Reproductive outcomes among women exposed to a brominated flame retardant in utero.

The authors studied 194 women exposed to polybrominated biphenyls (PBB) in utero when their mothers consumed products accidentally contaminated in Michigan in 1973. Generalized estimating equations were used to examine the effect of in utero PBB exposure on adult pregnancy-related outcomes. Compared to those with the lowest exposure (≤1 ppb), those with mid-range (>1-3.16 ppb) and high (≥3.17 ppb) PBB exposure had increased odds of spontaneous abortion with wide confidence intervals (odds ratio [OR] = 2.75, 95% confidence interval [CI] = 0.64-11.79, OR = 4.08, 95% CI = 0.94-17.70; respectively; p for trend = .05). Exposure during infancy to PBB-contaminated breast milk further increased this risk. Time to pregnancy and infertility were not associated with in utero exposure to PBB. Future studies should examine the suggested relationship between spontaneous abortion and other brominated flame retardants.

Incidence of thyroid disease following exposure to polybrominated biphenyls and polychlorinated biphenyls, Michigan, 1974-2006.

Thyroid hormones, which influence body metabolism and development, could be affected by persistent organic pollutants. We sought to examine the relationship between polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) and thyroid disease. We employed incidence density sampling to perform a nested case control analysis of the Michigan Long-Term PBB Cohort. Cohort members (n=3333) were exposed to PBBs through contaminated cattle feed in 1973-1974 and to PCBs through daily life. Those with detectable serum PBB and PCB concentrations at enrollment were categorized into tertiles of PBB and PCB exposure. Case-patients were cohort members answering "Yes" to "Has a healthcare provider ever told you that you had a thyroid problem?" during follow-up interviews; control-patients were cohort members answering "No". We used odds ratios (OR) with 95% confidence intervals (CI) to compare odds of thyroid disease by PBB and PCB exposure and by various risk factors. Total cumulative thyroid disease incidence after 33 years was 13.9% among women and 2.6% among men. After adjusting for body mass index, we found no statistically significant differences in odds of any type of thyroid disease among women or men with elevated PBB or PCB exposure. Compared to control-patients, women with thyroid disease had increased odds of being overweight/obese (OR=2.82, 95% CI: 1.94-4.11) and developing infertility (OR=1.71, 95% CI: 1.08-2.69), diabetes (OR=1.61, 95% CI: 1.04-2.51), or arthritis (OR=1.71, 95% CI: 1.18-2.50) during follow-up. Additional research should explore potential associations between PBBs/PCBs and thyroid disease among children exposed in utero.

Dietary exposure to brominated flame retardants and abnormal Pap test results.

OBJECTIVE: This study examined a possible association of dietary exposure to polybrominated biphenyls (PBBs), a brominated flame retardant, and self-reported abnormal Pap test results and cervical dysplasia as a precursor to cervical cancer. METHODS: Women in Michigan who ingested contaminated poultry, beef, and dairy products in the early 1970s were enrolled in a population-based cohort study in Michigan. Serum PBB and serum polychlorinated biphenyl (PCB) concentrations were measured. Reproductive history and health information, including Pap test results, were self-reported by participants. RESULTS: Of the women, 23% (223 of 956) reported an abnormal Pap test. In unadjusted analyses, self-reporting an abnormal Pap test was associated with younger age, current smoking (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.19-2.17), and longer duration of lifetime use of oral contraceptives (≥10 years; HR 1.92, 95% CI 1.21-3.06). When adjusting for PCB exposure, age at the interview, and smoking history, there was a slightly elevated risk of self-reporting an abnormal Pap test among the highly exposed women compared to women with nondetectable PBB concentrations (PBB≥13 µg/L, HR 1.23, 95% CI 0.74-2.06); however, the CI was imprecise. When breastfeeding duration after the initial PBB measurement was taken into account, there was a reduced risk of self-reporting an abnormal Pap test among the highly exposed women who breastfed for ≥12 months (HR 0.41, 95% CI 0.06-3.03; referent group: women with nondetectable PBB concentrations who did not breastfeed). CONCLUSIONS: It remains important to evaluate the potential reproductive health consequences of this class of chemicals as well as other potential predictors of abnormal Pap tests.

alcohol, smoking, and caffeine in relation to fecundability, with effect modification by NAT2.

