Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

The impact of prenatal parental tobacco smoking on risk of diabetes mellitus in middle-aged women.

Growing evidence indicates that parental smoking is associated with risk of offspring obesity. The purpose of this study was to identify whether parental tobacco smoking during gestation was associated with risk of diabetes mellitus. This is a prospective study of 44- to 54-year-old daughters (n = 1801) born in the Child Health and Development Studies pregnancy cohort between 1959 and 1967. Their mothers resided near Oakland California, were members of the Kaiser Foundation Health Plan and reported parental tobacco smoking during an early pregnancy interview. Daughters reported physician diagnoses of diabetes mellitus and provided blood samples for hemoglobin A1C measurement. Prenatal maternal smoking had a stronger association with daughters' diabetes mellitus risk than prenatal paternal smoking, and the former persisted after adjustment for parental race, diabetes and employment (aRR = 2.4 [95% confidence intervals 1.4-4.1] P < 0.01 and aRR = 1.7 [95% confidence intervals 1.0-3.0] P = 0.05, respectively). Estimates of the effect of parental smoking were unchanged when further adjusted by daughters' birth weight or current body mass index (BMI). Maternal smoking was also significantly associated with self-reported type 2 diabetes diagnosis (2.3 [95% confidence intervals 1.0-5.0] P < 0.05). Having parents who smoked during pregnancy was associated with an increased risk of diabetes mellitus among adult daughters, independent of known risk factors, providing further evidence that prenatal environmental chemical exposures independent of birth weight and current BMI may contribute to adult diabetes mellitus. While other studies seek to confirm our results, caution toward tobacco smoking by or proximal to pregnant women is warranted in diabetes mellitus prevention efforts.

The Early Determinants of Adult Health Study.

This issue of the Journal features collaborative follow-up studies of two unique pregnancy cohorts recruited during 1959-1966 in the United States. Here we introduce the Early Determinants of Adult Health (EDAH) study. EDAH was designed to compare health outcomes in midlife (age 40s) for same-sex siblings discordant on birthweight for gestational age. A sufficient sample of discordant siblings could only be obtained by combining these two cohorts in a single follow-up study. All of the subsequent six papers are either based upon the EDAH sample or are related to it in various ways. For example, three papers report results from studies that significantly extended the 'core' EDAH sample to address specific questions. We first present the overall design of and rationale for the EDAH study. Then we offer a synopsis of past work with the two cohorts to provide a context for both EDAH and the related studies. Next, we describe the recruitment and assessment procedures for the core EDAH sample. This includes the process of sampling and recruitment of potential participants; a comparison of those who were assessed and not assessed based on archived data; the methods used in the adult follow-up assessment; and the characteristics at follow-up of those who were assessed. We provide online supplementary tables with much further detail. Finally, we note further work in progress on EDAH and related studies, and draw attention to the broader implications of this endeavor.

Effect of maternal coffee, smoking and drinking behavior on adult son's semen quality: prospective evidence from the Child Health and Development Studies.

Fetal exposure to caffeine is associated with adverse pregnancy outcomes. Animal and human studies suggest that caffeine may have effects on the developing reproductive system. Here we report on mothers' smoking, coffee and alcohol use, recorded during pregnancy, and semen quality in sons in the age group of 38-47 years. Subjects were a subset of the Child Health and Development Studies, a pregnancy cohort enrolled between 1959 and 1967 in the Kaiser Foundation Health Plan near Oakland, California. In 2005, adult sons participated in a follow-up study (n = 338) and semen samples were donated by 196 participants. Samples were analyzed for sperm concentration, motility and morphology according to the National Cooperative Reproductive Medicine Network (Fertile Male Study) Protocol. Mean sperm concentration was reduced by approximately 16 million sperms for sons with high prenatal exposure (5 cups of maternal coffee use per day) compared with unexposed sons (P-value for decreasing trend = 0.09), which translates to a proportionate reduction of 25%. Mean percent motile sperm decreased by approximately 7 points (P-value = 0.04), a proportionate decline of 13%, and mean percent sperm with normal morphology decreased by approximately 2 points (P-value = 0.01), a proportionate decline of 25%. Maternal cigarette and alcohol use were not associated with son's semen quality. Adjusting for son's contemporary coffee, alcohol and cigarette use did not explain the maternal associations. Findings for son's coffee intake and father's prenatal coffee, cigarette and alcohol use were non-significant and inconclusive. These results contribute to the evidence that maternal coffee use during pregnancy may impair the reproductive development of the male fetus.

