Jennifer D. Peck

A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: a 2000-2009 update.

This review of human studies of caffeine and reproductive health published between January 2000 and December 2009 serves to update the comprehensive review published by Leviton and Cowan (2002). The adverse reproductive outcomes addressed in this review include: (1) measures of subfecundity; (2) spontaneous abortion; (3) fetal death; (4) preterm birth; (5) congenital malformations; and (6) fetal growth restriction. Methodologic challenges and considerations relevant to investigations of each reproductive endpoint are summarized, followed by a brief critical review of each study. The evidence for an effect of caffeine on reproductive health and fetal development is limited by the inability to rule out plausible alternative explanations for the observed associations, namely confounding by pregnancy symptoms and smoking, and by exposure measurement error. Because of these limitations, the weight of evidence does not support a positive relationship between caffeine consumption and adverse reproductive or perinatal outcomes.

Intra- and inter-individual variability of urinary phthalate metabolite concentrations in Hmong women of reproductive age

The reproducibility of urinary phthalate metabolite concentrations has not been well characterized in non-pregnant women of reproductive age. Our primary study objectives were to describe the distribution of urinary phthalate metabolites concentrations among a population of Hmong women of reproductive age, and to evaluate intra- and inter-individual variability of phthalate metabolite concentrations. Ten phthalate metabolites were measured in first-morning urine samples collected from 45 women and 20 of their spouses, who were members of the Fox River Environment and Diet Study cohort in Green Bay, Wisconsin. Repeated first-morning urine samples were collected and analyzed from 25 women, who provided up to three samples over ∼1 month. Measurement variability was assessed using intraclass correlations (ICCs) and surrogate category analysis. Linear mixed models were used to evaluate the associations between participant characteristics and phthalate metabolite concentrations. Nine of the 10 phthalate metabolites were detected in >80% of all analyzed samples, of which seven were detected in all samples. As a measure of reliability, ICCs were strongest for monobenzyl phthalate (0.64) and weakest for the metabolites of di(2-ethylhexyl)phthalate (DEHP) (ranging from 0.13 to 0.22). Similarly, surrogate category analysis suggested that a single urine sample characterized an average 1-month exposure with reasonable accuracy across low, medium and high tertiles for all metabolites, except the DEHP metabolites. Geometric mean concentrations of monoethyl phthalate increased with age, but patterns by education, income, body mass index, environmental tobacco smoke or season were not observed when measures were adjusted for urinary dilution. Our results suggest that the participant characteristics assessed in this study have limited influence on inter-individual variability of phthalate metabolite concentrations. With regard to intra-individual variability, our results suggest that urinary concentrations of some phthalate metabolites are more reproducible over time and are less subjected to exposure misclassification than others (e.g., metabolites of DEHP).

Conjugated equine estrogen influence on mammographic density in postmenopausal women in a substudy of the women's health initiative randomized trial.

PURPOSE Increased mammographic density is associated with increased breast cancer risk and reduced sensitivity of screening mammography and is related to hormone exposure. However, the effects of conjugated equine estrogens (CEEs) alone on mammographic density in diverse racial/ethnic populations are not established. We examined the effect of CEE alone on mammographic density in a subsample of the Womens Health Initiative (WHI) clinical trial participants. PATIENTS AND METHODS In the WHI trial, women were randomly assigned to daily CEE 0.625 mg or placebo. The effect of CEE on mammographic percent density was determined over 1 and 2 years in a stratified random sample of 435 racially and ethnically diverse participants from 15 of 40 WHI clinics. RESULTS Use of CEE resulted in mean increase in mammographic percent density of 1.6 percentage points (95% CI, 0.8 to 2.4) at year 1 compared with a mean decrease of 1.0 percentage point (95% CI, -1.7 to -0.4) in the placebo group (P < .001). The effect persisted for 2 years, with a mean increase of 1.7 percentage points (95% CI, 0.7 to 2.7) versus a mean decrease of 1.2 percentage points (95% CI, -1.8 to -0.5; P < .001) in the hormone and placebo groups, respectively. These effects were greater in women age 60 to 79 years (P = .03 for interaction across age). CONCLUSION Use of CEE results in a modest but statistically significant increase in mammographic density that is sustained over at least a 2-year period. The clinical significance of the CEE effect on mammographic density remains to be determined.

