1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five U.S. studies.

BACKGROUND: Environmental exposure to organochlorines has been examined as a potential risk factor for breast cancer. In 1993, five large U.S. studies of women located mainly in the northeastern United States were funded to evaluate the association of levels of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and polychlorinated biphenyls (PCBs) in blood plasma or serum with breast cancer risk. We present a combined analysis of these results to increase precision and to maximize statistical power to detect effect modification by other breast cancer risk factors. METHODS: We reanalyzed the data from these five studies, consisting of 1400 case patients with breast cancer and 1642 control subjects, by use of a standardized approach to control for confounding and assess effect modification. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) by use of the random-effects model. All statistical tests were two-sided. RESULTS: When we compared women in the fifth quintile of lipid-adjusted values with those in the first quintile, the multivariate pooled OR for breast cancer associated with PCBs was 0.94 (95% CI = 0.73 to 1.21), and that associated with DDE was 0.99 (95% CI = 0.77 to 1.27). Although in the original studies there were suggestions of elevated breast cancer risk associated with PCBs in certain groups of women stratified by parity and lactation, these observations were not evident in the pooled analysis. No statistically significant associations were observed in any other stratified analyses, except for an increased risk with higher levels of PCBs among women in the middle tertile of body mass index (25-29.9 kg/m(2)); however, the risk was statistically nonsignificantly decreased among heavier women. CONCLUSIONS: Combined evidence does not support an association of breast cancer risk with plasma/serum concentrations of PCBs or DDE. Exposure to these compounds, as measured in adult women, is unlikely to explain the high rates of breast cancer experienced in the northeastern United States.

Lack of effect of psychosocial stress on maternal corticotropin-releasing factor and catecholamine levels at 28 weeks' gestation.

OBJECTIVE: Corticotropin-releasing factor (CRF) and catecholamines are among the major hormones activated during the adaptive response to stressful stimuli. In pregnant women, serum CRF and catecholamines levels increase during labor and preterm delivery. The aim of the present study was to evaluate whether psychosocial stress measures are correlated with serum CRF or urinary catecholamine [ie, epinephrine, norepinephrine (NE), dopamine (DA)] levels in healthy midtrimester pregnant women. METHODS: A large group of white pregnant women (n = 382) participated in the present study. The Work Conditions Questionnaire and the Psychiatric Epidemiology Research Interview were administered to measure job stress and general life stress, respectively. Urine and blood specimens were collected at 28 weeks of gestation at the time of psychosocial evaluation. Epinephrine, NE, and DA were quantified in the urine by a highly sensitive method based on an amperometric detector. Serum CRF and cortisol levels were measured in blood specimens by using specific radioimmunoassays. RESULTS: Serum CRF and cortisol levels did not vary between patients with high and low scores on psychological tests, and no correlation was found between CRF and cortisol levels. One job stress measure, low job latitude, was significantly associated with a mild increase in NE and DA levels in the afternoon and night (P < .05, analysis of variance). Serum cortisol levels were inversely correlated with NE in the morning (r = -0.447; P =.002) and night segments (r = -0.391; P = .007) and with DA in the night period (r = -0.367; P = .013). CONCLUSION: The absence of a significant relationship between CRF/cortisol and psychosocial stress measures in pregnant women suggests that the hypothalamic-pituitary-adrenal response to psychosocial stress may be masked at midtrimester by the constantly high levels of placental CRF, whose control is beyond the influence of environmental stressors.

The rationale for a national prospective cohort study of environmental exposure and childhood development.

Evidence is growing that pre- and perinatal exposures and factors play a role in not only childhood but adulthood disorders. Therefore, there is a compelling need to undertake a national cohort study to evaluate the effects of such factors, ideally through adult life. Several recent developments, including advancements in computer technology, the management, storage, and analysis of biological specimens, and the rapid growth of genetic markers, facilitate the evaluation of the influence of environmental exposures on the subsequent risk of developmental abnormalities and disease. The rationale behind the establishment of such a cohort is discussed.

Organochlorine exposures and breast cancer risk in New York City women.

