Piera M. Cirillo

DDT and Breast Cancer in Young Women: New Data on the Significance of Age at Exposure

Background Previous studies of DDT and breast cancer assessed exposure later in life when the breast may not have been vulnerable, after most DDT had been eliminated, and after DDT had been banned. Objectives We investigated whether DDT exposure in young women during the period of peak DDT use predicts breast cancer. Methods We conducted a prospective, nested case–control study with a median time to diagnosis of 17 years using blood samples obtained from young women during 1959–1967. Subjects were members of the Child Health and Development Studies, Oakland, California, who provided blood samples 1–3 days after giving birth (mean age, 26 years). Cases (n = 129) developed breast cancer before the age of 50 years. Controls (n = 129) were matched to cases on birth year. Serum was assayed for p,p′-DDT, the active ingredient of DDT; o,p′-DDT, a low concentration contaminant; and p,p′-DDE, the most abundant p,p′-DDT metabolite. Results High levels of serum p,p′-DDT predicted a statistically significant 5-fold increased risk of breast cancer among women who were born after 1931. These women were under 14 years of age in 1945, when DDT came into widespread use, and mostly under 20 years as DDT use peaked. Women who were not exposed to p,p′-DDT before 14 years of age showed no association between p,p′-DDT and breast cancer (p = 0.02 for difference by age). Conclusions Exposure to p,p′-DDT early in life may increase breast cancer risk. Many U.S. women heavily exposed to DDT in childhood have not yet reached 50 years of age. The public health significance of DDT exposure in early life may be large.

Preeclampsia and Cardiovascular Disease Death: Prospective Evidence From the Child Health and Development Studies Cohort

This study prospectively investigates the contribution of pregnancy complications and other reproductive age risk factors on the risk of subsequent cardiovascular disease death. Participants were 14 403 women in the Child Health and Development Studies pregnancy cohort drawn from the Kaiser Permanente Health Plan in California. Only women with nonmissing parity and no previously diagnosed heart conditions were included. A total of 481 had observed preeclampsia, and 266 died from cardiovascular disease. The median age at enrollment was 26 years, and the median follow-up time was 37 years. Cardiovascular disease death was determined by linkage with the California Department of Vital Statistics. Observed preeclampsia was independently associated with cardiovascular disease death (mutually adjusted hazard ratio: 2.14 [95% CI: 1.29 to 3.57]). The risk of subsequent cardiovascular disease death was notably higher among women with onset of preeclampsia by 34 weeks of gestation (hazard ratio: 9.54 [95% CI: 4.50 to 20.26]). At 30 years of follow-up and a median age of 56 years, the cumulative cardiovascular disease death survival for women with early preeclampsia was 85.9% compared with 98.3% for women with late preeclampsia and 99.3% for women without preeclampsia. Women with preeclampsia had an increased risk of cardiovascular disease death later in life, independent of other measured risk factors. These findings reinforce previously reported recommendations that a history of preeclampsia should be used to target women at risk for cardiovascular disease. Additionally, women with preeclampsia earlier in pregnancy may be particularly at risk for cardiovascular disease death and could be targeted for early and intensive screening and intervention.

Prenatal DDT Exposure and Testicular Cancer: A Nested Case-Control Study

ABSTRACT The authors examined maternal serum levels of DDT-related compounds in relation to sons risk of testicular cancer 30 years later. Fifteen of 9,744 live-born sons were diagnosed with germ cell testicular cancer and had maternal serum samples. Cases were matched to three controls on race and birth year. Maternal serum DDT-related compounds, measured in the early postpartum, were associated with her sons risk of testicular cancer. Despite low statistical power, we observed that mothers of cases had a significantly higher ratio of p,p′-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) to p,p′-DDE (1,1′-dichloro-2,2′-bis(p-chlorophenyl)ethylene) and lower o,p′-DDT (1,1,1-tricholoro-2-(p-chlororphenyl)-2-(o-chlorophenyl)ethane). These findings are consistent with earlier exposure to DDT and with slower p,p′-DDT elimination among mothers of cases. Whether these associations could be direct, or operate via other pathways is unknown. Further research on interindividual differences in DDT metabolism could provide clues to testicular cancer etiology.