Is Bisphenol-A Exposure During Pregnancy Associated with Blood Glucose Levels or Diagnosis of Gestational Diabetes?

Recent epidemiological studies indicate bisphenol A (BPA), an estrogenic chemical used in production of epoxy, polycarbonate, and plastic may increase risk of insulin resistance and type 2 diabetes. Exposure to BPA during pregnancy may contribute to development of gestational diabetes mellitus (GDM), a precursor to type 2 diabetes in women. This pilot study examined the association between BPA exposure, fasting blood glucose levels (FBG), and GDM diagnosis during pregnancy. Banked urine samples from 22 cases of GDM and 72 controls were analyzed for total (free BPA + conjugates) urinary BPA concentrations (μg/L). FBG levels (mg/dl) were obtained from 1-h 50-g glucose tolerance tests (GTT) that women underwent for routine GDM screening (mean gestational age = 26.6 weeks, SD = 3.8). Those with an initial screening value ≥135 mg/dl underwent 3-h 100 g oral GTT. GDM diagnoses were made when the initial screening value was ≥200 mg/dl or when values at ≥2 time points exceeded 3-h oral GTT thresholds. Among controls, median FBG levels (mg/dL) did not differ across exposure tertiles, defined according to the distribution of total specific-gravity-adjusted urinary BPA concentrations. Logistic regression models controlling for race/ethnicity did not provide evidence of association between BPA exposure and case status across increasing tertiles of BPA exposure (number of GDM cases/controls in tertile1: 13/24; in tertile 2: 6/24; in tertile 3: 3/24). Findings do not support a relationship between total urinary BPA concentrations and altered glucose metabolism during pregnancy. However, due to study limitations, findings need to be interpreted with caution.

Maternal diabetes and renal agenesis/dysgenesis†‡

BACKGROUND Renal agenesis and dysgenesis are potentially lethal congenital malformations affecting 2 to 5 infants per 10,000 live births annually in the United States. The low prevalence of these malformations has complicated understanding of potential risk factors. Maternal diabetes (type 1, type 2, and gestational) has been evaluated extensively as a risk factor for other congenital malformations, but only a limited number of studies have assessed the association between diabetes and renal agenesis. METHODS We conducted a population-based case-control study of deliveries after 20 weeks gestation in Texas Health Service Region 6 (Houston/Galveston area) from January 1, 2000 to December 31, 2002. Cases of renal agenesis/dysgenesis (n = 89) were ascertained from the Texas Birth Defects Registry. Cumulative incidence sampling was used to randomly select, from birth and fetal death records, 356 controls frequency matched to cases by delivery year and vital status. Maternal diabetes and other covariates were collected from vital records. RESULTS The odds of renal agenesis/dysgenesis were 3.1 (95% confidence interval [CI], 1.1-9.3) times greater among deliveries of mothers with diabetes compared to deliveries of mothers without diabetes, controlling for matching factors. CONCLUSIONS Our results are consistent with prior, but limited, research identifying diabetes as a risk factor for renal agenesis/dysgenesis. While these data did not differentiate diabetes diagnoses by type, the results suggest that maternal diabetes may be associated with renal malformations. Further study is warranted.

Vitamin D and calcium supplementation and one-year change in mammographic density in the Women's Health Initiative Calcium and Vitamin D Trial

Background: Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density. Methods: We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Womens Health Initiative hormone therapy (HT) and calcium and vitamin D (CaD) trials. Women were randomized to receive 1,000 mg/d of elemental calcium carbonate plus 400 IU/d of vitamin D3 or placebo. Results: After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% CI = 0.81–1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95% CI = 0.61–1.11) vs. 1.16 (95% CI = 0.92–1.45) in women randomized to active HT. In sensitivity analyses limited to women taking ≥80% of study supplements, ratios were 0.67 (95% CI = 0.41–1.07) in women not assigned to HT and 1.07 (95% CI = 0.79–1.47) women assigned to HT. Conclusions: We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year. Impact: Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study. Cancer Epidemiol Biomarkers Prev; 21(3); 462–73. ©2012 AACR.