A hospital-based case-control study of breast cancer risk related to organochlorine (OC) exposure was conducted in a multiethnic setting in New York City. We enrolled 175 breast cancer patients and 355 control patients. The overall racial/ethnic distribution was 57% Caucasian, 21% Hispanic, 22% African-American; cases and controls were frequency-matched by age and race/ethnicity. Tumor markers (estrogen and progesterone receptors, p53, erbB-2) were assessed and organochlorines (DDE, DDT, trans-nonachlor, and higher (HPCB) and lower (LPCB) chlorinated biphenyls) were measured in blood serum. Tumors among minority women were of slightly higher stage than among Caucasians, but tumor markers were similar across the racial/ethnic groups. DDE levels were highest among African-American and Hispanic women; DDT was highest among Hispanics; HPCBs were highest among African-Americans; LPCBs were lowest among Hispanics; and trans-nonachlor was highest among African-Americans. However, OC levels were not associated with risk for breast cancer, nor did OCs differ with respect to tumor stage or tumor markers. Higher DDE levels were associated with increasing body mass index (BMI), but with decreasing level of education, frequency of nulliparity, and frequency of family history of breast cancer. HPCB levels decreased with BMI and were not correlated with breast cancer risk factors. These relationships can be attributed to historical patterns of exposure and to metabolic differences in OCs related to BMI.

Concordance among measures of pregnancy outcome based on fetal size and duration of gestation.

Epidemiologic and clinical studies of pregnancy outcome often consider a variety of related, overlapping outcome measures. The overlap among these measures was analyzed using data from the Mount Sinai Hospital Perinatal Data Base, New York City, New York. A total of 52,621 births from 1986 through 1996 were included, with information on gender, ethnicity, birth weight, and gestational age assigned based on last menstrual period or early ultrasound. The authors considered very low birth weight (VLBW) (<1,500 g), low birth weight (LBW) (<2,500 g), degrees of preterm delivery (less than 32, 34, and 37 weeks' gestation), and small for gestational age (less than the 10th percentile of weight for gestational age) births. Infants at the extremes of gestational age (<32 or 34 weeks' gestation) were almost always LBW (97.6 and 91.7%, respectively), and those who were VLBW were almost always preterm (99.2%). However, only 69.2% of LBW infants were preterm, and 50.2% of preterm infants were LBW (kappa = 0.54). Only for VLBW and less than 32 weeks' gestation were both measures of overlap at least 70% (kappa = 0.98). The lack of concordance among measures suggests that multiple outcome measures be considered and that results from analyses using disparate measures not be compared directly.

Placental abruption and adverse perinatal outcomes.

CONTEXT: Pregnancies complicated by abruption result in increased frequency of perinatal death and decreased fetal size and gestational duration, yet the extent of placental separation and its effect on these adverse outcomes is unknown. OBJECTIVE: To assess the contribution of placental abruption and extent of placental separation to stillbirth, preterm delivery, and fetal growth restriction. DESIGN: Hospital-based, retrospective cohort study. SETTING: Mount Sinai Hospital, New York City, NY. PARTICIPANTS: A total of 53,371 pregnancies occurring in 40,789 women who were delivered of singleton births between 1986 and 1996. MAIN OUTCOME MEASURES: Risks and relative risks for stillbirth (>20 weeks), preterm delivery (<37 weeks), and fetal growth restriction (birth weight below 10th percentile for gestational age) in relation to abruption. RESULTS: The incidence of abruption was 1 % (n = 530). Abruption was associated with an 8.9-fold (95% confidence interval [CI], 6.0-13.0) adjusted relative risk (aRR) of stillbirth. Preterm birth proportions among women with and without abruption were 39.6% and 9.1 %, respectively, yielding an aRR of 3.9 (95% CI, 3.5-4.4). In the abruption group, 14.3% of neonates were growth restricted, compared with 8.1 % among all other births (aRR, 2.0; 95% CI, 1.5-2.4). Extent of placental separation had a profound effect on stillbirth (aRR for 75% separation, 31.5; 95% CI, 17.0-58.4), although evident only among those with at least 50% separation. However, the risk of preterm delivery was substantially increased even for mild abruptions (aRR for 25% separation, 5.5; 95% CI, 4.2-7.3). CONCLUSIONS: In this cohort, placental abruption had a profound impact on stillbirth, preterm delivery, and fetal growth restriction. The risk of stillbirth was dramatically increased for severe placental separation, but preterm delivery was common even among women with lesser degrees of placental separation.

Pesticides and inner-city children: exposures, risks, and prevention.

