An artificial intelligence approach for investigating multifactorial pain-related features of endometriosis.

Endometriosis is a debilitating, chronic disease that is estimated to affect 11% of reproductive-age women. Diagnosis of endometriosis is difficult with diagnostic delays of up to 12 years reported. These delays can negatively impact health and quality of life. Vague, nonspecific symptoms, like pain, with multiple differential diagnoses contribute to the difficulty of diagnosis. By investigating previously imprecise symptoms of pain, we sought to clarify distinct pain symptoms indicative of endometriosis, using an artificial intelligence-based approach. We used data from 473 women undergoing laparoscopy or laparotomy for a variety of surgical indications. Multiple anatomical pain locations were clustered based on the associations across samples to increase the power in the probability calculations. A Bayesian network was developed using pain-related features, subfertility, and diagnoses. Univariable and multivariable analyses were performed by querying the network for the relative risk of a postoperative diagnosis, given the presence of different symptoms. Performance and sensitivity analyses demonstrated the advantages of Bayesian network analysis over traditional statistical techniques. Clustering grouped the 155 anatomical sites of pain into 15 pain locations. After pruning, the final Bayesian network included 18 nodes. The presence of any pain-related feature increased the relative risk of endometriosis (p-value < 0.001). The constellation of chronic pelvic pain, subfertility, and dyspareunia resulted in the greatest increase in the relative risk of endometriosis. The performance and sensitivity analyses demonstrated that the Bayesian network could identify and analyze more significant associations with endometriosis than traditional statistical techniques. Pelvic pain, frequently associated with endometriosis, is a common and vague symptom. Our Bayesian network for the study of pain-related features of endometriosis revealed specific pain locations and pain types that potentially forecast the diagnosis of endometriosis.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Prospectively assessed perceived stress associated with early pregnancy losses among women with history of pregnancy loss.

STUDY QUESTION: What is the association between perceived stress during peri-conception and early pregnancy and pregnancy loss among women who have experienced a prior pregnancy loss? SUMMARY ANSWER: Daily perceived stress above the median is associated with over a 2-fold risk of early pregnancy loss among women who have experienced a prior loss. WHAT IS KNOWN ALREADY?: Women who have experienced a pregnancy loss may be more vulnerable to stress while trying to become pregnant again. While prior research has indicated a link between psychological stress and clinically confirmed miscarriages, research is lacking among a pre-conceptional cohort followed prospectively for the effects of perceived stress during early critical windows of pregnancy establishment on risk of both hCG-detected pregnancy losses and confirmed losses, while considering important time-varying confounders. STUDY DESIGN, SIZE, DURATION: Secondary data analysis of the EAGeR trial (2007-2011) among women with an hCG-detected pregnancy (n = 797 women). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women from four US clinical centers enrolled pre-conceptionally and were followed ≤6 cycles while attempting pregnancy and, as applicable, throughout pregnancy. Perceived stress was captured via daily diaries and end-of-month questionnaires. Main outcome measures include hCG-detected and clinically recognized pregnancy losses. MAIN RESULTS AND THE ROLE OF CHANCE: Among women who had an hCG-confirmed pregnancy, 188 pregnancies (23.6%) ended in loss. Women with high (>50th percentile) versus low (≤50th percentile) peri-implantation or early pregnancy weekly perceived stress had an elevated risk of experiencing any pregnancy loss (hazard ratio (HR): 1.69, 95% CI: 1.13, 2.54) or clinical loss (HR: 1.58, 95% CI: 0.96, 2.60), with higher risks observed for women experiencing an hCG-detected loss (HR: 2.16, 95% CI: 1.04, 4.46). Models accounted for women's age, BMI, employment, marital status, income, education, race, parity, prior losses, exercise and time-varying nausea/vomiting, caffeine, alcohol and smoking. LIMITATIONS, REASONS FOR CAUTION: We were limited in our ability to clearly identify the mechanisms of stress on pregnancy loss due to our sole reliance on self-reported perceived stress, and the lack of biomarkers of different pathways of stress. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insight on early pregnancy perceived stress and risk of pregnancy loss, most notably hCG-detected losses, among women with a history of a prior loss. Our study is an improvement over past studies in its ability to account for time-varying early pregnancy symptoms, such as nausea/vomiting, and lifestyle factors, such as caffeine, alcohol and smoking, which are also risk factors for psychological stress and pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S): This work 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 numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Additionally, K.C.S. was supported by the National Institute on Aging of the National Institutes of Health under Award Number K01AG058781. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: #NCT00467363.

