Perfluorooctanoate and changes in anthropometric parameters with age in young girls in the Greater Cincinnati and San Francisco Bay Area.

METHODS: We conducted a study of per- and polyfluoroalkyl substance biomarkers, including PFOA, in girls from Greater Cincinnati (CIN, N = 353) and the San Francisco Bay Area (SFBA, N = 351). PFOA was measured in the baseline serum sample collected in 2004-2007 of 704 girls at age 6-8 years. Mixed effects models were used to derive the effect of PFOA on BMI, waist-to-height and waist-to-hip ratios over increasing age in this longitudinal cohort. RESULTS: Median PFOA serum concentrations were 7.3 (CIN) and 5.8 (SFBA) ng/mL, above the U.S. population median for children 12-19 years in 2005-2006 (3.8 ng/mL). Log-transformed serum PFOA had a strong inverse association with BMIz in the CIN girls (p = 0.0002) and the combined two-site data (p = 0.0008); the joint inverse effect of PFOA and Age*PFOA weakened at age at 10-11 years. However, in the SFBA group alone, the relationship was not significant (p = 0.1641) with no evidence of changing effect with age. The effect of PFOA on waist:height ratio was similar to BMIz at both sites, but we did not find a significant effect of PFOA on waist:hip ratio in either the CIN or SFBA girls. CONCLUSIONS: PFOA is associated with decreased BMI and waist:height ratio in young girls, but the strength of the relationship decreases with age. Site heterogeneity may be due to greater early life exposure in Cincinnati. DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services.

Increased female autosomal burden of rare copy number variants in human populations and in autism families.

Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10(-5)) and gene content (P=4.1 × 10(-3)). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.

Phthalate exposure and pubertal development in a longitudinal study of US girls.

STUDY QUESTION: Does phthalate exposure during early childhood alter the timing of pubertal development in girls? SUMMARY ANSWER: Urinary concentrations of high-molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. WHAT IS KNOWN ALREADY: Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. STUDY DESIGN, SIZE, AND DURATION: This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6-8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 µg/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age-specific body mass-index percentile, one of the strongest predictors of pubertal onset. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (ΣDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary ΣDEHP (medians: 510 and 59 µg/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. LIMITATIONS, REASONS FOR CAUTION: While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. WIDER IMPLICATIONS OF THE FINDINGS: Phthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests.

Influence of exposure assessment methods on risk estimates in an epidemiologic study of total trihalomethane exposure and spontaneous abortion.

Trihalomethanes are common contaminants of chlorinated drinking water. Studies of their health effects have been hampered by exposure misclassification, due in part to limitations inherent in using utility sampling records. We used two exposure assessment methods, one based on utility-wide sampling averages, and one based on measurements from the utility sampling site closest to the subject's residence, to reestimate total trihalomethane (TTHM) exposure for 4212 participants in a preexisting study of risk factors for spontaneous abortion (SAB). For both approaches we performed unweighted, weighted, and subset analyses. The weighted and subset analyses were intended to reduce exposure misclassification, and were based on within-utility variance in TTHM measurements for the utility-wide average approach, and the distance between the subject's residence and sampling site for the closest-site approach. In general, the utility-wide average methods produced odds ratios equivalent to or slightly higher than the closest-site methods. Odds ratios obtained using the utility-wide average, but not the closest-site, approach also became progressively stronger in the weighted and subset analyses. A dose-response was seen between SAB and an exposure metric incorporating both TTHM concentration (utility-wide average approach) and personal ingestion, with SAB rates ranging from 8.3% to 13.7% (unweighted), 7.9% to 16.6% (variance weighted), and 6.6% to 23.1% (low-variance subset). Utility-wide average TTHM exposure assessment methods together with variance-based weights and subsets are relatively simple exposure assessment techniques, which may increase the epidemiologic usefulness of utility sampling records.

Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight.

