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Background In 2016, the Japanese government set the National Action Plan on antimicrobial resistance to reduce antibiotic prescriptions. However, the trends and variations of antibiotic prescription patterns in a routine healthcare setting during the fiscal year 2013–2018 across different clinics at a national level are unclear. Methods This retrospective cohort study included all clinics with >100 pediatric outpatients with infectious diseases per month during the fiscal year 2013–2018 using a national database in Japan. We investigated the trends in antibiotic prescription rates and their patterns and variations across different clinics over the six years following the 2019 World Health Organization Access, Watch, Reserve antibiotic groups, and Amoxicillin Index. Results A total of 2278 clinics with 94,414,170 infectious disease-related visits were eligible for the study. Most clinics showed higher Watch percentages (median 85.4%; IQR, 68.5–95.1) than Access percentages (median, 13.8%; IQR, 4.2–30.7) and Amoxicillin Index (median, 13.3%; IQR, 3.9–30.4). The introduction of the Action Plan changed annual absolute reductions in the antibiotic prescription rates from −16.0 DOTs/1000 visitors (95%CI, −16.4–15.6) to −239.3 per 1000 visitors (95%CI, −240.0–238.6). However, these impacts were heterogeneous across clinics. From 2013 to 2018, 41.4% reduced the antibiotic prescription rates by >33.3% (median, −1035.5 DOTs/1000 visitors; IQR, −1519.4–680.2), 18.7% did not change the rates (median, −40.3 DOTs/1000 visitors; IQR, −168.4–68.6), and 7.3% increased the rates by >10% (499.5 DOTs per 1000 visitors; IQR, 232.6–837.5). Conclusions We observed the National Action Plan's impacts and extensive prescription variations across different pediatric clinics. However, one-fourth of clinics did not improve antibiotic prescription patterns even after introducing the Action Plan.

The human microbiota is a key contributor to many aspects of human health and its composition is largely influenced by diet. There is a growing body of scientific evidence to suggest that gut dysbiosis (microbial imbalance of the intestine) is associated with inflammatory and immune-mediated diseases (e.g., inflammatory bowel disease and asthma). Regular consumption of fermented foods (e.g., kimchi, kefir, etc.) may represent a potential avenue to counter the proinflammatory effects of gut dysbiosis. However, an assessment of the available literature in this research area is lacking. Here we provide a critical review of current human intervention studies that analyzed the effect of fermented foods on the composition and/or function of the human gut microbiota. A total of 19 human intervention studies were identified that met this search criteria. In this review, we discuss evidence that consumption of fermented foods may modify the gut microbiota in humans. Further, there is cursory evidence to suggest that gut microbiota compositional changes mediate associations between fermented food consumption and human health outcomes. Although promising, there remains considerable heterogeneity in the human populations targeted in the intervention studies we identified. Larger longitudinal feeding studies with longer follow-up are necessary to confirm and enhance the current data. Further, future studies should consider analyzing microbiota function as a means to elucidate the mechanism linking fermented food consumption with human health. This review highlights methodologic considerations for intervention trials, emphasizing an expanse of research opportunities related to fermented food consumption in humans.

