Preconception sleep duration, non-daytime work schedules, and incidence of spontaneous abortion: a prospective cohort study.

STUDY QUESTION: To what extent do self-reported sleep duration and non-daytime work schedules in either partner affect the rate of spontaneous abortion (SAB)? SUMMARY ANSWER: Incidence of SAB had little association with female sleep duration and a modest positive association with male short sleep duration, female work at night, and discrepant work schedules among partners. WHAT IS KNOWN ALREADY: Several studies have reported an association between short sleep duration in either partner and reproductive health outcomes, including fecundability. Moreover, certain types of female occupational exposures during pregnancy have been associated with an increased risk of SAB. No studies have evaluated SAB risk in relation to male sleep and work schedules, or joint exposures within a couple. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9357 female participants and 2602 of their male partners residing in North America (June 2013 to April 2023). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants enrolled when they were attempting pregnancy and completed self-administered baseline questionnaires about their average sleep duration and work schedules. Among those who conceived, we ascertained SAB and gestational age at loss via follow-up questionnaires. We used multivariable Cox proportional hazards models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% CIs relating SAB with sleep duration and non-daytime work schedules for female and male participants, and the couple. We used inverse probability weighting to account for potential selection bias due to the possibility of differential participation of male partners with respect to the exposures. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to female participants with recommended sleep (7-8.9 h), those reporting short sleep duration (<6 h) did not have a higher rate of SAB (HR 0.88, 95% CI 0.69, 1.13). Short self-reported sleep duration among male participants was modestly associated with a higher rate of SAB (adjusted and weighted HR 1.30, 95% CI 0.96, 1.75). Female night work at night (adjusted HR 1.19, 95% CI 1.02, 1.38) and male non-daytime work (adjusted and weighted HR 1.26, 95% CI 1.00, 1.59) were associated with modestly higher rates of SAB, whereas female rotating shift work was not (adjusted HR 0.91, 0.78, 1.05) compared with daytime workers. Couples in which work schedules were discrepant had an elevated rate of SAB if the male partner worked a non-daytime shift (adjusted and weighted HR 1.46, 95% CI 1.13, 1.88) compared with couples in which both members worked during the day. The corresponding HR if only the female partner worked a non-daytime shift was 1.21 (95% CI 0.92, 1.58). LIMITATIONS, REASONS FOR CAUTION: Data on sleep duration and work schedules were based on self-report, which is vulnerable to misclassification, particularly since participants were asked to report their average sleep duration during the past month. Work exposures were heterogeneous, as many different types of employment may require night and shift work and may have different associations with SAB. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with previous research indicating that some types of female employment schedules may be associated with SAB incidence. This is the first study to indicate a relationship between SAB and male employment schedules, indicating that discrepant work schedules within a couple might be relevant. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01HD105863 (PIs: L.A.W. and M.L.E.), R01HD086742 (PIs: L.A.W. and E.E.H.), and R21HD072326 (PI: L.A.W.). PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a consultant for AbbVie, Inc. and the Gates Foundation. M.L.E. is an advisor for and holds stock in Ro, Hannah, Dadi, Underdog, Vseat, & Doveras. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Quantitative Assessment of Systematic Bias: A Guide for Researchers.

Observational research provides valuable opportunities to advance oral health science but is limited by vulnerabilities to systematic bias, including unmeasured confounding, errors in variable measurement, or bias in the creation of study populations and/or analytic samples. The potential influence of systematic biases on observed results is often only briefly mentioned among the discussion of limitations of a given study, despite existing methods that support detailed assessments of their potential effects. Quantitative bias analysis is a set of methodological techniques that, when applied to observational data, can provide important context to aid in the interpretation and integration of observational research findings into the broader body of oral health research. Specifically, these methods were developed to provide quantitative estimates of the potential magnitude and direction of the influence of systematic biases on observed results. We aim to encourage and facilitate the broad adoption of quantitative bias analyses into observational oral health research. To this end, we provide an overview of quantitative bias analysis techniques, including a step-by-step implementation guide. We also provide a detailed appendix that guides readers through an applied example using real data obtained from a prospective observational cohort study of preconception periodontitis in relation to time to pregnancy. Quantitative bias analysis methods are available to all investigators. When appropriately applied to observational studies, findings from such studies can have a greater impact in the broader research context.