We examined the association of exposure to environmental tobacco smoke with birth weight and gestational age in a large, prospective study. We also compared these endpoints between infants of active maternal smokers and those of non-smoking, non-ETS exposed women. Pregnant women were interviewed by telephone during the first trimester, and pregnancy outcome was determined for 99%. Among the 4,454 singleton live births that could be linked to their birth certificate, we confirmed increased risks of low birth weight and small for gestational age with heavier maternal smoking (> 10 cigarettes/day), as well as noting an increased risk for "very preterm" birth (< 35 weeks). These associations were generally stronger among infants of older (> or = 30 years) than those of younger mothers, as well as among non-whites. High environmental tobacco smoke exposure (> or = 7 hours/day in non-smokers) was moderately associated with low birth weight (adjusted odds ratio (AOR) 1.8, 95% confidence limits (95% CL) = 0.82, 4.1), preterm birth (AOR 1.6, 95% CL = 0.87, 2.9), and most strongly with very preterm birth (AOR 2.4, 95% CL = 1.0, 5.3). These associations were generally greater among non-whites than whites. The data support earlier studies suggesting that prenatal environmental tobacco smoke exposure, in addition to maternal smoking, affects infant health.

Caffeine consumption and menstrual function.

The relation between caffeine intake and menstrual function was examined in 403 healthy premenopausal women who belonged to Kaiser Permanente Medical Care Program in 1990-1991. A telephone interview collected information about caffeinated beverage intake as well as other lifestyle, demographic, occupational, and environmental factors. Subjects collected daily urine samples and completed a daily diary for an average of five menstrual cycles. Metabolites of estrogen and progesterone were measured in the urine, each cycle was characterized as anovulatory or ovulatory, and a probable day of ovulation was selected when appropriate. Logistic regression and repeated measures analyses were performed on menstrual parameters. Women whose caffeine consumption was heavy (>300 mg of caffeine per day) had less than a third of the risk for long menses (> or =8 days) compared with women who did not consume caffeine (adjusted odds ratio = 0.30, 95% confidence interval 0.14-0.66). Those whose caffeine consumption was heavy also had a doubled risk for short cycle length (< or =24 days) (adjusted odds ratio = 2.00, 95% confidence interval 0.98-4.06); this association was also evident in those whose caffeine consumption was heavy who did not smoke (adjusted odds ratio = 2.11, 95% confidence interval 1.03-4.33). Caffeine intake was not strongly related to an increased risk for anovulation, short luteal phase (< or =10 days), long follicular phase (> or =24 days), long cycle (> or =36 days), or measures of within-woman cycle variability.

Evidence for an association between environmental tobacco smoke exposure and birthweight: a meta-analysis and new data.

Because of the strong association of active smoking with fetal growth retardation, increasing interest has focused on whether there is also an association with exposure to environmental tobacco smoke (ETS). We examined this issue in a retrospective study and by conducting a review of the literature and data pooling. In our study, nonsmoking women with singleton livebirths born in 1986-87 (n = 992) provided information on exposure to ETS for 1 h or more per day and paternal smoking. The risk of low birthweight (LBW, < 2500 g) was not increased in infants of ETS-exposed women, but there was a somewhat increased risk for LBW at term (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.6, 4.8) and small-for-gestational-age (< 10th percentile of weight; OR = 1.4, 95% CI = 0.8, 2.5). These results were in the range of 16 other studies in the literature that had odds ratios from 1.0 to 2.2. A weighted average of the results of all studies on LBW at term or small-for-gestational-age yielded a pooled estimate of 1.2 [95% CI = 1.1, 1.3] in nonsmoking women. The pooled estimate of mean birthweight indicated a decrement of 28 g with ETS exposure of nonsmoking women [95% CI = -41, -16], with a greater decrement (about 40 g) seen among more homogeneous studies.

Exposure to environmental and mainstream tobacco smoke and risk of spontaneous abortion.

The authors examined the risk of spontaneous abortion from environmental tobacco smoke (ETS) exposure in a prospective study of over 5,000 women conducted in California during 1990-1991. Among nonsmokers, there was little association by hours of ETS exposure at home or work (adjusted odds ratio (OR) for any exposure = 1.01, 95% confidence interval (CI) 0.80-1.27), or by paternal smoking. However, the risks associated with ETS exposure were increased among nonsmokers who had moderate alcohol or heavy caffeine consumption. A moderate association with maternal smoking was observed (adjusted OR for > or = 5 cigarettes per day = 1.3, 95% CI 0.91-1.9).