PURPOSE: Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. We investigated the effects of alcohol, smoking, and caffeine on fecundability, and determined whether the effects were modified by NAT2. METHODS: Three NAT2 polymorphisms were genotyped in 319 women office workers participating in a prospective pregnancy study (1990-1994). Women were ages 20-41 and at risk for pregnancy. Discrete-time survival analysis was used to determine the effects of alcohol, smoking, and caffeine on fecundability and evaluate effect modification by NAT2. RESULTS: We followed 319 women (161 slow acetylators, 158 rapid) for an average of 8 menstrual cycles, resulting in 124 pregnancies. There was no effect of caffeine on fecundability. Drinking ≥1 alcoholic drink per day and current smoking were significantly associated with reduced fecundability, but only among slow acetylators (adjusted fecundability odds ratio [FOR] for smoking = 0.34; 95% confidence interval, 0.22-0.90; adjusted FOR for ≥1 drink per day = 0.20; 0.05-0.92). There was no effect among rapid acetylators. CONCLUSIONS: NAT2 status significantly modified the effects of alcohol and smoking on fecundability, emphasizing the importance of incorporating genetic and metabolic information in studies of reproductive health. Replication of this study is warranted.

Menstrual cycle variability and the likelihood of achieving pregnancy.

The menstrual cycle is an important indicator of underlying hormonal function. Although menstrual cycle variability (sometimes referred to as 'regularity') is associated with a variety of demographic, behavioral, occupational, and environmental factors, as well as with several chronic diseases, few studies have examined its association with fecundity. We investigated whether a woman's menstrual cycle variability was associated with the likelihood of her achieving pregnancy. In this prospective study, we analyzed 3,536 menstrual cycles from 401 women (aged 19-41) recruited from 1990-1994. The women provided daily diaries recording menstrual bleeding, intercourse, and birth control use. Urine samples were assayed for human chorionic gonadotropin to identify early pregnancies during each menstrual cycle. Each woman's menstrual cycle variability was defined by the standard deviation of her cycle lengths during followup. The median follow-up was eight cycles. The outcome was her per-cycle probability of pregnancy. We found that women with high menstrual cycle variability had a reduced (51% lower) per cycle probability of pregnancy (fecundity ratio: 0.49; 95% confidence interval: 0.31, 0.77) compared with women with minimal variability. This relationship was independent of a woman's age and her mean cycle length. Thus, researchers and clinicians using menstrual cycle characteristics as indicators of endocrine or reproductive health should include measures of cycle variability in addition to the more commonly examined cycle length.

Variability of phthalate monoester levels in daily first-morning urine from adult women: a pilot study.

Phthalate exposure is ubiquitous and may affect child and adolescent health through both in utero exposure and direct exposure during childhood. Variability in exposure within women is not well documented. We analyzed 90 first-morning urine samples collected by ten reproductive-age women for phthalate metabolites and creatinine. Monoethyl [122 ng/mL (geometric mean concentration = 139 microg/g creatinine)], monobutyl [85.4 ng/mL (97.0 microg/g creatinine)], monobenzyl [37.2 ng/mL (42.2 microg/g creatinine)], and mono-2-ethylhexyl phthalate [9.4 ng/mL (10.7 microg/g creatinine)] were detected in most (94.4%) samples. The concentrations ranged from 23.8-1090 ng/mL, 43-437 ng/mL, 12.4-186 ng/mL, and 1.3-31.1 ng/mL, respectively. We observed considerable variation in phthalate concentrations by day for individual women. The intraclass correlation coefficient, indicating the proportion of variance explained by differences between subjects, ranged from 0.40 (monobutyl) to 0.68 (monoethyl). Monobenzyl and monoethyl phthalates showed higher levels on weekends as compared with weekdays (p = .01 for both). We found no significant difference between monoester levels from different menstrual cycles. Phthalate concentrations vary considerably for an individual and may require multiple samples for accurate assessment

Maternal exposure to a brominated flame retardant and genitourinary conditions in male offspring.