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

BACKGROUND: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. OBJECTIVES: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. METHODS: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. RESULTS: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. CONCLUSIONS: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.

Overall and sex-specific risk factors for subjective cognitive decline: findings from the 2015-2018 Behavioral Risk Factor Surveillance System Survey.

BACKGROUND: Prior research indicates that at least 35% of Alzheimer's disease and related dementia risk may be amenable to prevention. Subjective cognitive decline is often the first indication of preclinical dementia, with the risk of subsequent Alzheimer's disease in such individuals being greater in women than men. We wished to understand how modifiable factors are associated with subjective cognitive decline, and whether differences exist by sex. METHODS: Data were collected from men and women (45 years and older) who completed the U.S. Behavioral Risk Factor Surveillance System Cognitive Decline Module (2015-2018), n = 216,838. We calculated population-attributable fractions for subjective cognitive decline, stratified by sex, of the following factors: limited education, deafness, social isolation, depression, smoking, physical inactivity, obesity, hypertension, and diabetes. Our models were adjusted for age, race, income, employment, marital and Veteran status, and accounted for communality among risk factors. RESULTS: The final study sample included more women (53.7%) than men, but both had a similar prevalence of subjective cognitive decline (10.6% of women versus 11.2% of men). Women and men had nearly equivalent overall population-attributable fractions to explain subjective cognitive decline (39.7% for women versus 41.3% for men). The top three contributing risk factors were social isolation, depression, and hypertension, which explained three-quarters of the overall population-attributable fraction. CONCLUSIONS: While we did not identify any differences in modifiable factors between men and women contributing to subjective cognitive decline, other factors including reproductive or endocrinological health history or biological factors that interact with sex to modify risk warrant further research.

How good are medical and death records for identifying dementia?

INTRODUCTION: Retrospective studies using administrative data may be an efficient way to assess risk factors for dementia if diagnostic accuracy is known. METHODS: Within-individual clinical diagnoses of Alzheimer's disease (AD) and all-cause dementia in ambulatory (outpatient) surgery, inpatient, Medicare administrative records and death certificates were compared with research diagnoses among participants of Cache County Study on Memory, Health, and Aging (CCSMHA) (1995-2008, N = 5092). RESULTS: Combining all sources of clinical health data increased sensitivity for identifying all-cause dementia (71%) and AD (48%), while maintaining relatively high specificity (81% and 93%, respectively). Medicare claims had the highest sensitivity for case identification (57% and 40%, respectively). DISCUSSION: Administrative health data may provide a less accurate method than a research evaluation for identifying individuals with dementing disease, but accuracy is improved by combining health data sources. Assessing all-cause dementia versus a specific cause of dementia such as AD will result in increased sensitivity, but at a cost to specificity.

Cervical mucus patterns and the fertile window in women without known subfertility: a pooled analysis of three cohorts.

STUDY QUESTION: What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? SUMMARY ANSWER: The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. WHAT IS KNOWN ALREADY: The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. STUDY DESIGN, SIZE, DURATION: This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. MAIN RESULTS AND THE ROLE OF CHANCE: The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. LIMITATIONS, REASONS FOR CAUTION: We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. STUDY FUNDING/COMPETING INTEREST(S): Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Opioid Misuse and Dependence Screening Practices Prior to Surgery.