Cigarette smoking and effects on menstrual function.

OBJECTIVE: To examine the relationship between smoking and menstrual function, using biologic measures rather than self-report of menstrual cycle characteristics. METHODS: In a prospective study, 408 women collected urine daily for one to seven menstrual segments (cycles), maintained daily diaries, and completed detailed interviews. Smoking data from the diaries were averaged over each segment and verified by cotinine assay. Urine samples were analyzed for metabolites of steroid hormones to define the day of ovulation and various menstrual characteristics, including: 1) segment, follicular, luteal phase, and menses length, 2) variability, and 3) anovulation. RESULTS: Heavy smoking (at least 20 cigarettes per day) was associated with nearly four times the risk of short segment (less than 25 days) as was nonsmoking (adjusted odds ratio 3.8, 95% confidence limits 1.1, 12.7). Mean segment length was on average 2.6 days shorter with heavy versus no smoking (95% confidence limits 0.14, 5.0), due almost entirely to shortening of the follicular phase. Women who smoked an average of ten or more cigarettes per day had significantly more variable segment and menses lengths than nonsmokers. Based on small numbers, the data suggested that with greater smoking, there was a possible increased risk of anovulation and short luteal phase. Segments of exsmokers with ten or more pack-years of exposure were more likely to be short and have shorter luteal phases than those of never smokers. CONCLUSION: The effects found in this study of smoking on the menstrual cycle might explain in part associations of smoking with other reproductive endpoints, such as subfecundity and early menopause.

Psychological stress in the workplace and menstrual function.

The relation between psychological stress at work and menstrual function was examined for 276 healthy, working, premenopausal women who participated in the California Women's Reproductive Health Study in 1990-1991. Subjects collected daily urine samples and completed a daily diary for an average of five menstrual cycles. Metabolites of estrogen and progesterone were measured in the urine, and computer algorithms were developed to characterize each cycle as ovulatory or anovulatory and to select a probable day of ovulation. A telephone interview collected information about psychological stress at work as well as other occupational, demographic, lifestyle, and environmental factors. Logistic regression was used to model stressful work and risk of anovulation (> or = 36 days without ovulating) and measures of within-woman cycle variability. Repeated measures analyses were performed on other menstrual cycle parameters. Stressful work (high demand in combination with low control) was not strongly related to an increased risk for anovulation or cycle variability or to any of the following cycle endpoints: short luteal phase (< or = 10 days), long follicular phase (> or = 24 days), long menses (> or = 8 days), or long cycle (> or = 36 days). However, women in stressful jobs had a more than doubled risk for short cycle length (< or = 24 days) compared with women not working in stressful jobs (adjusted odds ratio = 2.24, 95% confidence interval 1.09-4.59).

Use of urine biomarkers to evaluate menstrual function in healthy premenopausal women.

A total of 403 healthy, premenopausal women, residing near Santa Clara, California, were recruited from a large health care plan in California for a study of menstrual function. After a telephone interview, participants collected daily urine samples and recorded bleeding and other information in diaries. Data were collected during 1990-1991. Urine samples were analyzed for creatinine and for estradiol and progesterone metabolites by enzyme-linked immunoassay. Computer algorithms were developed to derive menstrual segment length, ovulatory status, day of ovulation, and other parameters from the urine and diary data. (We use "segment" rather than "cycle" to avoid implying that normal cycling occurred.) The average length of participation was 141 (standard deviation, 45) days. The mean segment length was 28.8 (standard deviation, 4.4) days; follicular phase length, 16.0 (standard deviation, 4.4) days; and luteal phase length, 12.9 (standard deviation, 1.7) days; 19 (4.7%) women experienced anovulatory episodes. In exploratory multivariate analyses, important associations included the following: age of > or = 35 years with decreased segment and follicular phase lengths; heavier weight (upper quartile) with anovulation and increased follicular phase and decreased luteal phase lengths; Hispanic ethnicity with anovulation and increased segment length; and past difficulty in achieving pregnancy with anovulation and increased length and variability of segments and follicular phases. Urine biomarkers can be used successfully to evaluate menstrual function in epidemiologic studies.