Background Although a link between regular yogurt consumption and mortality appears plausible, data are sparse and have yielded inconsistent results. Objectives We examined the association between regular yogurt consumption and risk of all-cause and cause-specific mortality among US women and men. Methods A total of 82,348 women in the Nurses' Health Study and 40,278 men in the Health Professionals Follow-Up Study without a history of cardiovascular disease (CVD) and cancer in 1980 (women) or 1986 (men) were followed up until 2012. Yogurt consumption was assessed by updated validated FFQs. Results During 3,354,957 person-years of follow-up, 20,831 women and 12,397 men died. Compared with no yogurt consumption, the multivariable-adjusted HRs (95% CIs) of mortality were 0.89 (0.86, 0.93), 0.85 (0.81, 0.89), 0.88 (0.84, 0.91), and 0.91 (0.85, 0.98) for ≤1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and >4 servings/wk in women (P-trend = 0.34), respectively. For men, the corresponding HRs (95% CIs) were 0.99 (0.94, 1.03), 0.98 (0.91, 1.05), 1.04 (0.98, 1.10), and 1.05 (0.95, 1.16), respectively. We further noted inverse associations for cancer mortality (multivariable-adjusted HR comparing extreme categories: 0.87; 95% CI: 0.78, 0.98; P-trend = 0.04) and CVD mortality (HR: 0.92; 95% CI: 0.79, 1.08; P-trend = 0.41) in women, although the latter was attenuated in the multivariable-adjusted model. Replacement of 1 serving/d of yogurt with 1 serving/d of nuts (women and men) or whole grains (women) was associated with a lower risk of all-cause mortality, whereas replacement of yogurt with red meat, processed meat (women and men), and milk or other dairy foods (women) was associated with a greater mortality. Conclusions In our study, regular yogurt consumption was related to lower mortality risk among women. Given that no clear dose-response relation was apparent, this result must be interpreted with caution.

Epidemiologic evidence suggests that environmental factors acting as endocrine disrupting chemicals (EDCs) are associated with mammographic breast density and the risk of breast cancer. Exposure to EDCs during puberty, a period of rapid breast development, may affect susceptibility to breast carcinogenesis.In a cohort of 366 Chilean adolescents from the Growth and Obesity Cohort Study, we evaluated the relation between urinary concentrations of 15 suspected EDC biomarkers across three pubertal time points (Tanner breast stage 1 (B1), 4 (B4), and 1-year post-menarche) and breast fibroglandular volume (FGV; percent FGV [%FGV] and absolute FGV [aFGV]) and total breast volume (tBV) at 2-years post-menarche. We used linear mixed models to test differences in creatinine-corrected EDC biomarker concentrations at B4 and 1-year post-menarche compared to B1 and calculated intraclass correlation coefficients (ICC) of EDC concentrations across time points to appraise the consistency of measurements. We fit multivariable generalized estimating equations (GEEs) to evaluate windows of susceptibility for the association between logUrinary EDC biomarker concentrations highly varied across pubertal time points (ICC range 0.01-0.30). For 12 EDCs, biomarker concentrations decreased over time. Triclosan measured at 1-year post-menarche was inversely associated with %FGV at 2-years post-menarche (β = -0.025, 95 % confidence interval = -0.041, -0.008). Mono(2-ethyl-5-carboxypentyl) phthalate and the sum of di(2-ethylhexyl) phthalate metabolite concentrations at B4 were positively associated with aFGV and tBV at 2-years post-menarche. No measured phenols were associated with aFGV and tBV, while no measured parabens were associated with %FGV and aFGV.Our study suggests relatively high variability in EDC biomarker concentrations across the peripubertal time period. We also found evidence to suggest that there may be pubertal windows of susceptibility to select EDCs for the association with adolescent breast density.

Background: Early menopause, defined as the cessation of ovarian function before the age of 45 y, affects ∼10% of women and is associated with higher risk of cardiovascular disease, osteoporosis, and other conditions. Few modifiable risk factors for early menopause have been identified, but emerging data suggest that high vitamin D intake may reduce risk.Objective: We evaluated how intakes of vitamin D and calcium are associated with the incidence of early menopause in the prospective Nurses' Health Study II (NHS2).Design: Intakes of vitamin D and calcium from foods and supplements were measured every 4 y with the use of a food-frequency questionnaire. Cases of incident early menopause were identified from all participants who were premenopausal at baseline in 1991; over 1.13 million person-years, 2041 women reported having natural menopause before the age of 45 y. We used Cox proportional hazards regression to evaluate relations between intakes of vitamin D and calcium and incident early menopause while accounting for potential confounding factors.Results: After adjustment for age, smoking, and other factors, women with the highest intake of dietary vitamin D (quintile median: 528 IU/d) had a significant 17% lower risk of early menopause than women with the lowest intake [quintile median: 148 IU/d; HR: 0.83 (95% CI: 0.72, 0.95); P-trend = 0.03]. Dietary calcium intake in the highest quintile (median: 1246 mg/d) compared with the lowest (median: 556 mg/d) was associated with a borderline significantly lower risk of early menopause (HR: 0.87; 95% CI: 0.76, 1.00; P-trend = 0.03). Associations were stronger for vitamin D and calcium from dairy sources than from nondairy dietary sources, whereas high supplement use was not associated with lower risk.Conclusions: Findings suggest that high intakes of dietary vitamin D and calcium may be modestly associated with a lower risk of early menopause. Further studies evaluating 25-hydroxyvitamin D concentrations, other dairy constituents, and early menopause are warranted.