Six million children live in poverty in America's inner cities. These children are at high risk of exposure to pesticides that are used extensively in urban schools, homes, and day-care centers for control of roaches, rats, and other vermin. The organophosphate insecticide chlorpyrifos and certain pyrethroids are the registered pesticides most heavily applied in cities. Illegal street pesticides are also in use, including tres pasitos (a carbamate), tiza china, and methyl parathion. In New York State in 1997, the heaviest use of pesticides in all counties statewide was in the urban boroughs of Manhattan and Brooklyn. Children are highly vulnerable to pesticides. Because of their play close to the ground, their hand-to-mouth behavior, and their unique dietary patterns, children absorb more pesticides from their environment than adults. The long persistence of semivolatile pesticides such as chlorpyrifos on rugs, furniture, stuffed toys, and other absorbent surfaces within closed apartments further enhances urban children's exposures. Compounding these risks of heavy exposures are children's decreased ability to detoxify and excrete pesticides and the rapid growth, development, and differentiation of their vital organ systems. These developmental immaturities create early windows of great vulnerability. Recent experimental data suggest, for example, that chlorpyrifos may be a developmental neurotoxicant and that exposure in utero may cause biochemical and functional aberrations in fetal neurons as well as deficits in the number of neurons. Certain pyrethroids exert hormonal activity that may alter early neurologic and reproductive development. Assays currently used for assessment of the toxicity of pesticides are insensitive and cannot accurately predict effects to children exposed in utero or in early postnatal life. Protection of American children, and particularly of inner-city children, against the developmental hazards of pesticides requires a comprehensive strategy that monitors patterns of pesticide use on a continuing basis, assesses children's actual exposures to pesticides, uses state-of-the-art developmental toxicity testing, and establishes societal targets for reduction of pesticide use.

Lead exposure among young urban women.

OBJECTIVE: Blood lead levels have declined among every age group in the United States, but urban minority residents remain at disproportionate risk for elevated lead levels. Our objective was to measure lead burden in young women of childbearing age in New York City. We also describe successful means of recruiting this population into a cohort study. MATERIAL AND METHODS: Healthy women aged 18-25 attending a New York City health care center in 1995-1998 were eligible for participation. Participants were recruited by health care providers, the study coordinator and the participants themselves. Venous blood samples were obtained for whole blood lead, ferritin and hematocrit measurements, and detailed questionnaires were administered. RESULTS: 239 women have been recruited to date. The population is predominately minority: 62% African-American, 33% Hispanic and 5% Caucasian/Asian. The average age of participants is 19.3 years. Recruitment of participants into the study is predominantly (55%) through "word of mouth" from previously enrolled participants. Few participants learned of the study through their health care providers. The mean blood lead level among study participants is 2.1 +/- 1.7 micrograms/dl, which is consistent with the most recent United States national survey. CONCLUSIONS: Blood lead levels are low in young, urban minority women of childbearing age in New York City. In this population, recruitment efforts were substantially enhanced with the help of enrolled participants and the health care community.

Methodological issues related to studies of lead mobilization during menopause.

While there has been a substantial decline in lead exposure in the United States during the past two decades, mobilization of existing lead stored in bone potentially represents an important endogenous source of exposure for menopausal women. It has been hypothesized that lead may be mobilized from skeletal stores during conditions of high bone turnover, such as during menopause. However, such mobilization has not been documented in prospective studies. This discussion is focussed on some of the methodological difficulties to be anticipated in longitudinal studies of lead mobilization specific to menopause and the issues that need to be taken into account when evaluating the results of such studies. To evaluate whether lead mobilization occurs during menopause, a prospective repeated measures design is needed using X-ray fluorescence analysis of lead in bone and serial measurements of blood lead. Potential confounders and effect modifiers also need to be taken into account in the statistical analysis.

Risk factors for preterm birth subtypes.

To assess epidemiologic risk factors for preterm birth subcategories in an urban population, we undertook a study of 31,107 singleton livebirths that took place at Mount Sinai Hospital in New York City between 1986 and 1994. We subdivided the preterm births into preterm premature rupture of the membranes, preterm labor, and medically induced births. We obtained information regarding the preterm subtypes and their epidemiologic risk factors from a computerized perinatal database. Adjusted odds ratios showed an increased risk for all three preterm birth subtypes in women who were black (1.9 for preterm premature rupture of membranes, 2.1 for preterm labor, and 1.7 for medically induced births) or Hispanic (1.7 for preterm premature rupture of membranes, 1.9 for preterm labor, and 1.6 for medically induced births), those who had had a previous preterm birth (3.2 for preterm premature rupture of membranes, 4.5 for preterm labor, and 3.3 for medically induced births), those who began prenatal care after the first trimester ( 1.4 for preterm premature rupture of membranes, 1.3 for preterm labor, and 1.3 for medically induced births), women who had been exposed to diethylstilbestrol in utero (3.1 for preterm premature rupture of membranes, 4.1 for preterm labor, and 3.7 for medically induced births), patients with preexisting diabetes mellitus (2.2 for preterm premature rupture of membranes, 2.4 for preterm labor, and 9.5 for medically induced births), and those with antepartum bleeding (2.8 for preterm premature rupture of membranes, 3.6 for preterm labor, and 3.7 for medically induced births). Other sociodemographic, constitutional, life-style, and obstetrical characteristics differed across the groups. Variation in some of the risk factors among the preterm subtypes implies that epidemiologic assessment of the more specific outcomes would be advisable.