Rate of caffeine metabolism and risk of spontaneous abortion.

In a case-control study of 73 women with and 141 women without spontaneous abortion, the authors determined the activity of the three principal caffeine-metabolizing enzymes--cytochrome P-4501A2 (CYP1A2), xanthine oxidase, and N-acetyltransferase 2--by measuring levels of caffeine metabolites in urine. After examining the effect of enzyme activity and different levels of caffeine intake, they concluded that there was no evidence that an interaction between enzyme activity and caffeine intake during pregnancy resulted in risk of spontaneous abortion. In a subsample comparing 24 cases with recurrent (two or more) spontaneous abortions and 21 controls with two or more livebirths and no previous spontaneous abortions, the unadjusted odds ratio for low CYP1A2 enzyme activity (below the median) was 0.92 (95% confidence interval (CI) 0.28-3.04) compared with higher CYP1A2 activity. The odds ratio for risk of recurrent spontaneous abortion and low xanthine oxidase activity (below the median) versus higher activity was 0.37 (95% CI 0.10-1.29). Phenotypically slow acetylators (N-acetyltransferase 2 index <0.37) had an odds ratio of 1.58 (95% CI 0.48-5.13) for recurrent loss compared with rapid acetylators. Thus, some association of the latter two caffeine-metabolizing enzymes with recurrent spontaneous abortion is suggested but may also be due to chance.

Genetic monitoring of malathion-exposed agricultural workers.

The aerial application of malathion over large urban populations in Southern California during the early 1990s raised concerns about adverse health effects, including the potential to cause genetic damage. Workers in the Mediterranean fruit fly eradication program, which involved application of malathion as ground treatment, were studied to examine micronucleus formation and mutation frequencies assessed by the glycophorin A (GPA) assay. In the 1992 pilot project the mean micronuclei level appeared higher in lymphocytes of exposed workers (n = 13) compared to controls (n = 4) (20.1 +/- 7.1 vs 14.3 +/- 7.2 respectively, P = 0.09). During the 1993 season, neither of the cohorts examined showed a higher level of micronuclei in workers exposed to malathion compared to unexposed, nor did the pooled total (n = 53; means = 17.8 +/- 7.2 vs 18.5 +/- 6.3, respectively), even after adjustment by multiple regression. The GPA variant frequency was not associated with malathion exposure in any of the cohorts. These results suggest that any potential risk of genotoxic damage from exposure to malathion is relatively low, but other assays may be more sensitive, and the sample size was small.

Moderate maternal alcohol consumption and risk of spontaneous abortion.

Maternal alcoholism is known to have adverse effects on reproduction and fetal development, but the effects of moderate consumption remain controversial. In a previous case-control study, we found a doubled risk of spontaneous abortion with an average consumption of seven or more drinks per week during the first trimester. To confirm this finding while avoiding potential biases from the case-control design, we examined moderate alcohol consumption in a prospective cohort study of over 5,000 pregnant women. An interview in the first trimester asked about alcohol consumption during the week before interview ("during the first trimester") and before pregnancy. We found an increased risk of spontaneous abortion in women who drank more than three drinks per week during the first trimester, with an adjusted odds ratio (OR) of 2.3 [95% confidence interval (CI) = 1.1-4.5]. The increased risk associated with this moderate alcohol consumption may be higher in first than in second trimester abortions, and it is even higher in the first 10 weeks (OR = 3.8; 95% CI = 1.7-8.7), based on small numbers. Consumption of alcohol before pregnancy was not strongly associated with spontaneous abortion.

Caffeinated beverages, decaffeinated coffee, and spontaneous abortion.