Background: Frequent dairy consumption in childhood has been related to higher growth-hormone concentrations that may affect mammary gland and pubertal development.Objective: We evaluated the relation of dairy intake to breast composition at Tanner stage 4 and age at menarche.Design: A total of 515 Chilean girls are included in the Growth and Obesity Cohort Study. The subjects have been followed longitudinally since they were 3-4 y old (from 2006 to the present). Starting in 2013, diet was assessed every 6 mo via a 24-h recall. The breast fibroglandular volume (FGV) was measured with the use of dual-energy X-ray absorptiometry at Tanner stage 4. The date of menarche was reported every 6 mo. Our analysis included 290 girls with data on prospective diet and breast composition and 324 girls with data on prospective diet and age at menarche.Results: The mean ± SD breast FGV and percentage of fibroglandular volume (%FGV) (i.e., FGV divided by total breast volume times 100) at Tanner stage 4 was 81.7 ± 32.2 cm3 and 42.0% ± 16.7%, respectively. Only sweetened, artificially flavored milk-based drinks were associated with the %FGV with girls who consumed >125 g/d having a %FGV that was 4.5% (95% CI: 0.9%, 8.1%) higher than that of girls who consumed none (P-trend = 0.007). Yogurt intake was associated with a lower FGV. Specifically, girls who consumed >125 g yogurt/d had -10.2 cm3 (95% CI: -20.2, -0.3 cm3) less FGV than did girls who consumed no yogurt (P-trend = 0.03). The majority (90.7%) of girls in our cohort attained menarche before the data analyses with a mean ± SD age at menarche of 11.9 ± 0.7 y. In multivariable models, low-fat dairy, low-fat milk, and yogurt intakes were associated with a later age at menarche. In particular, girls who consumed >125 g yogurt/d had menarche, on average, 4.6 mo (95% CI: 1.9, 7.4 mo) later than girls who consumed no yogurt (P-trend = 0.01).Conclusion: More-frequent consumption of sweetened, artificially-flavored milk-based drinks is associated with a higher %FGV, whereas higher yogurt intake is associated with a lower FGV and delayed age at menarche in Chilean girls.

Background: Regular milk consumption during childhood and adolescence is recommended for bone health. However, milk consumption increases circulating insulin-like growth factor I concentrations, and may also accelerate puberty. Objective: We prospectively investigated the association between milk consumption and age at menarche in the Growing Up Today Study. Methods: Study participants were 5583 US girls who were premenarcheal and ages 9–14 y in 1996. Girls were followed through 2001, at which time 97% of noncensored participants had reported menarche. Frequency of milk and meat consumption was calculated with the use of annual youth/adolescent food frequency questionnaires from 1996–1998. Intake of related nutrients was also measured. Age at menarche was self-reported annually through 2001. Results: During follow-up, 5227 girls attained menarche over 10,555 accrued person-years. In models adjusted for dietary and sociodemographic predictors of menarche, frequency of milk consumption did not predict age at onset of menarche (for >3 glasses of milk/d vs. 1.1–4 glasses/wk, HR: 0.93; 95% CI: 0.83, 1.04). After additional adjustment for body size, premenarcheal girls consuming >3 glasses of milk daily were 13% less likely (95% CI: 23%, 223%; P-trend

Telomere length correlates with morbidity and mortality. While telomere length appears to be influenced by hormone levels, the potential impact of exposure to endocrine-disrupting chemicals (EDCs) has not been studied. We examined the association between maternal gestational concentrations of biomarkers of EDC exposure and telomere length at birth in the Harvard Epigenetic Birth Cohort. EDC (phenols and phthalates) biomarker concentrations were measured in maternal spot urine samples during the first trimester and telomere length in maternal and cord blood collected at delivery among 181 mother-newborn singleton dyads. Maternal and newborn telomere length exhibited a positive correlation (Spearman ρ = 0.20 (p-value0.01). Infant telomere length was associated with maternal biomarker concentrations of specific EDCs, and most of these associations were observed to be infant sex-specific. Prenatal exposure to triclosan, a non-paraben phenol with antimicrobial properties, was one of the most strongly associated EDCs with telomere length; telomere length was 20% (95% CI 5%-33%) shorter among boys in the highest quartile of maternal biomarker concentrations compared to the lowest quartile. In contrast, we observed longer telomere length associated with increased gestational concentrations of mono-isobutyl phthalate, and among boys, with increased concentrations of mono-2-ethylhexyl phthalate. In this birth cohort, we observed associations between maternal gestational exposure to select EDC biomarkers and telomere length, most of which were sex-specific. These findings need to be confirmed in future studies.

Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.

Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ∼100 kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high level of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σ di(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.

Later menopause is a risk factor for breast and endometrial cancer, yet few studies have investigated dietary predictors of this potentially modifiable event. In particular, dairy contains hormones and growth factors that could potentially affect menopausal timing. We therefore assessed the association between regular consumption of dairy foods and related nutrients and age at natural menopause. We conducted a prospective analysis with up to 20 y of follow-up in 46,059 participants in the Nurses' Health Study who were premenopausal in 1980. We observed 30,816 events of natural menopause over 401,754 person-years. In the total population, the estimated mean age at natural menopause was 51.5 y for women who consumed no low-fat dairy and 51.5, 51.6, 51.7, and 51.8 y for women who consumed 0.1-1.0, 1.1-2.0, 2.1-3.0, and >3 servings of low-fat dairy daily, respectively. Premenopausal women 3 servings of low-fat dairy per day were 14% less likely (HR: 0.86; 95% CI: 0.77, 0.96; P-trend 6 servings/wk vs. 0-1 servings/mo: HR: 0.93; 95% CI: 0.89, 0.97; P-trend < 0.0001) but not for total high-fat dairy or whole milk. Dairy foods were not associated with age at menopause among women ≥51 y of age. These findings support the growing body of literature on the hormonally active nature of milk and dairy foods.

Physical and sexual abuse are prevalent social hazards. We sought to examine the association between childhood physical and sexual abuse and age at menarche.Among 68,505 participants enrolled in the Nurses' Health Study II, we investigated the association between childhood physical abuse and sexual abuse and menarche before age 11 years (early) or after age 15 years (late) using multivariate logistic regression analysis, mutually adjusting for both types of abuse.Fifty-seven percent of respondents reported some form of physical or sexual abuse in childhood. We found a positive dose-response association between severity of sexual abuse in childhood and risk for early menarche. Compared with women who reported no childhood sexual abuse, the adjusted odds ratio (AOR) for early menarche in women who reported childhood sexual abuse was 1.20 (95% confidence interval [CI]: 1.10, 1.37) for sexual touching and 1.49 (95% CI: 1.34, 1.66) for forced sexual activity. Severe physical abuse predicted early menarche (AOR = 1.22, 95% CI: 1.10, 1.37). Childhood physical abuse had a dose-response association with late age at menarche: AOR 1.17 (95% CI: 1.04, 1.32) for mild, 1.20 (95% CI: 1.08, 1.33) for moderate, and 1.50 (95% CI: 1.27, 1.77) for severe physical abuse. Sexual abuse was not associated with late menarche.Childhood abuse was prevalent in this large cohort of U.S. women. Severity of childhood sexual abuse was associated with risk for early onset of menarche, and physical abuse was associated with both early and late onset of menarche.