p53 haplotype determination in breast cancer.

Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.

Corticotropin-releasing factor and its binding protein: maternal serum levels in term and preterm deliveries.

OBJECTIVE: The primary objective of this investigation was to evaluate whether maternal serum corticotropin-releasing factor levels during pregnancy were predictive of spontaneous preterm delivery. STUDY DESIGN: Maternal serum levels of corticotropin-releasing factor and its binding protein were measured from 20 weeks of gestation in a cross-sectional study of 396 asymptomatic women at high risk for preterm delivery. RESULTS: Gestational age-specific corticotropin-releasing factor levels were not consistently or substantially increased for preterm compared with term deliveries, whether preterm delivery was due to preterm labor or preterm premature rupture of membranes. The binding protein for corticotropin-releasing factor did not vary according to gestational age until term, when it dropped substantially. CONCLUSION: Serum corticotropin-releasing factor levels do not appear to be an important predictor of preterm birth in asymptomatic patients who subsequently have either preterm labor or preterm premature rupture of membranes. Nevertheless, the drop in the corticotropin-releasing factor binding protein level at term suggests that the bioavailability of corticotropin-releasing factor increases as parturition approaches.

Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy.

There is little information available concerning the ontologic development of the human hypothalamic-pituitary-adrenal (HPA) axis nor of the potential interactions among fetal, maternal and placental-derived HPA axis hormones. This study evaluated levels of these hormones in matched maternal and fetal pairs during the second half of uncomplicated pregnancies. Immunoassays were used to measure serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and cortisol in 104 matched fetal and maternal blood samples. Fetal specimens were obtained by percutaneous umbilical blood sampling (PUBS) between 18 and 40 weeks in patients whose pregnancies resulted in healthy, term infants. Correlations among these hormones, and the effect of gestational age were assessed. Maternal CRH concentrations [median (range)] [1.10 ng/ml (0.15 to 23.69)] were significantly greater than fetal values [0.35 ng/ml (0.07 to 1.0)]. Levels of maternal CRH (r = 0.73; p < 0.001) but not fetal CRH (r = 0.01; p = 0.98) correlated with gestational age. Maternal ACTH decreased (r = -0.21; p = 0.04) while fetal ACTH increased (r = 0.35; p < 0.003) with gestational age. Both maternal (r = 0.45; p < 0.001) and fetal (r = 0.57; p < 0.001) cortisol levels increased with gestational age. Maternal serum CRH values correlated best with fetal cortisol (r = 0.40; p = 0.0002) and correlated modestly with maternal cortisol (r = 0.28; p = 0.01), fetal ACTH (r = 0.24; p = 0.03) and fetal CRH (r = 0.23; p = 0.04); but not with maternal ACTH (r = -0.12; p = 0.3). Maternal CRH concentrations increase in the third trimester and correlate with rising fetal cortisol levels.

Risk factors for cryptorchidism: a nested case-control study.

A nested case-control study of cryptorchidism (i.e. undescended testicles) was undertaken as part of a hospital-based cohort study of 6699 singleton male neonates in New York City. Since some of the cryptorchid infants experienced spontaneous descent of their testes, separate analysis was performed for this third group of 'late descenders' (n=140). Cases (n=63) represented infants whose testes remained undescended at the one year assessment. Controls (n=219) represented the next male infant who was delivered immediately after an infant who was cryptorchid at birth. The only independent risk factors for cryptorchidism were Asian ethnic group (adjusted odds ratio (OR) = 3.90, 95% confidence interval (CI) = 1.22-12.41), swollen legs or feet during pregnancy (adjusted OR = 2.16, 95% CI = 1.15-4.04), a family history of cryptorchidism (adjusted OR = 4.32, 95% CI = 1.91-9.80), low birthweight (adjusted OR = 4.10, 95% CI = 1.39-12.08), and use of analgesics during pregnancy (adjusted OR = 1.93, 95% CI = 1.03-3.62). Multiple logistic regression analysis was also performed to identify those factors that were associated with late testicular descent. In this analysis the independent risk factors were black or Hispanic ethnicity (adjusted OR = 2.05, 95% CI = 1.09-3.83), a family history of cryptorchidism (adjusted OR = 4.25, 95% CI = 1.84-9.78), consumption of cola-containing drinks during the pregnancy (adjusted OR = 2.09, 95% CI = 1.10-3.99), a low birthweight delivery (adjusted OR = 9.78, 95% CI = 3.39-28.20), and preterm birth (adjusted OR = 4.01, 95% CI = 1.66-9.70).