BACKGROUND: The upward trend in industrial nations in the incidence of male genitourinary (GU) conditions may be attributed to increased exposure to endocrine disruptors. Polybrominated biphenyl (PBB), a brominated flame retardant, is one such suspected endocrine disruptor. OBJECTIVE: We investigated the relationship between maternal serum levels of PBBs and GU conditions among male offspring exposed in utero. METHODS: In this cohort study of sons born to women accidentally exposed to PBBs during 1973-1974, we examined self-reported data on GU conditions among male offspring in relation to maternal serum PBB levels. We used generalized estimating equations to calculate odds ratios (ORs), controlling for gestational age at birth. RESULTS: Of 464 sons, 33 reported any GU condition (13 hernias, 10 hydroceles, 9 cryptorchidism, 5 hypospadias, and 1 varicocele). Four reported both hernia and hydrocele, and one both hernia and cryptorchidism. After adjustment for gestational age at birth, sons of highly exposed women (> 5 ppb) were twice as likely to report any GU condition compared with sons of the least exposed women [< or =1 ppb; OR = 2.0; 95% confidence interval (CI), 0.8-5.1]. This risk was increased when we excluded sons born after the exposure but before the mother's serum PBB measurement (OR = 3.1; 95% CI, 1.0-9.1). We found evidence of a 3-fold increase in reported hernia or hydrocele among sons with higher PBB exposure (test of trend p-value = 0.04). Neither hypospadias nor cryptorchidism was individually associated with PBB exposure. CONCLUSIONS: Although cryptorchidism and hypospadias were not associated with in utero PBB exposure, this study suggests that other GU conditions may be associated with exposure to endocrine-disrupting chemicals during development.

A cohort study of the association between secondary sex ratio and parental exposure to polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB).

BACKGROUND: Polybrominated biphenyl (PBB), a brominated flame retardant, was accidently mixed into animal feed in Michigan (1973-1974) resulting in human exposure through consumption of contaminated meat, milk and eggs. Beginning in 1976 individuals who consumed contaminated products were enrolled in the Michigan Long-Term PBB Study. This cohort presents a unique opportunity to study the association between parental exposures to PBB and offspring sex ratio. METHODS: We identified offspring of female PBB cohort participants (born 1975-1988) and obtained electronic birth records for those born in the state of Michigan. We linked this information to parental serum PBB and PCB concentrations collected at enrollment into the cohort. We modeled the odds of a male birth with generalized estimating equations accounting for the non-independence of siblings born to the same parents. We explored potential confounders: parental age and education at offspring's birth, parental body mass index at cohort enrollment, birth order, gestational age and year of offspring's birth. RESULTS: The overall proportion of male offspring among 865 live births to cohort mothers was 0.542. This was higher than the national male proportion of 0.514 (binomial test: p = 0.10). When both parents were in the cohort (n = 300), we found increased odds of a male birth with combined parents' enrollment PBB exposure > or = the median concentrations (3 microg/L for mothers; 6 microg/L for fathers) compared to combined parents' PBB exposure < the median concentrations (AOR = 1.43, 95% CI: 0.89-2.29), although this did not reach statistical significance. In addition, there was a suggestion of increased odds of a male birth for combined parents' enrollment PCB exposure > or = the median concentrations (6 microg/L for mothers; 8 microg/L for fathers) compared to combined parents' enrollment PCB exposure < the median concentrations (AOR = 1.53, 95% CI: 0.93-2.52). CONCLUSION: This study adds to the body of literature on secondary sex ratio and exposure to environmental contaminants. In this population, combined parental exposure to PBBs or PCBs increased the odds of a male birth. Further research is needed to corroborate these findings and shed light on the biological mechanisms by which these types of chemicals may influence the secondary sex ratio.

Assessing inter-generational transfer of a brominated flame retardant.

Studies have shown that the lipophilic nature of polybrominated biphenyl (PBB) causes it to preferentially accumulate in breast milk posing a potential hazard for suckling infants. The purpose of this study was to examine the inter-generational transfer of PBB from mother to child and whether this association was modified by maternal breast-feeding patterns. One hundred and forty-five mother-child pairs that were participants of the Michigan Long-Term PBB Study were included in this analysis. Mothers were exposed to PBB via contaminated food between 1973 and 1974 and children were exposed in utero and for some, through breast-feeding. Seventy-three percent of children had a non-detectable serum PBB concentration (limit of detection (LOD) = 1 microg L(-1)). Mothers' serum PBB concentration at enrollment ranged from or =8 microg L(-1), breast-feeding > or =5.5 months, maternal age at child's birth > or =28 years, and being born during the PBB exposure period. Among mothers with a detectable serum PBB concentration, those who breast-fed > or =5.5 months were 6 times more likely to have a child with a detectable serum PBB concentration, compared to a non-breast-fed child (95% C.I., 2.0-19.6).

In utero exposure to a brominated flame retardant and male growth and development.