We examined the relations between spontaneous abortion and the consumption of caffeine, individual caffeine-containing beverages (coffee, tea, and soda), and decaffeinated coffee in a prospective study of 5,144 pregnant women. We collected information about potential risk factors for spontaneous abortion, including consumption of caffeinated beverages and decaffeinated coffee before and during pregnancy, by interview in the first trimester. Neither total estimated caffeine nor individual caffeinated beverage consumption during the first trimester was associated with an appreciable increase in risk for spontaneous abortion. The adjusted odds ratio for consumption of greater than 300 mg per day of caffeine was 1.3 [95% confidence interval (CI) = 0.8-2.1] after adjustment for maternal age, pregnancy history, cigarette and alcohol consumption, employment, race, gestational age at interview, and marital and socioeconomic status. The adjusted odds ratio for spontaneous abortion related to consumption of three or more cups of decaffeinated coffee during the first trimester was 2.4 (95% CI = 1.3-4.7) in the same model. Although we could not demonstrate this with available data, we suspect that this association was due to bias resulting from the relations among fetal viability, symptoms of pregnancy such as nausea, and consumption patterns during pregnancy.

A prospective study of work-related physical exertion and spontaneous abortion.

We examined the relation of physical exertion to spontaneous abortion in a prospective study of 5,144 pregnant women. In a first trimester interview, we obtained data on employment and physical activity at work and at home, as well as other potential risk factors for spontaneous abortion. We measured exertion as follows: time spent working, standing and bending at work, hours between breaks, and hours spent doing housework or yardwork; shift worked; number of times lifted weights and more than 15 pounds at work or at home; number of children under age 5 years cared for at home. None of the exertion measures was appreciably associated with an increased risk of spontaneous abortion overall. In addition, physical activity at work and at home combined was not related to increased risk. For women with a history of two or more spontaneous abortions, standing at work more than 7 hours per day was associated with an adjusted odds ratio (OR) of 4.3 [95% confidence limits (CL) = 1.6, 11.7], whereas standing at work for 7 hours or less was associated with an adjusted OR of 1.7 (95% CL = 1.1, 2.6). Women without such a history who stood more than 7 hours at work had an adjusted OR near unity.

Bone mass and subtle abnormalities in ovulatory function in healthy women.

Women with occasional anovulatory or short luteal phase menstrual cycles have been reported to lose bone mineral density (BMD) at a greatly accelerated rate compared to women without such abnormalities. To investigate this association, we performed a longitudinal study of BMD in a group of healthy premenopausal women enrolled in a comprehensive study of ovulatory function. Subjects had collected daily urine samples that were analyzed for estrone and progesterone metabolites by enzyme-linked immunoassay. The 53 participants collected urine for an average of 4.1 cycles. Computer algorithms identified 7 (13.2%) women with luteal phase abnormalities (> 1 anovulatory cycle or cycle with luteal phase length < or = 10 days) and 17 (32.1%) women with other menstrual abnormalities. Areal BMD (grams per cm2) was measured at the lumbar spine, hip, and whole body using dual energy x-ray absorptiometry; BMD was measured 2-3 times over an average observation period of 17.5 months. At baseline, women with luteal abnormalities had mean BMD similar to those of the 29 women with no abnormal cycles: lumbar spine, 1.06 vs. 1.09 g/cm2; total hip, 0.95 vs. 0.94 g/cm2; whole body, 1.15 vs. 1.11 g/cm2 (P > 0.10; adjusted for age and weight at baseline, parity, physical activity level, and calcium intake). When compared at follow-up to women with no abnormal cycles, women with luteal abnormalities tended to gain BMD at the spine and hip (P > 0.10). On whole body measurement, women with luteal abnormalities tended to lose BMD compared to women with no abnormal cycles (-1.1%/yr vs. 0%/yr; P = 0.08); however, the magnitude of loss was not unusual for women in this age range and was within the coefficient of variation for replicate measurements. Neither mean luteal phase length, percent time in luteal phase, nor average daily excretion of progesterone metabolites was associated with baseline BMD or percent annual change in BMD at any measurement site. Thus, we did not confirm a relationship between luteal abnormalities and accelerated bone loss in this population of healthy premenopausal women.