Menstrual Irregularity and Cardiovascular Mortality

BACKGROUND Polycystic ovary syndrome, the most common cause of irregular menstrual cycles, is associated with an adverse cardiovascular risk profile. However, there are limited prospective studies confirming the link between polycystic ovary syndrome and cardiovascular mortality. METHODS We studied 15,005 pregnant women recruited from the Kaiser Foundation Health Plan in California between 1959 and 1966. The menstrual cycle pattern was assessed at baseline according to self-report, physician report, and medical record abstraction. Participants were matched to California Vital Status files annually until 2007 to identify deaths due to overall cardiovascular disease (CVD) and subsets of coronary heart disease (CHD) and cerebrovascular disease based on International Classification of Diseases codes. Cox proportional hazards models were used to estimate the association between irregular cycles and cardiovascular mortality. Missing covariate data were multiply imputated using standard methods. RESULTS During 456,298.5 person-years of follow-up, there were 666 CVD deaths, including 301 CHD deaths and 149 cerebrovascular deaths. Compared with women with regular cycles, women with irregular cycles had an increased risk for CHD mortality [age adjusted hazards ratio (HR) 1.42, 95% confidence interval (CI) 1.03-1.94]; however, the association was not statistically significant after adjustment for body mass index (adjusted HR 1.35, 95% CI 0.98-1.85). There was a nonsignificant increase in CVD mortality (age adjusted HR 1.21, 95% CI 0.97-1.52) but not cerebrovascular mortality (age adjusted HR 0.85, 95% CI 0.49-1.47). CONCLUSIONS In this large prospective cohort of pregnant women, we found an increase in age-adjusted risk for CHD mortality in women with irregular menstrual cycles. This risk was attenuated after adjustment for body mass index.

Pregnancy complications and cardiovascular disease death: 50-year follow-up of the Child Health and Development Studies pregnancy cohort.

Background— Few studies have investigated the combination of pregnancy complications that predict risk for cardiovascular disease (CVD) death and how risk changes with age. This report presents a comprehensive investigation of the relation of the occurrence of multiple pregnancy complications to CVD death over 5 decades in a large pregnancy cohort. Methods and Results— We examined pregnancy events (1959–1967) and CVD death through 2011 in 14 062 women from the Child Health and Development Studies. CVD death was determined by linkage to California Vital Statistics and National Death Index. Women were a median age of 26 years at enrollment and 66 years in 2011. Preexisting hypertension (hazard ratio, 3.5; 95% confidence interval, 2.4–5.1); glycosuria (hazard ratio, 4.2; confidence interval, 1.3–13.1); late-onset preeclampsia (after week 34, hazard ratio, 2.0; confidence interval, 1.2–3.5); and hemoglobin decline over the second and third trimesters (hazard ratio, 1.7; confidence interval, 1.2–2.7) predicted CVD death. Delivery of a small-for-gestation or preterm infant and early-onset preeclampsia (by week 34) significantly predicted premature CVD death (P<0.05 for age dependence). Preterm birth combined with hemorrhage, gestational hypertension, or preexisting hypertension identified women with a 4- to 7-fold increased risk of CVD death. Preeclampsia in combination with preexisting hypertension conferred a significant nearly 6-fold risk in comparison with a 4-fold risk for preexisting hypertension alone. Conclusions— We observed combinations of pregnancy complications that predict high risk of death and 2 new risk markers, glycosuria and hemoglobin decline. Obstetricians serve as primary care physicians for many young women and can readily use these complications to identify high-risk women to implement early prevention.Background— Few studies have investigated the combination of pregnancy complications that predict risk for cardiovascular disease (CVD) death and how risk changes with age. This report presents a comprehensive investigation of the relation of the occurrence of multiple pregnancy complications to CVD death over 5 decades in a large pregnancy cohort. Methods and Results— We examined pregnancy events (1959–1967) and CVD death through 2011 in 14 062 women from the Child Health and Development Studies. CVD death was determined by linkage to California Vital Statistics and National Death Index. Women were a median age of 26 years at enrollment and 66 years in 2011. Preexisting hypertension (hazard ratio, 3.5; 95% confidence interval, 2.4–5.1); glycosuria (hazard ratio, 4.2; confidence interval, 1.3–13.1); late-onset preeclampsia (after week 34, hazard ratio, 2.0; confidence interval, 1.2–3.5); and hemoglobin decline over the second and third trimesters (hazard ratio, 1.7; confidence interval, 1.2–2.7) predicted CVD death. Delivery of a small-for-gestation or preterm infant and early-onset preeclampsia (by week 34) significantly predicted premature CVD death ( P <0.05 for age dependence). Preterm birth combined with hemorrhage, gestational hypertension, or preexisting hypertension identified women with a 4- to 7-fold increased risk of CVD death. Preeclampsia in combination with preexisting hypertension conferred a significant nearly 6-fold risk in comparison with a 4-fold risk for preexisting hypertension alone. Conclusions— We observed combinations of pregnancy complications that predict high risk of death and 2 new risk markers, glycosuria and hemoglobin decline. Obstetricians serve as primary care physicians for many young women and can readily use these complications to identify high-risk women to implement early prevention. # CLINICAL PERSPECTIVES {#article-title-51}

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.

Prenatal exposure to the pesticide DDT and hypertension diagnosed in women before age 50: a longitudinal birth cohort study.

Background: Elevated levels of the pesticide DDT (dichlorodiphenyltrichloroethane) have been positively associated with blood pressure and hypertension in studies among adults. Accumulating epidemiologic and toxicologic evidence suggests that hypertension during adulthood may also be affected by earlier life and possibly the prenatal environment. Objectives: We assessed whether prenatal exposure to the pesticide DDT increases risk of adult hypertension. Methods: We examined concentrations of DDT (p,p´- and o,p´-) and its metabolite p,p´-DDE (dichlorodiphenyldichloroethylene) in prenatal serum samples from a subset of women (n = 527) who had participated in the prospective Child Health and Development Studies birth cohort in the San Francisco Bay area while they were pregnant between 1959 and 1967. We surveyed daughters 39–47 years of age by telephone interview from 2005 to 2008 to obtain information on self-reported physician-diagnosed hypertension and use of hypertensive medication. We used multivariable regression analysis of time to hypertension based on the Cox proportional hazards model to estimate relative rates for the association between prenatal DDT exposures and hypertension treated with medication in adulthood, with adjustment for potential confounding by maternal, early-life, and adult exposures. Results: Prenatal p,p´-DDT exposure was associated with hypertension [adjusted hazard ratio (aHR) = 3.6; 95% CI: 1.8, 7.2 and aHR = 2.5; 95% CI: 1.2, 5.3 for middle and high tertiles of p,p´-DDT relative to the lowest tertile, respectively]. These associations between p,p´-DDT and hypertension were robust to adjustment for independent hypertension risk factors as well as sensitivity analyses. Conclusions: These findings suggest that the association between DDT exposure and hypertension may have its origins early in development.

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.

Effects of work and life stress on semen quality

OBJECTIVE To evaluate associations between work-related stress, stressful life events, and perceived stress and semen quality. DESIGN Cross-sectional analysis. SETTING Northern California. PATIENT(S) 193 men from the Child Health and Development Studies evaluated between 2005-2008. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Measures of stress including job strain, perceived stress, and stressful life events; outcome measures of sperm concentration, percentage of motile sperm, and percentage of morphologically normal sperm. RESULT(S) We found an inverse association between perceived stress score and sperm concentration (estimated coefficient b=-0.09×10(3)/mL; 95% confidence interval [CI]=-0.18, -0.01), motility (b=-0.39; 95% CI=-0.79, 0.01), and morphology (b=-0.14; 95% CI, -0.25, -0.04) in covariate-adjusted linear regression analyses. Men who experienced two or more stressful life events in the past year compared with no stressful events had a lower percentage of motile sperm (b=-8.22; 95% CI, -14.31, -2.13) and a lower percentage of morphologically normal sperm (b=-1.66; 95% CI, -3.35, 0.03) but a similar sperm concentration. Job strain was not associated with semen parameters. CONCLUSION(S) In this first study to examine all three domains of stress, perceived stress and stressful life events but not work-related stress were associated with semen quality.

A Cohort study evaluation of maternal PCB exposure related to time to pregnancy in daughters

BackgroundPolychlorinated biphenyls (PCBs) remain ubiquitous environmental contaminants. Developmental exposures are suspected to impact reproduction. Analysis of mixtures of PCBs may be problematic as components have a complex correlation structure, and along with limited sample sizes, standard regression strategies are problematic. We compared the results of a novel, empirical method to those based on categorization of PCB compounds by (1) hypothesized biological activity previously proposed and widely applied, and (2) degree of ortho- substitution (mono, di, tri), in a study of the relation of maternal serum PCBs and daughter’s time to pregnancy.MethodsWe measured PCBs in maternal serum samples collected in the early postpartum in 289 daughters in the Child Health and Development Studies birth cohort. We queried time to pregnancy in these daughters 28–31 years later. We applied a novel weighted quantile sum approach to find the bad-actor compounds in the PCB mixture found in maternal serum. The approach includes empirical estimation of the weights through a bootstrap step which accounts for the variation in the estimated weights.ResultsBootstrap analyses indicated the dominant functionality groups associated with longer TTP were the dioxin-like, anti-estrogenic group (average weight, 22%) and PCBs not previously classified by biological activity (54%). In contrast, the unclassified PCBs were not important in the association with shorter TTP, where the anti-estrogenic groups and the PB-inducers group played a more important role (60% and 23%, respectively). The highly chlorinated PCBs (average weight, 89%) were mostly associated with longer TTP; in contrast, the degree of chlorination was less discriminating for shorter TTP. Finally, PCB 56 was associated with the strongest relationship with TTP with a weight of 47%.ConclusionsOur empirical approach found some associations previously identified by two classification schemes, but also identified other bad actors. This empirical method can generate hypotheses about mixture effects and mechanisms and overcomes some of the limitations of standard regression techniques.