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.

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.

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.

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.

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.

Association of endocrine disruptors and obesity: perspectives from epidemiological studies.

Although changes in diet and physical activity are undoubtedly key causal factors related to the increase in obesity, there is growing interest in the possibility that endocrine disrupting chemicals (EDCs) may affect obesity-related pathways by altering cell signalling involved in weight and lipid homeostasis. Proposed mechanisms that could underlie associations between EDCs and obesity include effects on thyroid and steroid hormones, and activation of peroxisome proliferator-activated receptors, which play a major role in adipocyte differentiation and energy storage. Most evidence supporting the hypothesis that EDCs affect obesity comes from laboratory studies. We summarize the limited epidemiological literature on the topic, including prospective studies of human prenatal exposure to EDCs. We also present findings from a cross-sectional study of levels of six phthalate metabolites and body mass index (BMI) and waist circumference (WC), using data from the U.S. National Health and Nutrition Examination Survey. We found positive associations between BMI and WC among adult males for most phthalate metabolites. For example, in males aged 20-59, the adjusted mean BMI across quartiles of mono-benzyl phthalate was 26.7, 27.2, 28.4, 29.0 (p-trend = 0.0002). In females, BMI and WC increased with quartiles of mono-ethyl phthalate in 12-19 year olds (adjusted mean BMI = 22.9, 23.8, 24.1, 24.7, p-trend = 0.03), and a similar but less strong pattern was seen in 20-59 year olds. By contrast, higher levels of mono-2-ethylhexyl phthalate were associated with lower BMI in adolescent girls and females aged 20-59. This exploratory analysis found several associations between phthalate metabolites and obesity, including notable differences by gender. However, the cross-sectional data are a limitation. Additional prospective studies of the association between exposures to EDCs, especially during development, and obesity are warranted. As this field of research advances, there are challenging methodological questions that must be considered by both epidemiologists and toxicologists.

Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers' reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34). Our data suggest a possible association between the mother's prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters' elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.

Case-control study of childhood acute lymphoblastic leukemia and residential radon exposure.

BACKGROUND: Several ecologic analyses have shown significant positive associations between mean indoor radon concentrations and risk of leukemia at all ages (acute myeloid leukemia and chronic lymphocytic leukemia) and for children (all leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia [ALL]). As part of an age-matched, case-control study of childhood ALL in the United States, we investigated the association between the incidence of ALL in children under age 15 years and indoor radon exposure. METHODS: Radon detectors were placed in current and previous homes of subjects where they resided for 6 months or longer. Children were included in analyses if radon measurements covered 70% or more of the 5-year period prior to diagnosis for case subjects (or from birth for case subjects under age 5 years) and the corresponding reference dates for control subjects. Radon levels could be estimated for 97% of the exposure period for the eligible 505 case subjects and 443 control subjects. RESULTS: Mean radon concentration was lower for case subjects (65.4 becquerels per cubic meter [Bqm(-3)]) than for control subjects (79.1 Bqm(-3)). For categories less than 37, 37-73, 74-147, and 148 or more Bqm(-3) of radon exposure, relative risks based on matched case-control pairs were 1.00, 1.22, 0.82, and 1.02, respectively, and were similar to results from an unmatched analysis. There was no association between ALL and radon exposure within subgroups defined by categories of age, income, birth order, birth weight, sex, type of residence, magnetic field exposure, parental age at the subject's birth, parental occupation, or parental smoking habits. CONCLUSIONS: In contrast to prior ecologic studies, the results from this analytic study provide no evidence for an association between indoor radon exposure and childhood ALL.

Cancer risk in men exposed in utero to diethylstilbestrol.

BACKGROUND: An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

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.

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.

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring.

OBJECTIVE: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. METHODS: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. RESULTS: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64. 1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). CONCLUSION: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

Birth weight and breast cancer risk.

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

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.

Association of delayed conception with caffeine consumption.

This cross-sectional study investigated the relation between intake of caffeine-containing beverages and time to conception in a population of 1,909 married women in New Haven, Connecticut, between May 12, 1980 and March 12, 1982. Women were interviewed shortly after the first prenatal visit regarding the length of time taken to conceive the index pregnancy, consumption of caffeine during pregnancy, and other exposures occurring prior to and during pregnancy. In logistic regression analyses, intake of caffeine from coffee, tea, and caffeinated soft drinks was associated with an increased risk of a delay of conception of 1 year or more. Compared with no caffeine use, consumption of 1-150 mg/day of caffeine resulted in an odds ratio for delayed conception of 1.39 (95% confidence interval (CI) 0.90-2.13), consumption of 151-300 mg/day of caffeine was associated with an odds ratio of 1.88 (95% CI 1.13-3.11), and that of over 300 mg/day (the equivalent of approximately three cups of coffee) resulted in an odds ratio of 2.24 (95% CI 1.06-4.73), after controlling for last method of birth control used, parity, and number of cigarettes per day. When the risk of conception for each cycle was examined using a discrete analogue of the Cox proportional hazards model, women who reported drinking over 300 mg/day of caffeine had a 27% lower chance of conceiving for each cycle, and those who reported drinking less than 300 mg/day had a 10% reduction in per cycle conception rates compared with women who consumed no caffeine. Risks for coffee, tea, and colas were examined simultaneously in logistic models and were found not to improve the fit of a model that contained a variable for total caffeine intake from all sources.

Effect of marijuana use in pregnancy on fetal growth.

In a prospective study of 3,857 pregnancies ending in singleton live births at Yale-New Haven Hospital, New Haven, Connecticut, in 1980-1982, 9.5% of mothers reported using marijuana (4.1% occasionally and 5.4% at least 2-3 times monthly). Among white women, regular use was associated with an increased risk of delivering a low birth weight (less than 2,500 gm) infant (odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.2) and small for gestational age infant (OR = 2.3, 95% CI = 1.3-4.1) after adjustment for other risk factors. Nonwhite marijuana users were not at further increased risk for delivering a low birth weight or small gestational age infant beyond the elevated rates of these conditions already experienced by nonwhites in general. Marijuana use was also related to preterm delivery (gestational age less than 37 weeks from last menstrual period) in white women (OR = 1.9, 95% CI = 1.0-3.9) but not nonwhite women. Occasional use was unrelated to the risk of low birth weight, small for gestational age, or preterm delivery.

Diethylstilbestrol revisited: a review of the long-term health effects.

PURPOSE: To review the literature on the long-term health effects of exposure to diethylstilbestrol (DES) among women prescribed DES during pregnancy (DES mothers), among their children exposed inutero to the drug (DES sons and daughters) and among the progeny of these exposed sons and daughters (DES grandchildren). DATA SOURCES: English-language articles were identified through MEDLINE and CANCERLIT searches and through review of the bibliographies of identified articles. STUDY SELECTION: All human studies relevant to long-term health effects of exposure to DES were reviewed. DATA EXTRACTION: Descriptive data on existing DES cohorts were extracted from early publications. Risk estimates for health effects were extracted from published reports. DATA SYNTHESIS: An estimated 5 to 10 million Americans received DES during pregnancy or were exposed to the drug in utero. Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, < 2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10,000. The association between DES exposure and testicular cancer in DES sons remains controversial. Exposure to DES has also been linked to reproductive tract abnormalities in DES sons and daughters that consist of immune system disorders and psychosexual effects. No evidence for transgenerational effects currently exists. Recommendations for screening persons exposed to DES are reviewed. CONCLUSIONS: Further research is needed to define long-term health effects related to DES exposure. Such research would provide a basis for counseling persons exposed to DES and would further understanding of environmental and pharmacologic compounds similar to DES.