Self-reported periodontitis and fecundability in a population of pregnancy planners.

STUDY QUESTION: Is a history of periodontitis among women associated with reduced fecundability? SUMMARY ANSWER: A history of periodontitis, as assessed by three different self-reported measures, may be associated with reduced fecundability. WHAT IS KNOWN ALREADY: Periodontitis is a chronic inflammatory condition affecting the hard and soft tissues surrounding the teeth. Few studies have evaluated the association between periodontitis and time to pregnancy, and findings are mixed. It is hypothesized that periodontitis may adversely affect time to pregnancy. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of 2764 female pregnancy planners residing in North America (March 2015-June 2020). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible participants had been attempting pregnancy for six or fewer menstrual cycles at enrollment and were not using fertility treatment. Women answered questions about their oral health. Pregnancy was ascertained via bi-monthly follow-up questionnaires. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs) for three different measures indicative of a history of periodontitis: ever diagnosed with periodontitis (N = 265), ever received treatment for periodontitis (N = 299), and ever had an adult tooth become loose on its own (N = 83). We adjusted for potential confounders and precision variables. Women at risk of misclassification of periodontitis diagnosis due to pregnancy-related gingivitis were reclassified in a sensitivity analysis. MAIN RESULTS AND THE ROLE OF CHANCE: All three indices of periodontitis may be associated with reduced fecundability. FRs were 0.89 (95% CI 0.75-1.06) comparing women with and without a previous periodontitis diagnosis, 0.79 (95% CI 0.67-0.94) comparing women with and without previous periodontitis treatment, and 0.71 (95% CI 0.44-1.16) comparing women with and without a tooth that became loose. After reclassification of pregnancy-related gingivitis in the sensitivity analysis, the FR for periodontitis diagnosis was 0.83 (95% CI 0.68-1.00). Weaker FRs were observed among parous women as compared with nulliparous women for periodontitis diagnosis and tooth becoming loose, but not for periodontitis treatment. LIMITATIONS, REASONS FOR CAUTION: Though we used validated self-report measures of periodontitis, clinical confirmation is the gold standard. These questions may be functioning as markers of different levels of periodontitis severity, but we were unable to measure disease severity in this population. Finally, we cannot eliminate the possibility of unmeasured confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the first preconception prospective cohort study to evaluate the association between self-reported periodontitis and fecundability. Our results indicate that periodontitis may be associated with lower fecundability. STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by R01HD086742/Eunice Kennedy Shriver National Institute of Child Health and Human Development and R21HD072326/Eunice Kennedy Shriver National Institute of Child Health and Human Development. PRESTO has received in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, FertilityFriend.com, and Kindara.com for primary data collection. L.A.W. is a fibroid consultant for AbbVie, Inc. J.C.B., S.W., J.Y., K.J.R., E.E.H., and B.H. have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Male cellular telephone exposure, fecundability, and semen quality: results from two preconception cohort studies.

