Systemic inflammation and menstrual cycle length in a prospective cohort study.

BACKGROUND: Local inflammation plays an important role in normal folliculogenesis and ovulation, and conditions of chronic systemic inflammation, such as obesity and polycystic ovarian syndrome, can disrupt normal follicular dynamics. OBJECTIVE: This study aimed to determine the association between systemic inflammation, as measured by C-reactive protein levels, and menstrual cycle length. STUDY DESIGN: This study was a secondary analysis using data from Time to Conceive, a prospective time-to-pregnancy cohort study. The association between cycle length and C-reactive protein was analyzed using multivariable linear mixed and marginal models adjusted for age, race, education, body mass index, time since oral contraceptive use, alcohol, smoking, caffeine consumption, and exercise. Time to Conceive enrolled women aged 30 to 44 years with no history of infertility who were attempting to conceive for <3 months. Serum C-reactive protein levels were measured on cycle day 2, 3, or 4. Participants recorded daily menstrual cycle data for ≤4 months. RESULTS: Main outcome measures included menstrual cycle length and follicular and luteal phase lengths. Multivariable analysis included 1409 cycles from 414 women. There was no linear association between C-reactive protein levels and menstrual cycle length. However, compared with <1 mg/L, a C-reactive protein level >10 mg/L was associated with >3 times the odds (adjusted odds ratio, 3.7; 95% confidence interval, 1.67-8.11) of long cycles (defined as ≥35 days). When evaluating follicular phase length, a C-reactive protein level of >10 mg/L was associated both with follicular phases that were 1.7 (95% confidence interval, 0.23-3.09) days longer and with >2 times the odds of a long follicular phase (adjusted odds ratio, 2.2; 95% confidence interval, 1.05-4.74). CONCLUSION: There is a potential pathophysiological association between systemic inflammation and menstrual cycle changes. Further studies are needed to determine if systemic inflammation alters the menstrual cycle or if long menstrual cycles are a marker for elevated systemic inflammation.

Association between donor gamete use and supernumerary embryo disposition decisions.

PURPOSE: The aim of this study is to determine if donor gamete use is associated with patients' decisions regarding disposition of supernumerary embryos. METHODS: Patients who intended to undergo an IVF cycle at a single academic center signed an embryo disposition consent form to indicate their disposition preferences for any supernumerary embryos. A retrospective chart review was performed to obtain the embryo disposition declarations and demographic information. The primary outcome was the distribution of embryo disposition choices between patients who used donor gametes compared to patients who did not use donor gametes. Fisher's exact test was used to compare groups. Logistic regression models were created to determine the association between donor gamete use and disposition decision after adjusting for patient age, body mass index, and nulliparity. RESULTS: Five hundred six patients were included. Ninety-one (18.0%) patients used donor gametes [46 (9.0%) donor oocytes, 52 (10.3%) donor sperm]. Patients using donor gametes differed from those not using donor gametes when making decisions concerning death of the patient (P < 0.01), simultaneous death (P = 0.04), separation (P < 0.01), discontinuation of ART (P = 0.01), and time-limited storage (P < 0.01). Most patients, regardless of donor or autologous gamete use, awarded embryos to themselves or their partner if given the option. For patients who did not choose this option, excess embryos were generally awarded to research or discarded rather than donating to another couple. Patients using donor gametes were more likely to award embryos to research over discarding. CONCLUSION: Patients using donor gametes made different choices regarding supernumerary embryo disposition compared to patients not using donor gametes.

Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial.

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.

Inflammation and Conception in a Prospective Time-to-Pregnancy Cohort.

BACKGROUND: Inflammation may contribute to subfertility but this has not been well-explored in large prospective cohort studies. METHODS: We conducted a prospective 12-month cohort study of time to pregnancy in North Carolina, the Time to Conceive study (2010-2016). Participants were 30-44 years old, without a history of infertility (N = 727). We analyzed blood samples with a high sensitivity assay for C-reactive protein (CRP). Women reported their weight, height, and other covariates. We natural log-transformed CRP and examined it (1) linearly, after exploration using restricted cubic splines and (2) in categories based on American Heart Association criteria. We estimated fecundability ratios (FRs) with log-binomial discrete-time-to-pregnancy models. Separate models included an interaction term with body mass index (BMI). RESULTS: The adjusted estimated FR per natural log-unit increase in CRP level was 0.97 (confidence interval [CI] = 0.91, 1.0). The FR (CI) for high CRP (>10 mg/L) compared with low CRP (<1 mg/L) was 0.78 (0.52, 1.2). Compared with normal-weight women with low CRP, women with obesity and high CRP had lower estimated fecundability, but the confidence interval was wide (FR = 0.63; CI = 0.35, 1.1). There was no pattern in the estimated fecundability across levels of CRP within categories of BMI. CONCLUSIONS: There was no evidence of an association between CRP and fecundability either alone or within levels of BMI. Further studies of CRP and fecundability should include higher levels of CRP and additional markers of inflammation.

The relationship of plasma antioxidant levels to semen parameters: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial.

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.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

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.

Serum omega-3 and omega-6 fatty acid concentrations and natural fertility.

STUDY QUESTION: Are serum omega-3 and omega-6 essential fatty acid concentrations associated with the probability of conceiving? SUMMARY ANSWER: There is no strong association between serum concentrations of omega-3 and omega-6 fatty acids and the probability of conceiving naturally. WHAT IS KNOWN ALREADY: Omega-3 and omega-6 fatty acid serum concentrations have been shown to play an important role in reproduction in animal models, while conflicting results have been reported in human studies of infertile women. It is unknown to what extent omega fatty acid serum concentrations impact natural fertility. STUDY DESIGN, SIZE, DURATION: A nested, case-control study was conducted consisting of 200 participants [fertile: conceived within 3 cycles of attempt (n = 50), subfertile: conceived within 4 and 12 cycles of attempt (n = 100) and infertile: did not conceive within 12 cycles of attempt (n = 50)] randomly selected from the Time to Conceive cohort, a prospective time-to-pregnancy study (2008 to 2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the Time to Conceive study, women aged 30-44 years who were trying to conceive for <3 months and had no history of infertility were recruited and followed until the end of their pregnancy or ~1 year of pregnancy attempt. For this study, serum collected early in the woman's pregnancy attempt was analysed for anti-Müllerian hormone (AMH) and omega-3 and omega-6 fatty acid concentrations by liquid chromatography-mass spectrometry. The primary outcome was a positive home pregnancy test. The secondary outcomes were miscarriage and serum AMH level. A discrete-time Cox proportional hazards model was used to estimate the fecundability ratio. The odds ratios for miscarriage were calculated using logistic regression. The association between serum omega fatty acid concentrations and AMH level (natural log transformed) was analysed using Pearson's Correlation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 200 women provided 1321 cycles for analysis.Mean omega-3, omega-6 and omega-6:omega-3 ratios did not significantly differ between the fertile, subfertile and infertile groups. There were no associations (all fecundability ratios ~1.0) between pregnancy and individual omega-3 fatty acid concentrations, including alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid, or omega-6 fatty acids, including linoleic acid (LA), dihommo-gamma linolenic acid and arachidonic acid. There was no significant association between any individual omega fatty acid serum concentration and the age-adjusted odds of miscarriage. No association was found between any serum omega fatty acid concentration and AMH. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the sample size. Omega-3 and omega-6 fatty acid concentrations were derived from serum provided at a single timepoint in the first cycle of enrollment. Serum concentrations may therefore not be representative of all critical timepoints in the menstrual cycle or throughout their attempts to conceive. Additionally, women enrolled in this study were 30 years of age and older, and therefore the findings may not apply to younger women. WIDER IMPLICATIONS OF THE FINDINGS: These data would suggest that omega-3 and omega-6 serum levels are not associated with natural fertility or risk of miscarriage. However, due to the above-mentioned limitations, future investigation is still needed to determine whether omega-3 fatty acid supplementation may benefit women planning to conceive naturally. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Division of Reproductive Endocrinology and Infertility at the University of North Carolina at Chapel Hill, by the NIH/NICHD (R21 HD060229-01 and R01 HD067683-01) and, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES103333). Dr. Jukic received vitamin D supplements for a research study from Theralogix, Inc. The authors have no other conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Analgesic use at ovulation and implantation and human fertility.

BACKGROUND: Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability. OBJECTIVE: The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle. STUDY DESIGN: We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids. RESULTS: Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability. CONCLUSION: Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: We 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 METHODS: This 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. RESULTS: A 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). CONCLUSIONS: In 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.

The efficiency of single institutional review board review in National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network-initiated clinical trials.

BACKGROUND/AIMS: Timely review of research protocols by institutional review boards leads to more rapid initiation of clinical trials, which is critical to expeditious translation from bench to bedside. This observational study examined the impact of a single institutional review board on time and efforts required to initiate clinical trials by the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. METHODS: Collection of data from the same six main clinical sites for three current clinical trials and two past clinical trials, including time from institutional review board submission to approval, pages submitted, consent form length, number of required attachments, other regulatory requirements, order of review at central or local sites, and language in documents at individual participating sites. Results from two past clinical trials were also included. RESULTS: While time required for actual institutional review board submission's review and initial approval was reduced with use of a single institutional review board for multicenter trials (from a mean of 66.7-24.0 days), total time was increased (to a mean of 111.2 or 123.3 days). In addition to single institutional review board approval, all institutions required local approval of some components (commonly consent language and use of local language), which varied considerably. The single institutional review board relied on local institutions for adding or removing personnel, conflict of interest review, and auditing of activities. CONCLUSION: A single institutional review board reduced time for initial review and approval of protocols and informed consents, although time for the entire process was increased, as individual institutions retained oversight of components of required regulatory review. In order to best achieve the National Institute of Health's goals for improved efficiency in initiation and conduct of multisite clinical research, greater coordination with local institutional review boards is key to streamlining and accelerating initiation of multisite clinical research.

25-Hydroxyvitamin D and Long Menstrual Cycles in a Prospective Cohort Study.

BACKGROUND: Vitamin D insufficiency is associated with subfertility and prolonged estrus cycles in animals, but humans have not been well studied. METHODS: A prospective time-to-pregnancy study, Time to Conceive (2010-2015), collected up to 4 months of daily diary data. Participants were healthy, late reproductive-aged women in North Carolina who were attempting pregnancy. We examined menstrual cycle length as a continuous variable and in categories: long (35+ days) and short (≤25 days). Follicular phase length and luteal phase length were categorized as long (18+ days) or short (≤10 days). We estimated associations between those lengths and serum 25-hydroxyvitamin D (25[OH]D) using linear mixed models and marginal models. RESULTS: There were 1,278 menstrual cycles from 446 women of whom 5% were vitamin D deficient (25[OH]D, <20 ng/ml), 69% were between 20 and 39 ng/ml, and 26% were 40 ng/ml or higher. There was a dose-response association between vitamin D levels and cycle length. Compared with the highest 25(OH)D level (≥40 ng/ml), 25(OH)D deficiency was associated with almost three times the odds of long cycles (adjusted odds ratio [aOR] = 2.8 [95% confidence interval (CI) = 1.0, 7.5]). The aOR was 1.9 (1.1, 3.5) for 20 to <30 ng/ml. The probability of a long follicular phase and the probability of a short luteal phase both increased with decreasing 25(OH)D. CONCLUSIONS: Lower levels of 25(OH)D are associated with longer follicular phase and an overall longer menstrual cycle. Our results are consistent with other evidence supporting vitamin D's role in the reproductive axis, which may have broader implications for reproductive success.

Anti-Müllerian hormone levels and incidence of early natural menopause in a prospective study.

STUDY QUESTION: Are anti-Müllerian hormone (AMH) levels assessed in women aged 32-44 associated with risk of incident early natural menopause? SUMMARY ANSWER: We observed strong, significant associations between lower AMH levels and higher risk of early menopause. WHAT IS KNOWN ALREADY: The ability to predict risk early menopause, defined as menopause before age 45, prior to fertility decline would improve options for family planning and cardiovascular disease prevention. Though AMH is an established marker of menopause timing in older reproductive-aged women, whether AMH is associated with risk of early menopause has not been evaluated. STUDY DESIGN, SIZE, DURATION: We assessed these relations in a nested case-control study within the prospective Nurses' Health Study II cohort. Premenopausal blood samples were collected in 1996-1999. Participants were followed until 2011 for early natural menopause, with follow-up rates >94%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Early menopause cases (n = 327) were women reporting natural menopause between blood collection and age 45. Controls (n = 491) experienced menopause after age 45 and included 327 cases matched to controls on the basis of age at blood draw (±4 months) and other factors. AMH levels up to 12 years before early menopause were assayed in 2016. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/ml decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). In polynomial regression models including linear and quadratic terms for AMH, odds ratios for early menopause for women with AMH levels of 1.5, 1.0 and 0.5 ng/ml compared to 2.0 ng/ml were 2.6, 7.5 and 23 (all P < 0.001). Significant associations were observed irrespective of smoking status, adiposity, infertility history and menstrual cycle characteristics. Furthermore, models assessing the predictive ability of AMH showed high concordance, and C-statistics were high, ranging from 0.68 (age ≤35) to 0.93 (age 42). LIMITATIONS, REASONS FOR CAUTION: Our population was relatively homogenous with respect to race/ethnicity. Further work in more ethnically diverse populations is needed. WIDE IMPLICATION OF THE FINDINGS: To our knowledge, this is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by UM1CA176726, R01CA67262, and R01HD078517 from the U.S. Department of Health and Human Services, National Institutes of Health. No competing interests declared.

Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age.

Importance: Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective: To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants: Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures: Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures: The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results: A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

The effect of antidepressants on fertility.

BACKGROUND: Information on the effects of different pharmaceuticals on fertility is sparse. Human and animal models indicate that antidepressant use could have a negative effect on fertility through alteration of levels of the neurosteroid, allopregnanolone. OBJECTIVE: The objective of this study is to assess the effects of antidepressants on the natural fertility in women. STUDY DESIGN: A secondary analysis of data from Time to Conceive, a prospective cohort study, was conducted. Women ages 30 to 44 years without a history of infertility, early in their attempts to conceive, were followed with standardized pregnancy testing until pregnancy was detected. Medication use was assessed at enrollment, daily for up to 4 months, and then monthly. For this analysis, discrete time regression models were created to calculate the association between antidepressant use and fecundability. Potential confounders-age, body mass index, caffeine, alcohol use, and education-were included in all models. RESULTS: Ninety-two (9.6%) of 957 women reported antidepressant use while attempting to conceive. Women taking antidepressants were more likely to be non-Hispanic Caucasian (91% vs 75%, P < .01) and to consume alcoholic beverages (74% vs 61%, P < .01). Antidepressant use at enrollment had an adjusted fecundability ratio (FR) of 0.86 (95% confidence interval [CI], 0.63-1.20). However, time-varying analyses suggested that antidepressant use in a given cycle is associated with a reduced probability of conceiving in that cycle (adjusted FR, 0.75; 95% CI, 0.53-1.06). After adjusting for history of depression or restricting the analysis to women who reported a history of depression, the association between antidepressant use and decreased fecundability remained [adjusted FR, 0.66 (95% CI, 0.45-0.97) and (adjusted FR, 0.64; 95% CI, 0.43-0.94), respectively]. CONCLUSION: Our data suggest that antidepressants may reduce the probability of a woman with a history of depression to conceive naturally. Future studies are needed to differentiate the extent to which this association is due to the antidepressant itself versus the underlying depression.

Anti-Müllerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa.

BACKGROUND: Few data exist regarding anti-Müllerian hormone, a marker of ovarian reserve, in relation to environmental factors with potential ovarian toxicity. METHODS: This analysis included 420 women from Limpopo, South Africa studied in 2010-2011. Women were administered comprehensive questionnaires, and plasma concentrations of anti-Müllerian hormone and dichlorodiphenyltrichloroethane were determined. We used separate multivariable models to examine the associations between natural log-transformed anti-Müllerian hormone concentration (ng/ml) and each of the lifestyle, reproductive, and environmental factors of interest, adjusted for age, body mass index, education, and parity. RESULTS: The median age of women was 24 years (interquartile range [IQR] = 22 to 26); the median anti-Müllerian hormone concentration was 3.1 ng/ml (IQR = 2.0 to 6.0). Women who reported indoor residual spraying in homes with painted walls (indicative of exposure to pyrethroids) had 25% lower (95% confidence interval [CI] = -39%, -8%) anti-Müllerian hormone concentrations compared with women who reported no spraying. Little evidence of decreased anti-Müllerian hormone concentrations was observed among women with the highest dichlorodiphenyltrichloroethane levels. Compared with women who used an electric stove, no association was observed among women who cooked indoors over open wood fires. The findings also suggested lower anti-Müllerian hormone concentrations among women who drank coffee (-19% [95% CI = -31%, -5%]) or alcohol (-21% [95% CI = -36%, -3%]). CONCLUSIONS: These are among the first data regarding anti-Müllerian hormone concentrations relative to pesticides and indoor air pollution. Our results are suggestive of decreased ovarian reserve associated with exposure to pyrethroid pesticides, which is consistent with laboratory animal data.

Lower plasma 25-hydroxyvitamin D is associated with irregular menstrual cycles in a cross-sectional study.

