high AMH (fourth quartile of each), ie, the "PCOS-like phenotype," were assessed. RESULTS: No significant relationships were identified between dietary intake of carbohydrates, percent calories from any macronutrient or overall diet quality (ie, Mediterranean diet score) and relevant hormones (insulin, AMH, and total and free testosterone). Likewise, no significant relationships were identified between dietary factors and the occurrence of a subclinical PCOS-like phenotype. CONCLUSIONS: Despite evidence of a subclinical continuum of a PCOS-related phenotype of elevated androgens and AMH related to sporadic anovulation identified in previous studies, dietary carbohydrate and diet quality do not appear to relate to these subclinical endocrine characteristics in women without overt PCOS.

Dietary factors and luteal phase deficiency in healthy eumenorrheic women.

STUDY QUESTION: Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? SUMMARY ANSWER: Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. WHAT IS KNOWN ALREADY: LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN RESULTS AND THE ROLE OF CHANCE: LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with LPD: fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, REASONS FOR CAUTION: The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.

Preconception low dose aspirin and time to pregnancy: findings from the effects of aspirin in gestation and reproduction randomized trial.

OBJECTIVE: The objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss. DESIGN: This was a multicenter, block-randomized, double-blind, placebo-controlled trial. Participants were block-randomized by center and eligibility stratum. SETTING: The study was conducted at four U.S.A. medical centers (2007-2012). PARTICIPANTS: Participants women aged 18-40 years actively attempting pregnancy, stratified by eligibility criteria: the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss. INTERVENTION: Daily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy. MAIN OUTCOME MEASURE: Time to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured. RESULTS: Of the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (FOR: 1.28; 95%CI: 1.02, 1.62). CONCLUSIONS: Preconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss.

Gonadotropin surge-inhibiting/attenuating factors: a review of current evidence, potential applications, and future directions for research.

Animal studies in the 1980s suggested the existence of an ovarian hormone, termed gonadotropin surge-inhibiting/attenuating factor (GnSIF/AF), that modulates pituitary secretion of luteinizing hormone (LH). Given the importance of identifying regulatory factors of the hypothalamic-pituitary-ovarian axis and the accumulating data suggesting its existence, we conducted a comprehensive literature search using PubMed, Web of Science, Scopus, and Embase to identify articles related to GnSIF/AF. The search generated 161 publications, of which 97 were included in this study. Several attempts have been made to identify and characterize this hormone and several candidates have been identified, but the protein sequences of these putative GnSIF/AF factors differ widely from one study to another. In addition, while the RF-amide RFRP-3 is known foremost as a neuropeptide, some research supports an ovarian origin for this non-steroidal hormone, thereby suggesting a role for RFRP-3 either as a co-modulator of GnSIF/AF or as a gonadotropin-inhibiting factor in the hypothalamus (GnIH). Discovery of the KNDy neurons that modulate GnRH secretion, on the other hand, further encourages the search for substance(s) that modulate their activity and that indirectly affect LH secretion and the hypothalamic-pituitary-ovarian axis. While it has remained an elusive hormone, GnSIF/AF holds many potential applications for contraception, in vitro fertilization, and/or cancer as well as for understanding polycystic ovary syndrome, metabolic diseases, and/or pubertal development. In this review, we rigorously examine the available evidence regarding the existence of GnSIF/AF, previous attempts at its identification, limitations to its discovery, future directions of research, and potential clinical applications.