Bisphenol A (BPA) is a chemical suspected of causing endocrine and metabolic disruption in animals and humans. In rodents, in utero exposure to low-dose BPA is associated with weight gain. Detectable levels of BPA are found in most Americans due to its widespread use in the manufacture of food and drink packaging. We hypothesized that urinary BPA concentrations would be positively associated with general and central obesity.Cross-sectional analysis of urinary BPA concentrations, body mass index, and waist circumference in 2747 adults (aged 18-74), using pooled data from the 2003/04 and 2005/06 National Health and Nutrition Examination Surveys.The creatinine-adjusted geometric mean urinary BPA concentration was 2.05μg/g creatinine (25th percentile: 1.18, 75% percentile: 3.33). Relative to those in the lowest BPA quartile, participants in the upper BPA quartiles were more likely to be classified as obese (quartile 2 odds ratio (OR): 1.85, 95% confidence interval (CI): 1.22, 2.79; quartile 3 OR: 1.60, 95% CI: 1.05-2.44; quartile 4 OR: 1.76, 95% CI: 1.06-2.94). Higher BPA concentration was also associated with abdominal obesity (quartile 2 OR: 1.62, 95% CI: 1.11, 2.36; quartile 3 OR: 1.39, 95% CI: 1.02-1.90; quartile 4 OR: 1.58, 95% CI: 1.03-2.42).Higher BPA exposure is associated with general and central obesity in the general adult population of the United States. Reverse causation is of concern due to the cross-sectional nature of this study; longitudinal studies are needed to clarify the direction of the association.

Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.

Objective To investigate the relation between the fetal environment and endometriosis. Design Prospective cohort study. Setting Nurses' Health Study II with 10 years of follow-up. Participant(s) Eighty-four thousand, four hundred forty-six women aged 25–42 who had never been diagnosed with endometriosis, infertility, or cancer at baseline in 1989. Main outcome measure(s) Incidence of laparoscopically confirmed endometriosis according to birthweight, prematurity, multiple gestation, diethylstilbestrol (DES) exposure, and having been breastfed. Result(s) During 566,250 woman-years of follow-up, 1,226 cases of laparoscopically-confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, parity, race, and body mass index at age 18, we observed a linear increase in the incidence rate with decreasing birthweight (rate ratio [RR] = 1.3 for birthweight P value, test for trend=.01). In addition, women who were born as one of a multiple gestation (i.e., twins or greater number) were at increased risk even after controlling for birthweight (RR = 1.7, CI=1.2–2.5). The rate of endometriosis was also 80% greater among women exposed to diethylstilbestrol in utero (RR = 1.8, CI=1.2–2.8). Neither premature delivery nor having been breastfed were associated with the incidence of endometriosis. None of these effect estimates were modified by infertility status at the time of endometriosis diagnosis. Conclusion(s) The fetal environment is associated with subsequent laparoscopically confirmed endometriosis in this cohort of US women.

The age-related rise in breast cancer incidence is steeper prior to menopause. Hormonal changes during menopause are likely to be responsible for the less pronounced increase in risk after menopause. Hormone replacement therapy (HRT) elevates serum levels of estrogens to those of premenopausal women, thus eliminating the relative protection menopause confers. Epidemiologic evidence supports a positive association between HRT use and breast cancer risk that increases with increasing duration of use. This excess risk decreases after HRT cessation. Cell proliferation is the likely mechanism underlying the hormone-induced increase in breast cancer risk. The addition of progestin may increase the rate of cell proliferation beyond that of estrogen alone. Recent epidemiologic evidence indicates a higher breast cancer risk associated with combined estrogen and progestin use than with estrogen alone. Adoption of an HRT regimen should be an individual decision largely based on menopausal symptoms. The risk of osteoporosis and possibly of coronary heart disease may be reduced by HRT use but can also be decreased by lifestyle and risk factor modification. Such measures are not readily available for the prevention of cancer, and the risk–benefit evaluation of HRT use should take this fact into account.