BACKGROUND: In animals, low levels of vitamin D are associated with estrus cycle disturbances, but there are virtually no human data. We examined the association of 25-hydroxyvitamin D (25(OH)D) (a biomarker for vitamin D status) with menstrual cycle characteristics. METHODS: Women aged 35-44 were randomly selected from a Washington D.C. health plan and invited to participate in the Uterine Fibroid Study (1996-1999). Our analysis includes 636 women (57% were African-American) who provided a blood sample and completed a telephone interview that included gynecologic history. Women were asked their usual cycle length in the preceding year. Women who reported it was "too irregular to estimate" were classified as having irregular cycles (N=48). Women were excluded if they currently or recently used hormonal contraception or any other medication that influences menstrual cycles. 25(OH)D was measured by radioimmunoassay in stored plasma samples. RESULTS: The median 25(OH)D level was 12.0 ng/mL (interquartile range: 7.6, 19.7 ng/mL). After controlling for age, race, BMI, education, age of menarche, current smoking, alcohol use, and physical activity, a decrease in 25(OH)D of 10 ng/mL was associated with 1.9 times the odds of irregular cycles (Odds ratio (OR) (95% confidence interval (CI)): 1.9 (1.0, 3.4), p=0.04). 25(OH)D was not associated with the occurrence of short cycles (OR(CI): 1.08 (0.79, 1.48, p=0.6) or long cycles (OR(CI): 1.31 (0.66, 2.60), p=0.4). CONCLUSIONS: Lower levels of 25(OH)D were associated with irregular cycles, but not with short or long cycles. Vitamin D may play a role in regulating ovulatory function. Further investigation of potential mechanisms is warranted.

Effect of vaginal lubricants on natural fertility.

PURPOSE OF REVIEW: Vaginal lubricants are commonly utilized to facilitate more comfortable and enjoyable intercourse. The impact of these lubricants on fertility is unclear. The aim of this review is to summarize the current in-vitro and clinical data pertaining to lubricants' effect on natural conception. RECENT FINDINGS: In-vitro studies suggest lubricants can be toxic to sperm in the artificial laboratory environment. Lubricants formulated to be nontoxic to sperm have no effect on sperm motility or viability in vitro compared to controls. However, a recent longitudinal cohort study suggests lubricant use and choice has no effect of fecundity. SUMMARY: As a result of the conflicting in-vitro and clinical data, the effect of vaginal lubricants on fertility is still unresolved. A randomized controlled trial is needed to determine the effects of vaginal lubricants on fertility.

Markers of ovarian reserve as predictors of future fertility.

OBJECTIVE: To determine the association between ovarian reserve biomarkers and future fertility among late reproductive-age women. DESIGN: Cohort study of participants enrolled in Time to Conceive (TTC), a time-to-pregnancy cohort study of the ovarian reserve biomarkers. SETTING: Community. PATIENT(S): Women aged 30-44 years without a history of infertility who provided a blood sample at enrollment in TTC and who agreed to future follow-up. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The primary outcomes were probability of achieving a live birth >3 years after enrollment in TTC, diagnosis of infertility at any time, and time-to-pregnancy in future pregnancy attempts. RESULT(S): Women with diminished ovarian reserve, defined as those with an antimüllerian hormone (AMH) level <0.7 ng/mL or follicle-stimulating hormone (FSH) level ≥10 mIU/mL, did not have low risk of future live birth (relative risk [RR], 1.32; 95% confidence interval [CI], 0.95-1.83 and RR, 1.28; 95% CI, 0.97-1.70, respectively) compared with women with normal ovarian reserve after adjusting for age at blood draw, race, obesity, use of hormonal contraception, and year of enrollment in original study. Among women in the cohort that attempted to conceive, there was not a significant association between diminished ovarian reserve, as measured by AMH or FSH, and risk of future infertility (RR, 0.65; 95% CI, 0.21-2.07 and RR,1.69; 95% CI, 0.86-3.31, respectively). Similarly, there was no association between AMH and FSH levels and future fecundability (fecundability ratio, 0.97; 95% CI, 0.59, 1.60; and fecundability ration, 0.86; 95% CI, 0.55-1.36, respectively). CONCLUSION: Diminished ovarian reserve is not associated with reduced future reproductive capacity. Given the lack of association, women should be cautioned regarding use biomarkers of ovarian reserve as predictors of their future reproductive capacity.