STUDY QUESTION: To what extent is exposure to cellular telephones associated with male fertility? SUMMARY ANSWER: Overall, we found little association between carrying a cell phone in the front pants pocket and male fertility, although among leaner men (BMI <25 kg/m2), carrying a cell phone in the front pants pocket was associated with lower fecundability. WHAT IS KNOWN ALREADY: Some studies have indicated that cell phone use is associated with poor semen quality, but the results are conflicting. STUDY DESIGN, SIZE, DURATION: Two prospective preconception cohort studies were conducted with men in Denmark (n = 751) and in North America (n = 2349), enrolled and followed via the internet from 2012 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: On the baseline questionnaire, males reported their hours/day of carrying a cell phone in different body locations. We ascertained time to pregnancy via bi-monthly follow-up questionnaires completed by the female partner for up to 12 months or until reported conception. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs) for the association between male cell phone habits and fecundability, focusing on front pants pocket exposure, within each cohort separately and pooling across the cohorts using a fixed-effect meta-analysis. In a subset of participants, we examined selected semen parameters (semen volume, sperm concentration and sperm motility) using a home-based semen testing kit. MAIN RESULTS AND THE ROLE OF CHANCE: There was little overall association between carrying a cell phone in a front pants pocket and fecundability: the FR for any front pants pocket exposure versus none was 0.94 (95% CI: 0.0.83-1.05). We observed an inverse association between any front pants pocket exposure and fecundability among men whose BMI was <25 kg/m2 (FR = 0.72, 95% CI: 0.59-0.88) but little association among men whose BMI was ≥25 kg/m2 (FR = 1.05, 95% CI: 0.90-1.22). There were few consistent associations between cell phone exposure and semen volume, sperm concentration, or sperm motility. LIMITATIONS, REASONS FOR CAUTION: Exposure to radiofrequency radiation from cell phones is subject to considerable non-differential misclassification, which would tend to attenuate the estimates for dichotomous comparisons and extreme exposure categories (e.g. exposure 8 vs. 0 h/day). Residual confounding by occupation or other unknown or poorly measured factors may also have affected the results. WIDER IMPLICATIONS OF THE FINDINGS: Overall, there was little association between carrying one's phone in the front pants pocket and fecundability. There was a moderate inverse association between front pants pocket cell phone exposure and fecundability among men with BMI <25 kg/m2, but not among men with BMI ≥25 kg/m2. Although several previous studies have indicated associations between cell phone exposure and lower sperm motility, we found few consistent associations with any semen quality parameters. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Institutes of Health, grant number R03HD090315. In the last 3 years, PRESTO has received in-kind donations from Sandstone Diagnostics (for semen kits), Swiss Precision Diagnostics (home pregnancy tests), Kindara.com (fertility app), and FertilityFriend.com (fertility app). Dr. L.A.W. is a fibroid consultant for AbbVie, Inc. Dr. H.T.S. reports that the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to and administered by Aarhus University. None of these studies are related to the current study. Dr. M.L.E. is an advisor to Sandstone Diagnostics, Ro, Dadi, Hannah, and Underdog. Dr. G.J.S. holds ownership in Sandstone Diagnostics Inc., developers of the Trak Male Fertility Testing System. In addition, Dr. G.J.S. has a patent pending related to Trak Male Fertility Testing System issued. TRIAL REGISTRATION NUMBER: N/A.

Validity of self-reported endometriosis: a comparison across four cohorts.

STUDY QUESTION: How accurately do women report a diagnosis of endometriosis on self-administered questionnaires? SUMMARY ANSWER: Based on the analysis of four international cohorts, women self-report endometriosis fairly accurately with a > 70% confirmation for clinical and surgical records. WHAT IS KNOWN ALREADY: The study of complex diseases requires large, diverse population-based samples, and endometriosis is no exception. Due to the difficulty of obtaining medical records for a condition that may have been diagnosed years earlier and for which there is no standardized documentation, reliance on self-report is necessary. Only a few studies have assessed the validity of self-reported endometriosis compared with medical records, with the observed confirmation ranging from 32% to 89%. STUDY DESIGN, SIZE, DURATION: We compared questionnaire-reported endometriosis with medical record notation among participants from the Black Women's Health Study (BWHS; 1995-2013), Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N; 1990-2006), Growing Up Today Study (GUTS; 2005-2016), and Nurses' Health Study II (NHSII; 1989-1993 first wave, 1995-2007 second wave). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants who had reported endometriosis on self-administered questionnaires gave permission to procure and review their clinical, surgical, and pathology medical records, yielding records for 827 women: 225 (BWHS), 168 (E3N), 85 (GUTS), 132 (NHSII first wave), and 217 (NHSII second wave). We abstracted diagnosis confirmation as well as American Fertility Society (AFS) or revised American Society of Reproductive Medicine (rASRM) stage and visualized macro-presentation (e.g. superficial peritoneal, deep endometriosis, endometrioma). For each cohort, we calculated clinical reference to endometriosis, and surgical- and pathologic-confirmation proportions. MAIN RESULTS AND THE ROLE OF CHANCE: Confirmation was high-84% overall when combining clinical, surgical, and pathology records (ranging from 72% for BWHS to 95% for GUTS), suggesting that women accurately report if they are told by a physician that they have endometriosis. Among women with self-reported laparoscopic confirmation of their endometriosis diagnosis, confirmation of medical records was extremely high (97% overall, ranging from 95% for NHSII second wave to 100% for NHSII first wave). Importantly, only 42% of medical records included pathology reports, among which histologic confirmation ranged from 76% (GUTS) to 100% (NHSII first wave). Documentation of visualized endometriosis presentation was often absent, and details recorded were inconsistent. AFS or rASRM stage was documented in 44% of NHSII first wave, 13% of NHSII second wave, and 24% of GUTS surgical records. The presence/absence of deep endometriosis was rarely noted in the medical records. LIMITATIONS, REASONS FOR CAUTION: Medical record abstraction was conducted separately by cohort-specific investigators, potentially introducing misclassification due to variation in abstraction protocols and interpretation. Additionally, information on the presence/absence of AFS/rASRM stage, deep endometriosis, and histologic findings were not available for all four cohort studies. WIDER IMPLICATIONS OF THE FINDINGS: Variation in access to care and differences in disease phenotypes and risk factor distributions among patients with endometriosis necessitates the use of large, diverse population samples to subdivide patients for risk factor, treatment response and discovery of long-term outcomes. Women self-report endometriosis with reasonable accuracy (>70%) and with exceptional accuracy when women are restricted to those who report that their endometriosis had been confirmed by laparoscopic surgery (>94%). Thus, relying on self-reported endometriosis in order to use larger sample sizes of patients with endometriosis appears to be valid, particularly when self-report of laparoscopic confirmation is used as the case definition. However, the paucity of data on histologic findings, AFS/rASRM stage, and endometriosis phenotypic characteristics suggests that a universal requirement for harmonized clinical and surgical data documentation is needed if we hope to obtain the relevant details for subgrouping patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by Eunice Kennedy Shriver National Institute of Child Health and Development grants HD48544, HD52473, HD57210, and HD94842, National Cancer Institute grants CA50385, R01CA058420, UM1CA164974, and U01CA176726, and National Heart, Lung, and Blood Institute grant U01HL154386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. AS, SM, and KT were additionally supported by the J. Willard and Alice S. Marriott Foundation. MK was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. LA Wise has served as a fibroid consultant for AbbVie, Inc for the last three years and has received in-kind donations (e.g. home pregnancy tests) from Swiss Precision Diagnostics, Sandstone Diagnostics, Kindara.com, and FertilityFriend.com for the PRESTO cohort. SA Missmer serves as an advisory board member for AbbVie and a single working group service for Roche; neither are related to this study. No other authors have a conflict of interest to report. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. TRIAL REGISTRATION NUMBER: N/A.