BACKGROUND: A majority of surgical patients are prescribed opioids for pain management. Many patients have pre-existing chronic pain managed with opioids and/or opioid use disorders (OUDs), which can complicate perioperative management. Patients who use opioids prior to surgery are at increased risk of developing OUD after surgery. To date, no studies have examined the prevalence of opioid screening and electronic medical record (EMR) documentation prior to surgery. MATERIALS AND METHODS: A 40-item survey was administered to 268 patients at their first postoperative care visit at a single tertiary academic center from October 2017 to July 2018. A chart review of a random sample of 100 patients was performed to determine provider opioid screening prevalence in the presurgical setting. Log-binomial models were used to calculate prevalence ratios (PRs) to determine the provider role (surgeon, advanced practice clinicians [APC], surgical trainee) association with opioid screening documentation. Exploratory qualitative interviews were conducted with surgical providers to identify barriers to screening and screening documentation. RESULTS: Only 7% of patients were screened preoperatively for opioid use. A total of 38% of patients self-reported that they had used opioids in the past year. Of that group, only 3% had screening by a surgical provider prior to surgery documented in their EMR. Provider role was not associated with likelihood of opioid screening (surgeon versus trainee, PR = 1.2, 95% CI 0.2-8.5) (surgeons versus APCs, PR = 1.05, 95% CI 0.17-8.53). EMRs were discordant with patient survey results for patients with no ICD-10 codes for opioid use. The most common perceived barriers to preoperative screening were insufficient clinic time; logistics of who should screen/not required as part of their clinical workflow; not perceiving screening as a priority; and lack of expertise in the area of chronic opioid use and OUD. CONCLUSIONS: Preoperative screening for opioid use is uncommon, and EMRs are often discordant with patient self-reported use. Efforts to increase preoperative screening will need to address barriers screening practices and increasing health system support by incorporating screening into the clinical workflow and adding it to documentation templates.

Adiposity and Endometriosis Severity and Typology.

STUDY OBJECTIVE: Prior research has collectively shown that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN: Cross-sectional study among women with no prior diagnosis of endometriosis. SETTING: Fourteen clinical centers in Salt Lake City, UT, and San Francisco, CA. PATIENTS: A total of 495 women (of which 473 were analyzed), aged 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS: Gynecologic laparoscopy/laparotomy regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS: Participants underwent anthropometric assessments, body composition measurements, and evaluations of body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised American Society for Reproductive Medicine staging (I-IV) and typology of disease (superficial endometriosis [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation, were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. Although most confidence intervals were wide and overlapping, 3 general impressions emerged: (1) women with incident endometriosis had the lowest anthropometric/body composition indicators compared with those without incident endometriosis, (2) women with stage I or IV endometriosis had lower indicators compared with women with stage II or III, and (3) women with OE and/or DIE tended to have the lowest indicators, whereas women with SE had the highest indicators. CONCLUSION: Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.

The Baby-Friendly Hospital Initiative (BFHI): An Early Cross-Sectional Analysis of PRAMS Phase 8 Data on Hospital Practices and Breastfeeding Outcomes in Utah and Wyoming.

INTRODUCTION: Breastfeeding has immediate and long-term benefits for both maternal and child health. This study examines the association between Baby-Friendly Hospital Initiative (BFHI) experiences and breastfeeding outcomes in the Mountain West region. METHODS: A cross-sectional (retrospective secondary data analysis) was performed using the 2016 Pregnancy Risk Assessment Monitoring System (PRAMS) data. The participants were derived from a stratified random sample of 2,013 women living in Utah and Wyoming who recently had a live birth and who were surveyed on BFHI practices. The association between BFHI experiences and breastfeeding duration were assessed using crude and adjusted Poisson regression models, controlling for other BHFI experiences and maternal age, pre-pregnancy BMI, household income, smoking, alcohol, delivery method, and number of days spent in the hospital post delivery. RESULTS: 82.4% and 82.3% of women from Utah and Wyoming, respectively, reported breastfeeding for 2 months or longer. After controlling for other BFHI experiences and potential confounders, the one shared BFHI experience that was associated with breastfeeding for 2 months or longer vs less than 2 months was starting breastfeeding in the hospital (adjusted prevalence ratio [aPR]=1.49, 95% CI (1.12, 1.98) in Utah and aPR=2.03, 95% CI (1.13, 3.64) in Wyoming. Among women in Utah and Wyoming, only 5 of 7 BFHI steps were significant for breastfeeding duration in at least one state. CONCLUSION: There is substantial epidemiological support for health benefits to both mother and infant for exclusive breastfeeding to 6 months and prolonged breastfeeding until at least 1-year. Our findings suggest that women who initiate breastfeeding in the hospital may be more likely to breastfeed for a longer duration.