Whether environmental exposures alter the timing of puberty is the subject of increasing interest as pubertal age may have consequences for long term health. This study examines the association between exposure to a brominated flame retardant, polybrominated biphenyl (PBB), and puberty and growth. The population consists of sons born to women accidentally exposed to PBBs during 1973-74. Sons 5 to 17 years reported Tanner Stages and answered questions regarding current growth in a mailed questionnaire. Sons 18 to 30 years of age participated in a telephone interview in which they reported retrospective measures of development. Among sons 5-17 years, those with highest exposure (>3 ppb) were less likely to report advanced Tanner stage genital development (OR=0.4, 95% CI: 0.2-0.9) and were less likely to report advanced pubic hair development (OR=0.5; 95% CI: 0.2-1.0), after adjusting for current age, compared to those with lowest exposure (<= 1 ppb). No differences were seen in growth among sons 5-17. However, among sons 18-30 years, those with higher exposure were more likely to weigh less and have lower BMI as adults (test of trend p=0.01 and 0.04, respectively). They were less likely to recall being tall (OR=0.5; 95% CI 0.2-0.9) or heavy (OR=0.6; 95% CI 0.3-1.1) compared to their peers at age 11 years. These results suggest that sons exposed to PBBs in utero may be more likely to have delayed puberty. Further research is needed to corroborate these findings among structurally related compounds and shed light on the biological mechanisms that may be disrupted during puberty and development.

A decay model for assessing polybrominated biphenyl exposure among women in the Michigan Long-Term PBB Study.

The Michigan Long-Term PBB Study was established following exposure to polybrominated biphenyls (PBBs) in the early 1970s. Serum samples from cohort members were analyzed for PBB during 1976-1993. More than 20 years following this industrial incident, some participants still had measurable serum PBB concentration levels. Thus, there is continuing interest in understanding the elimination of PBB from the body. In the present study, we estimated serum PBB decay and investigated the effects of covariates on serum PBB decay rates among 406 female cohort members. We developed a decay model using a general linear mixed model, which attributes unique intercept and slope estimates for each individual while borrowing information across individuals for predicting these quantities. Age at exposure and body mass index (BMI) at the initial measurement were time-independent covariates. Time since exposure, smoking history, pregnancy status, and breast-feeding status were time-dependent covariates. Higher BMI was associated with a slower decay rate; smokers had a faster decay rate than nonsmokers; and increasing age at exposure was marginally associated with a slower decay rate. Our results suggest a faster serum PBB decay rate for women who breast-fed during the interval between serum PBB measurements. To evaluate the predictive performance of our modeling approach, we compared the results from this model with those from a previously developed ordinary least squares (OLS) two-stage decay model. The mixed-effects decay model predicted the observed serum PBB concentration levels significantly better than the OLS two-stage decay model (mixed-effects model, r=0.93; OLS two-stage model, r=0.86; P<0.0001).

Maternal exposure to polybrominated and polychlorinated biphenyls: infant birth weight and gestational age.

Understanding the influence of maternal exposures on gestational age and birth weight is essential given that pre-term and/or low birth weight infants are at risk for increased mortality and morbidity. We performed a retrospective analysis of a cohort exposed to polybrominated biphenyls (PBB) through accidental contamination of cattle feed and polychlorinated biphenyls (PCB) through residual contamination in the geographic region. Our study population consisted of 444 mothers and their 899 infants born between 1975 and 1997. Using restricted maximum likelihood estimation, no significant association was found between estimated maternal serum PBB at conception or enrollment PCB levels and gestational age or infant birth weight in unadjusted models or in models that adjusted for maternal age, smoking, parity, infant gender, and decade of birth. For enrollment maternal serum PBB, no association was observed for gestational age. However, a negative association with high levels of enrollment maternal serum PBB and birth weight was suggested. We also examined the birth weight and gestational age among offspring of women with the highest (10%) PBB or PCB exposure, and observed no significant association. Because brominated compounds are currently used in consumer products and therefore, are increasingly prevalent in the environment, additional research is needed to better understand the potential relationship between in utero exposure to brominated compounds and adverse health outcomes.

Endometriosis among women exposed to polybrominated biphenyls.