Male alcohol consumption and fecundability.

STUDY QUESTION: Does male alcohol consumption affect fecundability? SUMMARY ANSWER: In data pooled across Danish and North American preconception cohort studies, we found little evidence of an association between male alcohol consumption and reduced fecundability. WHAT IS KNOWN ALREADY: Experimental and clinical studies have shown that alcohol affects male reproductive physiology, mainly by altering male reproductive hormones and spermatogenesis. However, few epidemiologic studies have examined the association between alcohol consumption and male fertility. STUDY DESIGN, SIZE, DURATION: Data were collected from two ongoing prospective preconception cohort studies: the Danish 'SnartForaeldre' (SF) study (662 couples) and the North American 'Pregnancy Study Online' (PRESTO) (2017 couples). Participants included in the current analysis were enrolled from August 2011 through June 2019 (SF) and from June 2013 through June 2019 (PRESTO). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible men were aged ≥18 years in SF and ≥21 years in PRESTO, in a stable relationship with a female partner and not using contraception or receiving fertility treatment. In both cohorts, alcohol consumption/serving size was self-reported as number of beers (330 mL/12 oz.), glasses of white or red wine (120 mL/4 oz. each), dessert wine (50 mL/2 oz.) and spirits (20 mL/1.5 oz.). Overall alcohol consumption was categorized as none, 1-5, 6-13 and ≥14 standard servings per week. Total menstrual cycles at risk were calculated using data from female partners' follow-up questionnaires, which were completed every 8 weeks until self-reported pregnancy or 12 menstrual cycles, whichever came first. Analyses were restricted to couples that had been trying to conceive for ≤6 cycles at study entry. Proportional probability regression models were used to compute fecundability ratios (FRs) and 95% confidence interval (CIs). We adjusted for male and female age, female partner's alcohol consumption, intercourse frequency, previous history of fathering a child, race/ethnicity, education, BMI, smoking and consumption of sugar-sweetened beverages and caffeine. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative proportion of couples who conceived during 12 cycles of follow-up were 1727 (64.5%). The median (interquartile range) of total male alcohol consumption was 4.5 (2.0-7.8) and 4.1 (1.0-8.6) standard servings per week in the SF and PRESTO cohorts, respectively. In pooled analyses, adjusted FRs for male alcohol consumption of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 1.02 (95% CI: 0.90-1.17), 1.10 (95% CI: 0.96-1.27) and 0.98 (95% CI: 0.81-1.18), respectively. For SF, adjusted FRs of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 0.97 (95% CI: 0.73-1.28), 0.81 (95% CI: 0.60-1.10) and 0.82 (95% CI: 0.51-1.30), respectively. For PRESTO, adjusted FRs of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 1.02 (95% CI: 0.88-1.18), 1.20 (95% CI: 1.03-1.40) and 1.03 (95% CI: 0.84-1.26), respectively. LIMITATIONS, REASONS FOR CAUTION: Male alcohol consumption was ascertained at baseline only, and we did not distinguish between regular and binge drinking. In addition, we had insufficient numbers to study the effects of specific types of alcoholic beverages. As always, residual confounding by unmeasured factors, such as dietary factors and mental health, cannot be ruled out. Comorbidities thought to play a role in the reproductive setting (i.e. cancer, metabolic syndrome) were not considered in this study; however, the prevalence of cancer and diabetes was low in this age group. Findings for the highest categories of alcohol consumption (6-13 and ≥14 servings/week) were not consistent across the two cohorts. WIDER IMPLICATIONS OF THE FINDINGS: Despite little evidence of an association between male alcohol consumption and reduced fecundability in the pooled analysis, data from the Danish cohort might indicate a weak association between reduced fecundability and consumption of six or more servings per week. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Institutes of Health (R01-HD060680, R01-HD086742, R21-HD050264, R21-HD072326, R03-HD090315), the Novo Nordisk Foundation, Oticon Fonden, Politimester J.P.N. Colind og hustru Asmine Colinds mindelegat and Erna og Peter Houtveds studielegat. PRESTO receives in-kind donations from FertilityFriend.com, Kindara.com, Swiss Precision Diagnostics and Sandstone Diagnostics for the collection of data pertaining to fertility. Dr Wise serves as a consultant on uterine leiomyomata for AbbVie.com. All other authors declare no conflict of interest.

Lubricant use during intercourse and time to pregnancy: a prospective cohort study.

OBJECTIVE: To assess the extent to which lubricant use during intercourse is associated with time to pregnancy (TTP). DESIGN: Prospective cohort study. SETTING: Denmark and North America. POPULATION: A total of 6467 women aged 18-49 years who were not using contraception or fertility treatment. METHODS: We pooled data from two continuing prospective cohort studies of pregnancy planners in Denmark (2011-2017) and North America (2013-2017). Female participants completed bimonthly questionnaires for 12 months or until they reported pregnancy. After restricting the study to women without a history of infertility who had been trying to conceive for six or fewer cycles at enrollment, 6467 women were retained for analysis. Self-reported lubricant use was categorised as water-based/not pH balanced, water-based/pH balanced 'fertility friendly', silicone-based, oil-based, or a combination of these. We used proportional probability models to calculate fecundability ratios (FRs) and 95% confidence intervals (95% CIs) for the association between lubricant use and fecundability, after adjusting for cohort and sociodemographic and lifestyle factors. MAIN OUTCOME MEASURE: Fecundability. RESULTS: At baseline, 17.5% of participants reported the use of lubricants, most commonly water-based/not pH balanced (11.4%). Compared with non-use of lubricants, FRs were 1.02 (95% CI 0.93-1.11) for water-based/not pH-balanced lubricant use, 1.01 (95% CI 0.86-1.18) for water-based/pH balanced 'fertility friendly' lubricant use, 1.23 (95% CI 0.94-1.61) for oil-based lubricant use, and 1.27 (95% CI 0.93-1.73) for silicone-based lubricant use. Associations between oil-based lubricant use and fecundability were inconsistent across subgroups of study cohort, age, parity, and intercourse frequency. CONCLUSIONS: Lubricant use was not associated with reduced fecundability in the preconception cohorts of pregnancy planners studied. TWEETABLE ABSTRACT: Lubricant use during intercourse was not associated with time to pregnancy in a study of pregnancy planners.