The influences of sleep duration, chronotype, and nightwork on the ovarian cycle.

Despite research indicating that sleep disorders influence reproductive health, the effects of sleep on reproductive hormone concentrations are poorly characterized. We prospectively followed 259 regularly menstruating women across one to two menstrual cycles (the BioCycle Study, 2005-2007), measuring fasting serum hormone concentrations up to eight times per cycle. Women provided information about daily sleep in diaries and chronotype and night/shift work on a baseline questionnaire. We evaluated percent differences in mean hormone concentrations, the magnitude of shifts in the timing and amplitude of hormone peaks, and the risk for sporadic anovulation associated with self-reported sleep patterns and night/shift work. We estimated chronotype scores - categorizing women below and above the interquartile range (IQR) as "morning" and "evening" chronotypes, respectively. For every hour increase in daily sleep duration, mean estradiol concentrations increased by 3.9% (95% confidence interval [CI] 2.0, 5.9%) and luteal phase progesterone by 9.4% (CI 4.0, 15.2%). Receiving less than 7 hours of sleep per day was associated with slightly earlier rises in peak levels for several hormones. Women reporting night/shift work (n = 77) had lower testosterone relative to women employed without night/shift work (percent difference: -9.9%, CI -18.4, -0.4%). Women with morning chronotypes (n = 47) had earlier rises in estradiol during their cycles and potentially an earlier rise in luteinizing hormone. Compared to those who had intermediate chronotypes, women with evening chronotypes (n = 42) had a later luteinizing hormone peak of borderline statistical significance. A reduced risk for sporadic anovulation was suggested, but imprecise, for increasing hours of daily sleep leading up to ovulation (risk ratio 0.79, CI 0.59, 1.06), while an imprecise increased risk was observed for women with morning chronotypes (risk ratio 2.50, CI 0.93, 6.77). Sleep-related hormonal changes may not greatly alter ovarian function in healthy women, but have the potential to influence gynecologic health.

Preconception Perceived Stress Is Associated with Reproductive Hormone Levels and Longer Time to Pregnancy.

BACKGROUND: Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. METHODS: One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. RESULTS: Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). CONCLUSION: Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.

Factors in the Hospital Experience Associated with Postpartum Breastfeeding Success.

Introduction: Hospitals are in a unique position to promote, protect, and support breastfeeding. However, the association between in-hospital events and breastfeeding success within population-based samples has not been well studied. Materials and Methods: A stratified (by education and birth weight) systematic sample of 5,770 mothers taking part in the Utah Pregnancy Risk Assessment Monitoring System, 2012-2015, were included. Mothers, 2-4 months postpartum, completed the 82-item questionnaire, including if they had ever breastfed their new baby, and if so, current breastfeeding status. Relationships between in-hospital experiences and breastfeeding termination and duration were evaluated via Poisson and Cox proportional hazard regression models, respectively, adjusting for other in-hospital experiences, maternal age, race/ethnicity, maternal education, marital status, smoking, physical activity, delivery method, pregnancy complications, and length of hospital stay. Results: Of all, 94.4% of mothers self-reported breastfeeding initiation, of whom 18.8% had breastfed <2 months, having breastfed on average 3.2 weeks (standard error: 0.07). In fully adjusted models, mothers who reported receiving a pacifier, receiving formula, or had staff help them learn how to breastfeed had a higher prevalence of terminating breastfeeding before 2 months (adjusted prevalence ratio [aPR] = 1.13, 95% confidence interval [CI]: 0.97-1.32; aPR = 1.20, 95% CI: 1.07-1.36; and aPR = 1.25, 95% CI: 1.08-1.34). Conversely, mothers who reported starting and feeding only breast milk in the hospital and receiving a phone number to call for help with breastfeeding had a lower prevalence of breastfeeding termination before 2 months (aPR = 0.72, 95% CI: 0.61-0.86; aPR = 0.57, 95% CI: 0.51-0.64; and aPR = 0.91, 95% CI: 0.80-1.03). Adjusted Cox models showed similar direction of associations. Conclusions: Encouraging mothers to exclusively breastfeed in the hospital, and reducing gift packs containing pacifiers and formula, may be key areas United States hospitals can focus on to increase breastfeeding success. Prospective assessment in other geographical regions is needed to corroborate these findings.