PURPOSE: Coffee, caffeinated tea, and caffeine have been suggested to play a role in breast carcinogenesis or in the promotion or inhibition of tumor growth. Prior epidemiologic evidence has not supported an overall association between consumption of caffeinated beverages and risk of breast cancer, but consumption in some studies was low. METHODS: We studied this relation in the Swedish Mammography Screening Cohort, a large population-based prospective cohort study in Sweden comprising 59,036 women aged 40–76 years. Sweden has the highest coffee consumption per capita in the world. RESULTS: During 508,267 person-years of follow-up, 1271 cases of invasive breast cancer were diagnosed. Women who reported drinking 4 or more cups of coffee per day had a covariate-adjusted hazard ratio of breast cancer of 0.94 [95% confidence interval (CI) 0.75–1.28] compared to women who reported drinking 1 cup a week or less. The corresponding hazard ratio for tea consumption was 1.13 (95% CI 0.91–1.40). Similarly, women in the highest quintile of self-reported caffeine intake had a hazard ratio of beast cancer of 1.04 (95% CI 0.87–1.24) compared to women in the lowest quintile. CONCLUSIONS: In this large cohort of Swedish women, consumption of coffee, tea, and caffeine was not associated with breast cancer incidence.

This work was supported by Public Health Service grant R01 CA158313 from the National Cancer Institute, NIH, US Department of Health and Human Services (to KBM), and by the World Cancer Research Fund (2010/245).

Summary Background The mammary gland is largely undifferentiated before birth and may be particularly susceptible to intrauterine influences that could increase the risk of cancer through acceleration of cell proliferation or other pregnancy-related processes. Studies of migrant populations, animal data, and limited epidemiological evidence suggest that breast cancer may originate in utero. In a nested case-control study we assessed whether birthweight and other perinatal factors are associated with risk of breast cancer. Methods This case-control study was nested within the cohorts of the two Nurses' Health Studies. We used self-administered questionnaires to obtain information from the mothers of 582 nurses with invasive breast cancer and the mothers of 1569 nurses who did not have breast cancer (controls). Information on risk factors for breast cancer during adulthood were obtained from the nurses; multiple logistic regression analysis adjusted for these risk factors. Findings Birthweight was a significant predictor of breast-cancer risk. With women who weighed 4000 g or more at birth as the reference category, the adjusted odds ratios for breast cancer were 0·86 (95% CI 0·59–1·25) for birthweights of 3500–3999 g, 0·68 (0·48–0·97) for birthweights of 3000–3499 g, 0·66 (0·45–0·98) for birthweights of 2500–2999 g, and 0·55 (0·33–0·93) for birthweights below 2500 g (p for trend 0·004). Prematurity was not significantly associated with risk of breast cancer. Interpretation Birthweight is significantly associated with breast-cancer risk, which suggests that intrauterine factors or processes affect the risk of breast cancer in the offspring. High concentrations of pregnancy oestrogens may have an important role in breast carcinogenesis, but other pregnancy hormones or intrauterine factors may also be involved.