Folic acid supplementation and fecundability: a Danish prospective cohort study.

BACKGROUND/OBJECTIVES: Periconceptional folic acid (FA) supplementation reduces the risk of neural tube defects and has been associated with ovulatory function. However, only two studies have associated supplementation with multivitamins (MVs) that contained FA with increased pregnancy rates. We aimed to examine the association between FA supplementation (obtained either through single FA tablets or through MVs) and fecundability. SUBJECTS/METHODS: A prospective cohort study of 3895 Danish women who were planning a pregnancy between 2007 and 2011. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) in relation to FA supplementation (either through single FA tablets or MV) using a proportional probabilities regression model, with adjustment for potential socio-demographic, reproductive and lifestyle confounders. In stratified analyses, we also estimated FR with 95% CI in relation to FA supplementation for women with regular and irregular cycles, respectively, and for women with short (<27 days), medium (27-29 days) and long cycles (⩾30 days), respectively. RESULTS: FA supplementation was associated with increased fecundability (FR=1.15, 95% CI=1.06-1.25), compared with non-use. The adjusted FRs for FA supplement use relative to non-use were 1.35 (95% CI=1.12-1.65) and 1.11 (95% CI=1.01-1.22) for women with irregular and regular cycles, respectively, and 1.36 (95% CI=0.95-1.95), 1.10 (95% CI=0.98-1.22) and 1.24 (95% CI=1.10-1.41) for women with short (<27 days), medium (27-29 days) and long cycles (⩾30 days), respectively. CONCLUSIONS: FA supplementation was associated with increased fecundability, and this association appeared to be stronger among women with irregular cycles and among women with either short or long cycle length.

Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.

STUDY QUESTION: Is caffeine and caffeinated beverage consumption associated with the risk of spontaneous abortion (SAB)? SUMMARY ANSWER: While preconceptional caffeine consumption was not materially associated with an increased risk of SAB, consumption during early pregnancy was associated with a small increased risk of SAB, although the relation was not linear. WHAT IS KNOWN ALREADY: Caffeine has been hypothesized as a risk factor for SAB since the 1980s; however, results from previous studies have been conflicting. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 5132 Danish women planning pregnancy and enrolled from 2007 to 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women who conceived after entry into the Snart-Gravid cohort and who were aged 18-40, in a stable relationship with a male partner, and did not use fertility treatments to conceive. Women reported their daily caffeine and caffeinated beverage consumption on questionnaires before conception and during early pregnancy. All exposure measurements were prospective with respect to outcome ascertainment. We estimated hazard ratios (HRs) of SAB for categories of caffeine consumption in milligrams (mg) per day and the corresponding 95% confidence intervals (CIs) using Cox proportional hazards regression models with gestational weeks as the time scale. MAIN RESULTS AND THE ROLE OF CHANCE: There were 732 women (14.3%) who were identified as having a SAB. In the preconceptional period, caffeine consumption was not materially associated with SAB risk (HR comparing ≥300 with <100 mg/day: 1.09; 95% CI: 0.89, 1.33). In early pregnancy, the HRs for 100-199, 200-299 and ≥300 mg/day of caffeine consumption were 1.62 (95% CI: 1.19, 2.22), 1.48 (95% CI: 1.03, 2.13) and 1.23 (95% CI: 0.61, 2.46), respectively, compared with that for <100 mg/day. LIMITATIONS, REASONS FOR CAUTION: The observed results may be affected by non-differential exposure misclassification, reverse causation and residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date of prospectively measured, preconception caffeine consumption and risk of SAB. We were able to reduce the likelihood of differential left truncation bias and recall bias present in other analyses. STUDY FUNDING/COMPETING INTERESTS: Snart-Gravid was funded by the NICHD (R21-050264). Dr. Hahn's work was funded in part by the BU Reproductive, Perinatal, and Pediatric Epidemiology Training Grant NIH #T32HD052458. There are no competing interests.

Prenatal diethylstilbestrol exposure and risk of obesity in adult women.

Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women.

Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (ß), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (ß=-15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (ß=-20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (ß=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (ß=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml--indicators of low ovarian reserve--were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

A prospective cohort study of a woman's own gestational age and her fecundability.