Modifiable life style factors and risk for incident endometriosis.

BACKGROUND: Caffeine, alcohol, smoking and physical activity are known to alter sex steroid synthesis, which may affect hormone-dependent gynaecologic disease risk, such as endometriosis; however, few studies have assessed life style factors prior to endometriosis diagnosis. METHODS: Four hundred and seventy three women, ages 18-44 years, underwent laparoscopy or laparotomy, regardless of clinical indication, at 14 clinic sites, 2007-2009. Women with prior surgically confirmed endometriosis were excluded. Life style factors were assessed prior to surgery. Adjusted risk ratios (RR) of endometriosis by caffeine, alcohol, smoking (serum cotinine), and physical activity were estimated, adjusting for age, marital status, education, race/ethnicity, age at menarche, gravidity, BMI, study site, and other life style factors. RESULTS: There were no associations between women with endometriosis and alcohol consumption (RR 0.9, 95% CI 0.7, 1.3), caffeine consumption (RR 1.1, 95% CI 0.8, 1.5), or smoking (serum cotinine <10 vs ≥10 ng/mL; RR 1.0, 95% CI 0.7, 1.6). Similar null findings were found between endometriosis and weekly occurrences of physical activity and total walking, moderate, and vigorous activity; a modest trend was found between total daily sitting time and increased endometriosis risk. CONCLUSIONS: This study, which is unique in its capture of life style exposures prior to incident endometriosis diagnosis, largely found no association between alcohol, caffeine, smoking, and physical activity and risk of endometriosis.

Dietary minerals, reproductive hormone levels and sporadic anovulation: associations in healthy women with regular menstrual cycles.

Although minerals are linked to several reproductive outcomes, it is unknown whether dietary minerals are associated with ovulatory function. We hypothesised that low intakes of minerals would be associated with an increased risk of anovulation. We investigated associations between dietary mineral intake and both reproductive hormones and anovulation in healthy women in the BioCycle Study, which prospectively followed up 259 regularly menstruating women aged 18-44 years who were not taking mineral supplements for two menstrual cycles. Intakes of ten selected minerals were assessed through 24-h dietary recalls at up to four times per cycle in each participant. Oestradiol, progesterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex-hormone-binding globulin and testosterone were measured in serum up to eight times per cycle. We used weighted linear mixed models to evaluate associations between minerals and hormones and generalised linear models for risk of anovulation. Compared with Na intake ≥1500 mg, Na intake <1500 mg was associated with higher levels of FSH (21·3 %; 95 % CI 7·5, 36·9) and LH (36·8 %; 95 % CI 16·5, 60·5) and lower levels of progesterone (-36·9 %; 95 % CI -56·5, -8·5). Na intake <1500 mg (risk ratio (RR) 2·70; 95 % CI 1·00, 7·31) and Mn intake <1·8 mg (RR 2·00; 95 % CI 1·02, 3·94) were associated with an increased risk of anovulation, compared with higher intakes, respectively. Other measured dietary minerals were not associated with ovulatory function. As essential minerals are mostly obtained via diet, our results comparing insufficient levels with sufficient levels highlight the need for future research on dietary nutrients and their associations with ovulatory cycles.

Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women.

STUDY QUESTION: How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? SUMMARY ANSWER: Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. WHAT IS KNOWN ALREADY: Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. MAIN RESULTS AND THE ROLE OF CHANCE: Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, REASONS FOR CAUTION: Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. WIDER IMPLICATIONS OF THE FINDINGS: If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. Study FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.

Women's Reproductive History Before the Diagnosis of Incident Endometriosis.

BACKGROUND: Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. MATERIALS AND METHODS: The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity. RESULTS: Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1. CONCLUSIONS: Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.

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.

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.

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.