The role of DDE and polychlorinated biphenyl levels in preterm birth.

Maternal serum levels of DDE and polychlorinated biphenyls (PCB) and their congeners were compared for 20 women who had a spontaneous preterm delivery and 20 matched women who had delivered at term at Mount Sinai Medical Center in New York between October 1990 and August 1993. Since no substantial case-control differences were evident, these findings do not indicate that increased DDE or PCB levels are associated with spontaneous preterm birth.

Employment-related physical activity and pregnancy outcome.

Concern about possible adverse reproductive effects of employment reflects the increasing participation of pregnant women in the labor force. Although the literature on the effect of employment-related physical activity on pregnancy outcome is substantial, no general consensus has been reached. A growing number of studies, however, suggests that prolonged standing and long working hours may pose a risk to pregnancy. The provision of maternity benefits varies greatly between the United States and European countries. Current modifications of working conditions for both pregnant and non-pregnant women differ even among European countries.

Working conditions, maternity legislation, and preterm birth.

The review of the scientific literature on the role of employment-related physical activity suggests that prolonged standing and long working hours may increase the risk of preterm delivery. Although maternity legislation in many European countries has regulated work schedules and working conditions for pregnant women, none of the European countries except for France seems to have experienced a reduction in preterm rates. France has had both a comprehensive maternity legislation and a national program specifically aimed to reduce preterm birth. Despite the lack of reduction in preterm rates, paid maternity leave, guaranteed job protection, and regulation of hazardous working conditions remain a desirable societal goal for any industrialized nation.

Maternal and neonatal risk factors for cryptorchidism.

We assessed risk factors for cryptorchidism in a prospective hospital-based cohort study at Mount Sinai Hospital in New York City. We examined at birth 6,699 singleton male neonates who were delivered between October 1987 and October 1990. Follow-up examinations were undertaken at 3 months and 1 year for those diagnosed as cryptorchid at birth. We calculated prevalence ratios and adjusted odds ratios according to selected maternal and neonatal characteristics for those who remained cryptorchid at the 1-year assessment. We found elevated risks for maternal obesity [prevalence ratio = 2.42; 95% confidence interval (CI) = 1.11-5.27], for infants delivered by cesarean section (adjusted odds ratio = 2.17; 95% CI = 1.29-3.65), for low birthweight (adjusted odds ratio = 2.29; 95% CI = 1.12-4.70), for preterm birth (adjusted odds ratio = 2.25; 95% CI = 1.16-4.35), and for infants with congenital malformations (prevalence ratio = 13.97; 95% CI = 1.27-26.67). We observed a seasonal effect, with a peak in births of cryptorchid infants during September through November and a smaller peak during the months of March through May. We found no evidence that young women, white women, or primiparas were at increased risk.

An estrogen receptor genetic polymorphism and the risk of primary and secondary recurrent spontaneous abortion.

OBJECTIVE: A case-control study was undertaken to assess the association between an estrogen receptor gene variant and the risk of recurrent spontaneous abortions. STUDY DESIGN: The frequency of the estrogen receptor gene variant in blood lymphocyte deoxyribonucleic acid and other selected maternal characteristics was compared among 60 primary recurrent aborters, 61 secondary recurrent aborters, and 43 women who had had at least two live births but no spontaneous abortions. RESULTS: No association was evident between the estrogen receptor gene variant and the risk of either primary or secondary recurrent abortion. There were data suggesting that primary recurrent aborters in particular were more likely to report a family history of recurrent abortion and a family history of breast cancer. CONCLUSIONS: These findings indicate that the estrogen receptor polymorphism is not a genetic marker for recurrent spontaneous abortions. Therefore, as suggested by previous investigations, this polymorphism appears to be a marker for breast cancer risk only among the subgroups who have had a history of repeated abortions.