STUDY QUESTION: What is the magnitude of the association between a woman's gestational age at her own birth and her fecundability (cycle-specific probability of conception)? SUMMARY ANSWER: We found a 62% decrease in fecundability among women born <34 weeks of gestation relative to women born at 37-41 weeks of gestation, whereas there were few differences in fecundability among women born at later gestational ages. WHAT IS KNOWN ALREADY: One study, using retrospectively collected data on time-to-pregnancy (TTP), and self-reported data on gestational age, found a prolonged TTP among women born <37 gestational weeks (preterm) and with a birthweight ≤1500 g. Other studies of women's gestational age at birth and subsequent fertility, based on data from national birth registries, have reported a reduced probability of giving birth among women born <32 weeks of gestation. STUDY DESIGN, SIZE, DURATION: We used data from a prospective cohort study of Danish pregnancy planners ('Snart-Gravid'), enrolled during 2007-2011 and followed until 2012. In all, 2814 women were enrolled in our study, of which 2569 had complete follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women eligible to participate were 18-40 years old at study entry, in a relationship with a male partner, and attempting to conceive. Participants completed a baseline questionnaire and up to six follow-up questionnaires until the report of pregnancy, discontinuation of pregnancy attempts, beginning of fertility treatment, loss to follow-up or end of study observation after 12 months. MAIN RESULTS AND THE ROLE OF CHANCE: Among women born <34 gestational weeks, the cumulative probability of conception was 12, 28 and 48% within 3, 6 and 12 cycles, respectively. Among women born at 37-41 weeks of gestation, cumulative probability of conception was 47, 67 and 84% within 3, 6 and 12 cycles, respectively. Relative to women born at 37-41 weeks' gestation, women born <34 weeks had decreased fecundability (fecundability ratio (FR) 0.38, 95% confidence interval (CI): 0.17-0.82). Our data did not suggest reduced fecundability among women born at 34-36 weeks of gestation or at ≥42 weeks of gestation (FR 1.03, 95% CI: 0.80-1.34, and FR 1.13, 95% CI: 0.96-1.33, respectively). LIMITATIONS, REASONS FOR CAUTION: Data on gestational age, obtained from the Danish Medical Birth Registry, were more likely to be based on date of last menstrual period than early ultrasound examination, possibly leading to an overestimation of gestational age at birth. Such overestimation, however, would not explain the decrease in fecundability observed among women born <34 gestational weeks. Another limitation is that the proportion of women born before 34 weeks of gestation was low in our study population, which reduced the precision of the estimates. WIDER IMPLICATIONS OF THE FINDINGS: By using prospective data on TTP, our study elaborates on previous reports of impaired fertility among women born preterm, suggesting that women born <34 weeks of gestation have reduced fecundability. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the National Institute of Child Health and Human Development (R21-050264), the Danish Medical Research Council (271-07-0338), and the Health Research Fund of Central Denmark Region (1-01-72-84-10). The authors have no competing interests to declare.

The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium.

BACKGROUND: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. METHODS: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28,829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. RESULTS: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)≥30 vs BMI<25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (≥15 years vs <11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% CI: 1.60-3.15, P-heterogeneity=0.01). CONCLUSION: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.

Hypertension and risk of uterine leiomyomata in US black women.

BACKGROUND: Previous studies have found a positive association between hypertension and risk of hysterectomy-confirmed uterine leiomyomata (UL). The association of hypertension with UL confirmed by ultrasound or other surgery is less clear. METHODS: The present study evaluated the association of hypertension with UL incidence according to confirmation method (hysterectomy, other surgery or ultrasound) in the Black Women's Health Study, 1997-2007. We collected prospective data every 2 years on physician-diagnosed hypertension and UL in 22 530 premenopausal women. Validation sub-studies confirmed 99 and 96% of hypertension and UL self-reported diagnoses, respectively. Cox regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association of hypertension and UL, adjusting for potential confounders. RESULTS: During 172 162 person-years of follow-up, there were 6447 incident cases of UL confirmed by ultrasound (n = 5111), hysterectomy (n = 670) or other surgery (n = 666). Treated hypertension was associated with UL confirmed by hysterectomy (IRR = 1.32, 95% CI: 1.06, 1.63), but it was not associated with UL confirmed by ultrasound (IRR = 1.05, 95% CI: 0.96, 1.16) or other surgery (IRR = 1.13, 95% CI: 0.88, 1.46). CONCLUSIONS: Treated hypertension was associated with UL confirmed by hysterectomy, but not UL confirmed by other methods (other surgery or ultrasound). These data suggest it is premature to conclude that hypertension is related to an increased risk of UL. Additional studies are needed to assess whether the association with hysterectomy-confirmed UL can be explained by other sources of bias, such as patient or physician preferences for specific types of medical care.