Hydroxylated PCB metabolites (OH-PCBs) in archived serum from 1950-60s California mothers: a pilot study.

We are studying participants selected from the Child Health and Development Studies (CHDS), a longitudinal birth cohort of over 20,000 California pregnancies between 1959 and 1967, for associations between maternal body burden of organochlorine contaminants and thyroid function. We designed a pilot study using 30 samples selected among samples with high and low PCB concentrations to evaluate the feasibility of measuring OH-PCBs in the larger study population. GC-ECD and GC-NCI/MS were used to determine PCBs and OH-PCBs as methyl derivatives, respectively. Maternal serum levels of Sigma11PCBs and Sigma8OH-PCB metabolites varied from 0.74 to 7.99 ng/mL wet wt. with a median of 3.05 ng/mL, and from 0.12 to 0.98 ng/mL wet wt. with a median of 0.39 ng/mL, respectively. Average concentrations of Sigma8OH-PCB metabolites in the high PCB group were significantly higher than those in the low PCB group (p < 0.05). The levels of OH-PCB metabolites were dependent on PCB levels (r = 0.58, p < 0.05) but approximately an order of magnitude lower (p < 0.05). The average ratio of Sigma8OH-PCBs to Sigma11PCBs was 0.14 +/- 0.08. The primary metabolite was 4-OH-CB187 followed by 4-OH-CB107. Both of these metabolites interfere with the thyroid system in in vitro, animal, and human studies. OH-PCBs were detectable in all archived sera analyzed, supporting the feasibility to measure OH-PCB metabolites in the entire cohort.

Placental characteristics and reduced risk of maternal breast cancer.

BACKGROUND: Women who have preeclampsia during pregnancy are at reduced risk of subsequent breast cancer. We examined whether other markers of reduced placental size or function, including increased blood pressure during pregnancy, predict a reduction in maternal breast cancer. METHODS: The Child Health and Development Studies is a 40-year follow-up of pregnant women enrolled in the Kaiser Permanente health plan between 1959 and 1967. We identified 3804 white women for whom data were available on placental examinations and other study variables. As of 1997, 146 women had developed invasive breast cancer. Proportional hazards models were used to estimate associations of breast cancer with markers of placental function. All statistical tests were two-sided. RESULTS: A blood pressure increase between the second and third trimesters exhibited a linear relationship with breast cancer rate, with the highest quartile showing a 51% reduction (95% confidence interval [CI] = 20% to 70%) that was not explained by preeclampsia. Smaller placental diameter was independently associated with a reduced breast cancer rate; the association increased with age at first pregnancy (P =.008). Maternal floor infarction of the placenta was associated with a 60% reduction in breast cancer rate (95% CI = 12% to 82%). In combination, placental risk factors were associated with a reduction in the breast cancer rate of as high as 94% (95% CI = 80% to 98%). CONCLUSIONS: Smaller placentas, maternal floor infarction of the placenta, and increasing blood pressure during pregnancy were associated with reduced maternal breast cancer. In the case of smaller placental diameter, the larger reduction observed with older age at first pregnancy suggests a process in which promotion of an existing lesion is blocked. Elucidating the mechanisms for these associations could provide clues to breast cancer prevention and treatment.

Gender differences in hospitalizations for IDDM among adolescents in California, 1991. Implications for prevention.