PURPOSE: We examined the association between endometriosis and exposure to polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) among women inadvertently exposed to PBBs in 1973. METHODS: Serum PBBs and PCBs were measured in the late 1970s. Women self-reported endometriosis at interview in 1997. We constructed Cox models to estimate the relative incidence of endometriosis in relation to PBB and PCB levels. RESULTS: Seventy-nine of 943 women (9%) reported endometriosis. Compared with women with low PBB exposure (or=4 ppb) (HR = 0.90; 95% CI, 0.51-1.59) exposure did not have increased incidence of endometriosis. Increased incidence of endometriosis was suggested among women exposed to moderate PCB (5-8 ppb) (HR = 1.67; 95% CI, 0.91-3.10) and high PCB (>or=8 ppb) (HR = 1.68; 95% CI, 0.95-2.98) levels compared with low PCB exposure (

Risk of spontaneous abortion among women exposed to polybrominated biphenyls.

Accidental contamination of livestock in Michigan in 1973 with polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed individuals in 1976. At the time of enrollment, serum was collected and analyzed for PBBs and polychlorinated biphenyls (PCBs). In 1997, women aged 18 years or older and active in the registry were invited to participate in a telephone interview about their health. Using generalized estimating equations to account for correlated outcomes within the same woman, we assessed the risk of spontaneous abortion among 529 women with 1344 potentially exposed pregnancies. PBB and PCB exposure were not associated with risk of spontaneous abortion after adjusting for maternal age at conception, age at menarche, and prior infertility. Compared to pregnancies with PBB exposure below the limit of detection, those with levels above 2.9 ppb had a non-significant reduced odds of spontaneous abortion (adjusted OR=0.73; 95% CI=0.47-1.13). Compared to pregnancies with PCB exposure below the limit of detection, those with levels above 6.5 ppb had little difference in risk (adjusted OR=0.91; 95% CI=0.59-1.41). Maternal age at conception above 34 years was significantly associated with elevated risk of spontaneous abortion (OR=2.46; 95% CI=1.10-5.49). The effect of prior infertility was of borderline significance (OR=1.52; 95% CI=0.98-2.38). Older age at menarche was associated with decreased risk of spontaneous abortion (adjusted OR=0.58; 95% CI: 0.38-0.89, comparing menarche at 12-13 with menarche <12). Our results do not support an association between exposure to PBBs or PCBs and risk of spontaneous abortion.

Validity of self-reported menstrual cycle length.

PURPOSE: Self-reported menstrual cycle length has been associated with host and environmental factors and chronic disease risk. The purpose of this study is to evaluate the validity of self-reported cycle length. METHODS: The authors assessed the agreement between a woman's self-reported "usual" cycle length at study onset with the mean of her observed cycle lengths from prospective daily diaries for 398 women aged 19 to 41 years in the Mount Sinai Study of Women Office Workers (1990 to 1994). RESULTS: Forty-three percent of women self-reported usual cycle lengths more than 2 days different from their mean length. When self-reported cycle length was categorized (<26, 26 to 35, and >35 days) and compared with mean cycle length, 21% of women were misclassified. Women who were older, married, and with higher income were more likely to have accurately reported their menstrual cycle length. Women who had short or long mean cycle lengths (lowest and highest quintile of length) were less likely to self-report accurately, and accuracy decreased monotonically with increasing cycle variability. CONCLUSIONS: These findings show considerable measurement error in self-reported cycle length, as well as describe population subgroups that report menstrual cycle length with the greatest accuracy.

Menstrual cycle characteristics: associations with fertility and spontaneous abortion.

BACKGROUND: Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome. METHODS: We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy. RESULTS: Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4-1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9-9.6] and for longer cycles, OR = 3.0 [0.9-10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3-0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3-0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1-1.1]) when compared with 5-day bleeds. CONCLUSIONS: Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.

CYP17 genotype predicts serum hormone levels among pre-menopausal women.

BACKGROUND: CYP17, which encodes cytochrome P450c17alpha, mediates both steroid 17alpha-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYP17 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. METHODS: This is the first study to examine the relationship between CYP17 and estradiol (E2) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. RESULTS: Among women with body mass index (BMI) < or =25 kg/m2, those with the TC and CC genotypes had 19 and 42% higher E2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m2, hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths <27 days [odds ratio (OR) for TC=2.36, 95% confidence interval (CI)=1.24-4.52; OR for CC=5.59, 95% CI=1.53-20.43 compared to TT]. CYP17 genotype was not associated with menstrual bleed length or age at menarche. CONCLUSION: The CYP17 T27C polymorphism may be a marker of endocrine function.