Mortality in women given diethylstilbestrol during pregnancy.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Lifetime socioeconomic position in relation to onset of perimenopause.

STUDY OBJECTIVE: To assess the association between lifetime socioeconomic position and onset of perimenopause. DESIGN: Prospective cohort study. SETTING: Boston, Massachusetts. PARTICIPANTS: 603 premenopausal women aged 36-45 years at baseline who completed a cross sectional survey on childhood and adult socioeconomic position. MAIN OUTCOME MEASURES: Time to perimenopause, defined as time in months from baseline interview to a woman's report of (1) an absolute change of at least seven days in menstrual cycle length from baseline or subjective report of menstrual irregularity; (2) a change in menstrual flow amount or duration; or (3) cessation of periods for at least three months, whichever came first. MAIN RESULTS: Incidence of perimenopause was 1.75 times higher (95%CI 1.10 to 2.79) and median age at onset was 1.2 years younger (44.7 v 45.9 years) for women reporting childhood and adult economic distress compared with women reporting no lifetime economic distress. After adjustment for age, race/ethnicity, age at menarche, parity, oral contraceptive use, family history of early menopause, depression, smoking, and body mass index, the association weakened (incidence rate ratio (IRR)=1.59; 95%CI 0.97 to 2.61). Inverse associations were observed for most, but not all, measures of educational level. Measures of current household income were not associated with risk of perimenopause. CONCLUSIONS: This study suggests that adverse socioeconomic conditions across the lifespan, when measured in terms of economic hardship and low educational attainment, may be associated with an increased rate of entry into perimenopause.

Prevalence and predictors of chronic lower genital tract discomfort.

OBJECTIVE: We sought to determine the prevalence of chronic lower genital tract discomfort in the general population and to identify demographic and reproductive characteristics associated with this disorder. STUDY DESIGN: We surveyed a random sample of 480 women (age range, 20 to 59 years; 60 women for each 5-year age category) from 1 Boston area suburban community. Participants were asked to complete a 1-page self-administered optically scannable questionnaire that pertained to current and previous genital tract discomfort. RESULTS: After 2 mailings and 1 telephone follow-up, as well as the elimination of 42 ineligible women, 303 (70%) questionnaires were returned. Fifty-six women (18.5%) reported a history of lower genital tract discomfort that persisted for >3 months. Approximately 12% reported a history of chronic knife-like or excessive pain on contact to the genital area, whereas 6.6% experienced persistent lower genital tract itching or burning. Women who reported their age at menarche to be

Adult onset of major depressive disorder in relation to early life violent victimisation: a case-control study.

BACKGROUND: Major depressive disorder is a significant cause of morbidity among women in the USA. Women are twice as likely as men to be diagnosed with major depressive disorder, yet no known risk factors can account for this sex difference. We aimed to assess violent victimisation as a risk factor for depression in women. METHODS: We undertook a case-control study to assess the association between violent victimisation early in life and major depressive disorder in women. We randomly selected a population-based sample of women, aged 36-45 years, from the greater Boston area. In 1999, 236 cases and 496 controls (n=732) completed a self-administered questionnaire designed to ascertain a lifetime history of exposure to violent victimisation. Our main outcome measure was major depressive disorder, assessed by structured clinical interview for Diagnostic Statistical Manual IV (DSM-IV) criteria. FINDINGS: 363 (50%) of 732 respondents reported experience or fear of abuse as a child or adolescent. 68 were excluded because they reported violence as an adult only. Compared with women who reported no abuse, risk of depression was increased in women who reported any abuse as a child or adolescent (relative risk 2.5, 95% CI 1.9-3.0), physical abuse only (2.4, 1.8-3.0), sexual abuse only (1.8, 1.2-2.8), and both physical and sexual abuse (3.3, 2.5-4.1). Severity of abuse had a linear dose-response relation with depression. INTERPRETATION: Our results suggest a positive association between violent victimisation early in life and major depressive disorder in women.