Summary Background The relation between breastfeeding and breast-cancer risk has been examined in many studies; some have reported no association, and others a reduced risk, particularly among premenopausal women. In the only prospective cohort study, no association was found. We have assessed prospectively the association between breastfeeding and incidence of breast cancer among 89887 women in the US Nurses' Health Study. Methods In 1986, participants were asked about the number of months they breastfed for all their children combined. Parous women with no history of cancer were included in this analysis. During 6 years of follow-up (513015 person-years), 1459 invasive breast cancer cases were diagnosed. Findings Relative to women who had never breastfed, no significant overall association was found—after adjusting for established risk factors for breast cancer—between a history of having breastfed and subsequent development of breast cancer (relative risk [RR] 0·93, 95% Cl 0·83-1·03). No inverse trend was observed with duration of breastfeeding; women who breastfed for 2 years or longer had a RR of 1·11 (0·90-1·38). Among women who had given birth only once, women who had breastfed their child experienced a lower incidence of breast cancer (RR 0·68, 0·46-1·00). Among premenopausal women, who tended to be near menopause due to the age structure of the cohort, the RR of breast cancer for those who had lactated was 1·16 (0·89-1·50). Premenopausal women who had lactated for 1 year or more had a RR of 1·10 (0·78-1·57). Interpretation These data suggest that there is no important overall association between breast-feeding and the occurrence of breast cancer.

The purpose of the article was to examine the association of early life growth with age at menarche.Using data from a prospective birth cohort (n = 1134 women, 290 sibling sets), we assessed the association between postnatal growth at 4 months, 1 year, and 4 years and age at menarche, using generalized estimating equations and generalized linear random effects models.Overall, 18% of the cohort experienced early menarche (12 years). After accounting for postnatal growth in length, faster postnatal change in weight (per 10-percentile increase) in all three periods was associated with an increase (range 9%-20%) in the likelihood of having an early menarche. In adjusted linear models, faster weight gains in infancy and childhood were associated with an average age at menarche that was 1.1-1.3 months earlier compared with stable growth. The overall results were consistent for percentile and conditional growth models. Girls who experienced rapid growth (defined as increasing across two major Centers for Disease Control and Prevention growth percentiles) in early infancy had an average age at menarche that was 4.6 months earlier than girls whose growth was stable.Faster postnatal weight gains in infancy and early childhood before the age of 4 years are associated with earlier age at menarche.

We assessed the relation between duration of lactation and maternal incident myocardial infarction.This was a prospective cohort study of 89,326 parous women in the Nurses' Health Study.During 1,350,965 person-years of follow-up, 2540 cases of coronary heart disease were diagnosed. Compared with parous women who had never breastfed, women who had breastfed for a lifetime total of 2 years or longer had 37% lower risk of coronary heart disease (95% confidence interval, 23-49%; P for trend.001), adjusting for age, parity, and stillbirth history. With additional adjustment for early-adult adiposity, parental history, and lifestyle factors, women who had breastfed for a lifetime total of 2 years or longer had a 23% lower risk of coronary heart disease (95% confidence interval, 6-38%; P for trend = .02) than women who had never breastfed.In a large, prospective cohort, long duration of lactation was associated with a reduced risk of coronary heart disease.

In medical research, grant applications and research plans require the prespecification of any hypotheses to be studied. Although such a priori defined associations of interest are the primary goal of the research undertaken, much more data are usually available, in particular from large epidemiological cohort studies in which information on multiple exposures and outcomes is obtained. Only a fraction of possible relations between potential risk factors and diseases is specified before the study is initiated. Generally, the decision about what associations are of interest is based on evidence from basic research, work in animals, or other previous observational epidemiological studies. Cross-sectional studies and to some extent casecontrol studies are used to find undiscovered associations since data can be gathered fairly easily. Prospective studies are generally regarded as too expensive to be wasted on hypothesis generation, and the resources invested are thought to be used most efficiently for hypothesis testing or hypothesis confirmation. What, however, should be done with all the data collected and readily available but not specified in the original research plan? Should they be ignored and wasted? Or should they be saved for a few years or decades until some other studies have raised a hypothesis that can then be tested with the preserved cohort data? Epidemiologists and statisticians investigating all possible associations within a data set are often accused of data dredging or conducting fishing expeditions in search of statistical significance. Such critics, however, overlook the important danger of not studying an association when it actually exists (we define this as a type zero error). Savitz and colleagues 1 have recommended that existing data be exploited to address previously unanticipated research questions in the interest of time and resources. Whether the hypotheses were anticipated during data collection should not affect the validity of the results provided that the data are of high quality. 1