OBJECTIVE: Describe gender differences in hospitalizations for IDDM to investigate the need for gender-specific interventions to reduce diabetes-related morbidity. RESEARCH DESIGN AND METHODS: Analyses were based on hospital discharges with any mention of IDDM (n = 2,889) and the subset of these for IDDM as a principal diagnosis (n = 2,270) in California children, ages 0-18 years during 1991. Pregnancy-related hospitalizations were excluded. RESULTS: Females had more diabetes hospitalizations among discharges with any mention of diabetes, among discharges with diabetes as a principal diagnosis, and among discharges with diabetic ketoacidosis as a principal diagnosis. For diabetes as a principal diagnosis, females had 40% more hospitalizations, 44% more repeated hospitalizations, 23% more individuals hospitalized, and significantly higher rates of hospitalizations for ages 10-14 years (50 vs. 38 per 100,000) and for ages 15-18 years (68 vs. 29 per 100,000). Gender differences occurred primarily in adolescents, were independent of complicating conditions at the time of hospitalization, and were observed for diabetic ketoacidosis alone. CONCLUSIONS: Adolescent females had more diabetes hospitalizations than did males. The underlying cause may be biological or behavioral. Management protocols tailored for young women may be required to reduce hospitalizations for IDDM among females.

Sex differences in time from self-reported heart trouble to heart disease death in the Alameda County Study. Significance of time dependence of risk variable effects.

In a previous analysis from the Alameda County Study, it was observed that although men had higher heart disease mortality rates than women, there was no male excess in the prevalence of self-reported heart disease morbidity at baseline or in new reports of morbidity 9 years past baseline. This apparent contradiction might occur because women report less severe heart disease than men. In the present study, this hypothesis was evaluated by examining whether self-reported heart trouble was more strongly associated with subsequent heart disease mortality for men than for women in a representative sample of the population of Alameda County, California, selected in 1965 and followed for mortality for 19 years (n = 3,742). In a time-dependent Cox model, self-reported heart trouble was a stronger predictor of heart disease mortality for men, but only during the early years of follow-up (p = 0.00). This effect was due to a shorter time to death for men who reported heart trouble. The relative hazard for men reporting heart trouble was 6.6 (95% confidence interval (CI) 3.7-11.6) at baseline, declining to 3.2 (95% CI 2.2-4.5) by 5 years past baseline and 1.5 (95% CI 0.9-2.5) by 10 years past baseline. Self-reported heart trouble was a consistent predictor of subsequent heart disease mortality for women over the 19-year follow-up period (relative hazard = 2.0, 95% CI 1.4-2.8). Sex differences in the prognosis of self-reported heart trouble were masked in non-time-dependent analyses. These results illustrate that consideration of time dependence may be required for meaningful analysis of long-term cohort studies. Possible explanations of the shorter time to death for men who reported heart trouble are discussed.

Sex differentials in morbidity and mortality risks examined by age and cause in the same cohort.

Many studies indicate that women live longer than men but report more physical illness. This report is the first prospective study of sex ratios for morbidity and mortality due to a variety of causes in a single cohort: a random sample of 5,239 adults, aged 30 years or older in 1965, who have been followed through 1983 (19 years) by cause and age. For both cancer incidence and mortality there was a female excess before age 50 years, followed by a male excess peaking between ages 60 and 69 years. Sex ratios for ischemic heart disease mortality, on the other hand, indicated a male excess at virtually all ages, and that these sex ratios declined with age. However, three measures of heart disease morbidity (self-reported chest pain, heart trouble, and high blood pressure) demonstrated a female excess that did not vary by age. All four measures of functional disability (impaired self-care, impaired mobility, cessation of work, and reduction of work) demonstrated a female excess that did not vary by age (with the exception of a male excess in impaired self-care in adults aged 30 to 39 years). Further analyses of sex differences in health need to acknowledge the heterogeneity of the relation of sex to disease, and the complex age-sex interaction that varies remarkably with both cause and manifestation of outcome (morbidity vs. mortality).