Dietary vitamin D and calcium intake and mammographic density in postmenopausal women

Objective: Dietary intake of vitamin D and calcium may be related to risk of breast cancer, possibly by affecting mammographic density. However, the few studies that have evaluated the association between these nutrients and mammographic density in postmenopausal women have had inconsistent results. Methods: We conducted a cross-sectional analysis in 808 participants of the Mammogram Density Ancillary Study of the Womens Health Initiative. Mammographic percent density was measured using baseline mammograms taken before randomization of participants in the intervention trials. Vitamin D and calcium intake was assessed with a validated food frequency questionnaire and an inventory of current supplement use, both completed at baseline. Results: After adjustment for age, body mass index, regional solar irradiance, and other factors, we did not find a relationship between vitamin D or calcium intake and mammographic density. Mean mammographic percent densities in women reporting total vitamin D intakes of less than 100, 100 to 199, 200 to 399, 400 to 599, and 600 or greater IU/day were 5.8%, 10.4%, 6.2%, 3.8%, and 5.1%, respectively (P trend = 0.67). Results in women reporting a total calcium intake of less than 500, 500 to 749, 750 to 999, 1,000 to 1,199, and 1,200 or greater mg/day were 7.3%, 4.9%, 7.3%, 6.9%, and 7.11%, respectively (P trend = 0.51). We did not observe any effect modification by overall level of mammographic density or solar irradiance, but supplemental vitamin D use was associated with lower density in younger women (P interaction = 0.009). Conclusions: These findings do not support a relationship between dietary vitamin D or calcium intake and mammographic density in postmenopausal women. Additional studies should explore these associations in women of different ages and in relation to serum vitamin D levels.

Intrauterine tobacco exposure may alter auditory brainstem responses in newborns

This study of tobacco exposure and auditory processes was conducted in a predominantly low‐income population of 40 pregnant women and their newborns. Urinary cotinine concentrations and self‐reported smoking status were obtained from the mother during the first prenatal care visit. Auditory brainstem‐evoked responses (ABRs) were recorded in neonates to assess neuroelectrical activity of the auditory nerve following a sound stimulus. Infants of mothers with the highest cotinine concentrations (> 1,000 ng/ml) responded at a rate that was four times greater (hazard ratio 4.1, 95% confidence interval 1.4–11.5) than infants of non‐smoking mothers (cotinine ≤ 15 ng/ml). Associations with more moderate cotinine concentrations (> 15–1,000 ng/ml) were not observed. Enhanced ABRs may disrupt auditory processes related to speech perception, negatively affecting reading and language development during childhood. The results suggest that tobacco exposure during pregnancy may impair auditory function.

Socio-Environmental Factors Associated With Pubertal Development in Female Adolescents: The Role of Prepubertal Tobacco and Alcohol Use

PURPOSE Alcohol administered to laboratory animals has been shown to suppress puberty-related hormones and delay puberty by interfering with ovarian development and function. The effects of early substance use on human pubertal development are relatively unexplored. METHODS This cross-sectional study of 3,106 female adolescents, aged 11-21 years, evaluated the association between prepubertal alcohol and tobacco use and the onset of puberty. Ages at initial breast development, body hair growth, and menarche were self-reported. Prepubertal alcohol and tobacco use were defined as the age at first use before the age of pubertal development and accompanied by regular use. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. Logistic regression was used to estimate the association between substance use and delayed puberty, defined as lack of breast development by the age of 13 years. RESULTS Unadjusted models indicated prepubertal tobacco use was associated with a longer time required for breast development (HR = 0.74; 95% CI, 0.65-0.85) and body hair growth (HR = 0.81; 95% CI, 0.71-0.93). Prepubertal alcohol use was associated with late breast development (HR = 0.71; 95% CI, 0.57-0.88). The direction of the observed associations remained consistent after adjusting for covariates, but the magnitude of effects were attenuated and the upper bound of the 95% CIs exceeded the null value. Girls who used alcohol before puberty had four times the odds of having delayed puberty (OR = 3.99; 95% CI, 1.94-8.21) as compared with nonusers. CONCLUSION The results of this study suggest that the endocrine-disrupting effects of alcohol and tobacco use may alter the timing of pubertal development. These cross-sectional findings warrant further investigation.

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Background: Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown. Methods: We conducted an ancillary nested case-control study within the Women’s Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate. Results: Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51). Conclusions: We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications.