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To study maternal smoking during pregnancy and the risk of congenital urinary tract anomalies, we interviewed mothers of 118 affected infants born to residents of western Washington State during 1990 and 1991 and mothers of 369 control infants randomly selected from those without birth defects delivered during those years in five hospitals in King County, Washington. Maternal smoking was associated with an increased risk of congenital urinary tract anomalies in offspring (adjusted odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.2, 4.5). This risk was higher among light smokers (1-1000 cigarettes during the pregnancy) (OR = 3.7; 95% CI = 1.7, 8.6) than among heavy smokers (OR = 1.4; 95% CI = 0.6, 3.3). Our results corroborate previous findings and support the hypothesis of a causal relation.

In a population-based case-control study of breast cancer that included 2174 cases and 2009 population controls under 55 years of age, prior breast implants were reported by 36 cases versus 44 controls. After adjustment for the matching factors as well as variables associated with both breast cancer risk and breast enlargement (race, family history of breast cancer, body size, screening history), the relative risk of breast cancer associated with a prior implant was 0.6 (95% CI 0.4-1.0). The reduced risk persisted with increasing interval since surgery, arguing against selection bias as an explanation. Further, although a deficit of in situ tumors was seen among women with implants (RR = 0.2), the risk associated with implants remained reduced for both localized and distant tumors (RR = 0.8 for both stages). In a smaller group of women who had prior breast reduction surgery (10 cases, 13 controls), a reduced risk of breast cancer also was observed (RR = 0.7, 95% CI 0.3-1.6). The results of this study must be interpreted cautiously because of the small number of women involved and reliance on patient reports of prior operations. In not showing any elevation in breast cancer risk following a breast implant, our results confirm several record linkage studies but contradict some clinical studies that suggest an adverse effect. Additional investigations are needed in relation to specific types of breast implants, including the polyurethane-coated implants, which have been linked to high cancer rates in laboratory animals. (Plast. Reconstr. Surg. 97: 269. 1996.)

Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families. However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population. We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer.We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history. Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays. Alterations were defined by DNA sequencing.Germ-line BRCA1 mutations were identified in 6 of the 80 women. Four additional rare sequence variants of unknown functional importance were also identified. Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects.Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer. The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer. These results represent a minimal estimate of the frequency of BRCA1 mutations in this population. Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken.

Objective To assess the risk of cervical neoplasia associated with the use of ovulation-inducing agents such as clomiphene citrate (CC). Design Case-cohort study. Setting Infertility clinics in Seattle, Washington. Patients A cohort of 3,837 women evaluated for infertility at some time during 1974–1985. Main Outcome Measure Computer linkage with a population-based tumor registry was used to identify women diagnosed with cervical cancer before January 1, 1992. Data regarding infertility testing and treatment were abstracted from medical records for women who developed cancer and a randomly selected subcohort. Results Thirty-six women in the cohort developed in situ or invasive cervical cancer in comparison with an expected number of 67.8 cases (standardized incidence ratio=0.5, 95% confidence interval [CI] 0.4 to 0.7). Infertile women with fallopian tube abnormalities were at an increased risk of cervical cancer relative to women whose infertility was believed to be due to other causes. The risk among women who had taken CC was reduced relative to infertile women who had not used this drug (relative risk=0.4, 95% CI 0.2 to 0.8). This association was present both in women with and without tubal abnormalities. However, the size of the reduction in risk was not influenced by duration of use. Conclusions The hypothesis that use of antiestrogenic agents, such as CC, can lead to a reduced risk of cervical neoplasia warrants testing in other studies.

The purpose of this study was to assess: (1) the risk of breast cancer associated with use of ovulation-inducing agents (such as clomiphene citrate) as treatment for infertility; and (2) the risk associated with ovulatory abnormalities that result in infertility. We performed a case-cohort study among 3837 women evaluated for infertility at clinics in Seattle, Washington, at some time during 1974–1985. Computer linkage with a population-based tumor registry was used to identify women diagnosed with breast cancer before January 1, 1992. Data regarding infertility testing and treatment were abstracted from the infertility clinic medical records for women who developed breast cancer and a randomly selected subcohort. Twenty-seven women in the cohort developed in situ or invasive breast cancer, in comparison with an expected number of 28.8 cases (standardized incidence ratio, 0.9; 95% confidence interval (CI), 0.6–1.4). Infertile women with evidence of an ovulatory abnormality were at a risk of breast cancer similar to that of women whose infertility was believed to be due to other causes. The risk among women who had taken clomiphene was reduced relative to infertile women who had not used this drug (adjusted relative risk, 0.5; 95% CI, 0.2–1.2), but the reduction in risk did not increase with duration of use. The possibility that use of clomiphene as treatment for infertility lowers the risk of breast cancer should be examined in other, larger studies.

A high level of endogenous estrogen in utero has been hypothesized to be a possible risk factor for breast cancer. We used information from two population-based case-control studies to investigate the relation between perinatal factors and risk of invasive breast cancer among women age 21-45 years (746 cases, 960 controls) and women age 50-64 years (401 cases, 439 controls). Breast cancer cases were ascertained through a population-based cancer registry, and controls were selected by random digit dialing. After adjustment for age, menopausal status, and maternal smoking, the birthweight-breast cancer association in women age 21-45 years followed a J-shaped curve, with women whose birthweight was less than 2,500 gm [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.9-2.0] and 4,000 gm or more (OR = 1.7; 95% CI = 1.1-2.5) at increased risk. Women age 50-64 years who were 4,000 gm or more at birth appeared to be at slightly reduced risk of breast cancer (OR = 0.6; 95% CI = 0.3-1.1). With the exception of maternal smoking, there was little effect of other perinatal factors on breast cancer risk in either group. These results support the hypothesized association between intrauterine estrogen exposure and subsequent risk of breast cancer.

To determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection.Prospective cohort study of 158 HIV-seropositive and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic and colposcopic findings.Subjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIN. Anal specimens were screened for HPV DNA.HG-AIN developed in eight (5.4%) and 24 (15.2%) HIV-seronegative and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 countor = 500 x 10(6)/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests.The association of HG-AIN with HIV, independent of HPV type, level of HPV detection and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.

Background : The success of tamoxifen in reducing the occurrence of contralateral breast cancer among breast cancer patients in clinical trials has prompted the study of its use in the primary prevention of breast cancer. Long-term risks associated with tamoxifen therapy, however, are still being evaluated, particularly with respect to subsequent cancer occurrence at sites other than the breast. Purpose : This population-based, nested case-control study investigated the risks of second primary cancers of the ovary, endometrium, and contralateral breast among women receiving tamoxifen for breast cancer in conventional medical practice. Methods : A cohort of women diagnosed with breast cancer during 1978 through 1990 was identified from a population-based cancer registry. Case subjects included all women in the cohort who subsequently developed second primary ovarian (n = 39), endometrial (n = 42), or contralateral breast (n = 234) cancer prior to 1992. Control subjects were a random sample of the cohort who did not develop a second primary malignancy ; they were matched to the case subjects on age, disease stage, and year of initial breast cancer diagnosis (approximately two control subjects per case subject). Information on tamoxifen use as well as on potential risk factors for the second primary cancers was obtained through medical record abstractions and physician questionnaires. Results : The percentage of women who had received tamoxifen was 18% and 20%, respectively, among ovarian cancer case subjects and control subjects ; 26% and 31%, respectively, among endometrial cancer case subjects and control subjects; and 10% and 18%, respectively, among contralateral breast cancer case subjects and control subjects. The mean duration of tamoxifen use was less than 2 years for all groups. The relative risks for ovarian and endometrial cancers in women who took tamoxifen were relatively low but were consistent with no association (for ovarian cancer, matched odds ratio [mOR] = 0.6 and 95% confidence interval [CI] = 0.2-1.8 ; for endometrial cancer, mOR = 0.6 and 95% CI = 0.2-1.9). Tamoxifen therapy was associated with a decreased risk of contralateral breast cancer (mOR = 0.5 ; 95% CI = 0.3-0.9), especially if the drug had been taken for more than 1 year (mOR = 0.4 ; 95% CI = 0.2-0.9) or if the women were postmenopausal at initial breast cancer diagnosis (mOR = 0.4 ; 95% CI = 0.2-0.8). Conclusions and Implications: These data suggest that short durations of tamoxifen therapy are not associated with an increased risk of endometrial or ovarian cancer but are associated with a reduction in contralateral breast cancer risk. It would not be appropriate, however, to generalize these results to women who receive tamoxifen for longer periods.

To study the relation of maternal periconceptional vitamin use to the risk of a congenital urinary tract anomaly (CUTA), we conducted a case-control study using the Washington State Birth Defect Registry. We identified CUTA cases with no known chromosomal abnormality in seven counties in western Washington State occurring between January 1, 1990, and December 31, 1991. We randomly selected a sample, as controls, of all infants delivered in five large hospitals in King County who did not have a birth defect and who were born in the same year as the cases. About 55% of all infants in King County and a smaller proportion of infants in the other six counties are delivered in these five hospitals. We interviewed mothers of 118 cases and 369 controls to obtain information about their vitamin use during the pregnancy and during the year before the conception. After adjustment for maternal race, family income, county of maternal residence, and birth year, we found that women who used multivitamins during the first trimester had only 15% the risk of bearing a child with a CUTA compared with women who did not take vitamins [odds ratio (OR) = 0.15; 95% confidence interval (CI) = 0.05-0.43]. The reduction was smaller for use restricted to the second or third trimesters (OR = 0.31; 95% CI = 0.09-1.02). Among women who used vitamins during the first trimester, vitamin use before conception was not associated with any further reduction in the risk, nor did there appear to be an association with the amount or brand of vitamin used.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To evaluate in twin pregnancies the characteristics parity, race, smoking, and age, known to be risk factors for preeclampsia in non-twin pregnancies. Methods: All twin pregnancies (3407) and approximately twice as many singletons (8287) were assembled using Washington state birth certificates from the period 1984–1988. Results: In singleton pregnancies, preeclampsia was more common in women who were younger, black, poor, nulliparous, and nonsmokers. In twin pregnancies, similar associations were found, but were only statistically significant for age, race, and parity. There were no significant differences in the risk factors between twin and singleton women. Logistic regression showed that twin pregnancy carries a relative risk (RR) of 3.5 (95% confidence interval [CI] 3.0–4.2), nulliparity an RR of 4.0 (95% CI 3.3–4.8), and black race an RR of 1.8 (95% CI 1.2–2.6) for preeclampsia. In each case, this risk is independent of the other risk factors. Conclusion: Twin pregnancy carries nearly a fourfold increased risk of preeclampsia, independent of race and parity, and the risk of a nulliparous twin pregnancy is 14 times that of a parous singleton pregnancy. Risk factors in a singleton pregnancy act similarly in a twin pregnancy. Thus, any pathophysiologic model for preeclampsia needs to account for the risk twin pregnancy poses as well as other risk factors, such as parity and race.

We assessed the risk of cutaneous malignant melanoma associated with the presence of ovulatory abnormalities and with the use of ovulation-inducing agents (such as clomiphene citrate) in a cohort of 3,837 women evaluated at infertility clinics in Seattle, WA, between 1974 and 1985. Computer linkage with a population-based tumour registry was used to identify women diagnosed with melanoma before 1992. Data regarding infertility testing and treatment were abstracted from the infertility clinic medical records for women who developed cancer and a randomly selected subcohort. Twelve women in the cohort developed cutaneous malignant melanoma, in comparison with an expected number of 6.8 cases (standardized incidence ratio = 1.8; 95% confidence interval (CI) 0.9-3.1). Within the cohort, risk was increased among women who had used clomiphene during 12 or more menstrual cycles (relative risk = 2.2; 95% CI 0.5-10.2). All four of the women with this duration of clomiphene use who developed melanoma had ovulatory abnormalities, and three had also used human chorionic gonadotropin (HCG). No elevation in risk associated with the presence of ovulatory abnormalities was observed in the absence of at least 12 cycles of clomiphene exposure; also, there was no increased risk associated with long-term use of clomiphene among women without ovulatory abnormalities, but the number of such women was very small. Thus, it is not certain to what extent the observed increased risk of melanoma in this cohort (if not due to chance) may be attributable to the use of clomiphene or HCG, or is a reflection of some underlying hormonal abnormality for which the drug was administered.

The authors analyzed data from a population-based case-control study of breast cancer in middle-aged women residing in King County, Washington, to examine the relation between occupation and breast cancer risk. A total of 537 cases and 492 controls completed in-person interviews. Subjects provided job titles and years of employment for their three main occupations since age 18. While there were case-control differences in the frequency with which certain jobs were reported, all were within the limits of chance, given no true association. Also, few additional increases in risk were associated with long-term employment. Relative risk (RR) estimates were elevated for women working in precision textile and apparel jobs (six cases and one control, RR = 5.2). To a lesser extent, RR estimates were also elevated for receptionists, cosmetologists, and the category of painters/sculptors/printmakers. A slight increase in risk was associated with several occupations, including nursing and teaching.

ContextWomen using combined estrogen and progestin hormone replacement therapy (CHRT) have an increased risk of breast cancer; however, data on use for long durations and on risk associated with patterns of use are lacking.ObjectiveTo evaluate relationships between durations and patterns of CHRT use and risk of breast cancer by histological type and hormone receptor status.DesignPopulation-based case-control study.SettingThree counties in western Washington State.ParticipantsNine hundred seventy-five women 65-79 years of age diagnosed with invasive breast cancer from April 1, 1997, through May 31, 1999 (histology: 196 lobular cases, 656 ductal cases, 114 cases with other histological type, and 9 cases with an unspecified histological type; estrogen receptor (ER)/progesterone receptor (PR) status: 646 ER+/PR+ cases, 147 ER+/PR− cases, and 101 ER−/PR− cases [6 ER−/PR+ cases and 75 cases with unknown ER/PR status were not included in the analyses herein]) and 1007 population controls.Main Outcome MeasuresRisks of invasive lobular, ductal, ER+/PR+, ER+/PR−, and ER−/PR− breast carcinomas.ResultsWomen using unopposed estrogen replacement therapy (ERT) (exclusive ERT use), even for 25 years or longer, had no appreciable increase in risk of breast cancer, although the associated odds ratios were not inconsistent with a possible small effect. Ever users of CHRT (includes CHRT users who also had used ERT) had a 1.7-fold (95% confidence interval [CI], 1.3-2.2) increased risk of breast cancer, including a 2.7-fold (95% CI, 1.7-4.3) increased risk of invasive lobular carcinoma, a 1.5-fold (95% CI, 1.1-2.0) increased risk of invasive ductal carcinoma, and a 2.0-fold (95% CI, 1.5-2.7) increased risk of ER+/PR+ breast cancers. The increase in risk was greatest in those using CHRT for longer durations (users for 5-14.9 years and ≥15 years had 1.5-fold [95% CI, 1.0-2.3] and 1.6-fold [95% CI, 1.0-2.6] increases in risk of invasive ductal carcinoma, respectively, and 3.7-fold [95% CI, 2.0-6.6] and 2.6-fold [95% CI, 1.3-5.3] increases in risk of invasive lobular carcinoma, respectively. Associations of similar magnitudes were seen among users of both sequential and continuous CHRT. Risks of ER+/PR− and ER−/PR− tumors were not increased by use of any form of hormone replacement therapy; however, small numbers of these tumors limited power to detect possible associations.ConclusionThese data suggest that use of CHRT is associated with an increased risk of breast cancer, particularly invasive lobular tumors, whether the progestin component was taken in a sequential or in a continuous manner.

Breast cancer survivors have a 60 % higher risk of developing a second primary asynchronous contralateral breast cancer (CBC) compared to women's risk of developing a first primary breast cancer (FBC). However, little is known about how expression of tumor markers in first breast cancers influences CBC risk. We conducted a population-based nested case-control study among women 20-74 years of age diagnosed with a first breast cancer between 1996 and 2008 in western Washington State to evaluate the association between their tumor's estrogen receptor (ER), progesterone receptor (PR) and HER2-neu (HER2) expression, and risk of CBC. The study included 482 cases diagnosed with both a FBC and a CBC and 1,506 control women diagnosed only once with breast cancer identified through our local Surveillance, Epidemiology and End Results (SEER) cancer registry. Compared to the women whose FBC was ER+/PR+, those with ER-/PR- first tumors had a 1.6-fold (95 % confidence interval (CI): 1.2-2.3) increased risk of developing a CBC. When evaluated by joint ER/PR/HER2 status, compared to women with ER+/HER2- first cancers, those with HER2-overexpressing (ER-/HER2+) and triple-negative disease (ER-/PR-/HER2-) had 2.0-fold (95 % CI: 1.1-3.8) and 1.4-fold (95 % CI: 0.9-2.3) elevated risks of developing CBC, respectively. Beyond the known higher risks of mortality among patients diagnosed with more aggressive BC subtypes, here, we observe that they may also have increased risks of developing CBC.

Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent.We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ≥65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression.Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk.While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.

Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.

Certain events of reproductive life, especially completed pregnancies, have been found to influence a woman's risk of breast cancer. Prior studies of the relationship between breast cancer and a history of incomplete pregnancies have provided inconsistent results. Most of these studies included women beyond the early part of their reproductive years at the time induced abortion became legal in the United States.We conducted a case-control study of breast cancer in young women born recently enough so that some or most of their reproductive years were after the legalization of induced abortion to determine if certain aspects of a woman's experience with abortion might be associated with risk of breast cancer.Female residents of three counties in western Washington State, who were diagnosed with breast cancer (n = 845) from January 1983 through April 1990, and who were born after 1944, were interviewed in detail about their reproductive histories, including the occurrence of induced abortion. Case patients were obtained through our population-based tumor registry (part of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute). Similar information was obtained from 961 control women identified through random digit dialing within these same counties. Logistic regression analysis was used to estimate odds ratios and confidence intervals (CIs).Among women who had been pregnant at least once, the risk of breast cancer in those who had experienced an induced abortion was 50% higher than among other women (95% CI = 1.2-1.9). While this increased risk did not vary by the number of induced abortions or by the history of a completed pregnancy, it did vary according to the age at which the abortion occurred and the duration of that pregnancy. Highest risks were observed when the abortion was done at ages younger than 18 years--particularly if it took place after 8 weeks' gestation--or at 30 years of age or older. No increased risk of breast cancer was associated with a spontaneous abortion (RR = 0.9; 95% CI = 0.7-1.2).Our data support the hypothesis that an induced abortion can adversely influence a woman's subsequent risk of breast cancer. However, the results across all epidemiologic studies of this premise are inconsistent--both overall and within specific subgroups. The risk of breast cancer should be reexamined in future studies of women who have had legal abortion available to them throughout the majority of their reproductive years, with particular attention to the potential influence of induced abortion early in life.Epidemiologists compared data on 845 white women who were diagnosed with breast cancer between January 1983 and April 1990, were born after 1944, and lived in King, Pierce, or Snohomish counties in Washington State with data on 961 white women with no breast cancer from the same counties. They wanted to determine whether induced abortion increases the risk of breast cancer. Restricting cases to women born after 1944 allowed the researchers to focus only on legal induced abortions. When the researchers limited the analysis only to women who had been pregnant at least once, the risk of developing breast cancer in women who had had at least 1 induced abortion was 50% greater than those who had not had an induced abortion. This risk differed depending on the age at which the women underwent the induced abortion and the duration of that pregnancy. A gestational age (at the time of the first aborted pregnancy) of 9-12 weeks carried the highest risk of breast cancer (RR = 1.9 vs. 1.4 for =or 8 weeks and =or 13 weeks). Further, the breast cancer risk was greatest among women who underwent the induced abortion when they were less than 18 years old (relative risk [RR] = 2.5). It was especially high for women who were less than 18 years old and who had the abortion between 9 and 24 weeks of gestation (RR = 9). It was also high for those who were at least 30 years old at the time of the abortion (RR = 2.1). Spontaneous abortion was not associated with an increased risk (RR = 0.9). Neither the number of induced abortions nor the history of a completed pregnancy were associated with an increased risk of breast cancer. These findings suggest that an induced abortion during the last month of the first trimester increases the risk of breast cancer and that women who were at a very young age at the time of the first induced abortion face an increased risk of breast cancer.

Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility.We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them.There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk.Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

This population-based case-control study assessed the effect of current cigarette smoking on the risk of functional ovarian cyst development. Cases were all 15-39 year-old enrollees of Group Health Cooperative of Puget Sound (GHC) who had either an inpatient primary diagnosis of functional ovarian cyst in 1988 or 1989 (n = 61) or an outpatient primary diagnosis of functional ovarian cyst at five GHC primary care clinics (n = 37). Controls were randomly selected enrollees matched to cases on age, primary care clinic, and enrollment date (n = 239). A total of 36.7% of cases and 20.5% of controls were determined by medical record review to be current smokers. Compared with women who were not current smokers, the relative risk of a diagnosed functional ovarian cyst among smokers was 2.0 (95% confidence interval 1.1-3.5). This finding, in an area of little previous research, provides a promising lead in the investigation of the etiology of functional ovarian cysts and the effects of smoking on ovarian function in general.

While most studies have found no association between oral contraceptive use and breast cancer, several studies of younger women have reported an association with long-term oral contraceptive use. PURPOSE. We studied the relationship of patterns of oral contraceptive use to breast cancer risk among younger women. These women have had oral contraceptives available their entire reproductive lives and are now entering the breast cancer-prone years.A population-based, case-control study of breast cancer was conducted in three counties in western Washington State among women born in 1945 or later, ages 21-45. Case patients were 747 women with breast cancer diagnosed in 1983-1990 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. Control subjects were 961 women identified by random-digit telephone dialing. Subjects were interviewed in person, using pictures of brands of oral contraceptives and calendars of life events as recall aids.There was no increased incidence of breast cancer associated with ever having used oral contraceptives. Because only 8% of this cohort had never used oral contraceptives, short-term users (1 year) were combined with never users as the reference group for further analyses. A small increased risk of breast cancer was associated with long duration of oral contraceptive use (odds ratio foror = 10 years = 1.3; 95% confidence interval [CI] = 0.9-1.9; P for trend = .03), particularly among women aged 35 years or younger (odds ratio foror = 10 years = 1.7; 95% CI = 0.9-3.1). Breast cancer was also modestly related to oral contraceptive use early in reproductive life (odds ratio for use within 5 years of menarche = 1.3; 95% CI = 1.0-1.8; P for trend = .04) and to use of high-progestin-potency oral contraceptives for at least 1 year (odds ratio = 1.5; 95% CI = 1.1-2.1). These associations were adjusted for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. The associations were not further confounded by case-control differences in education, religion, breast feeding of offspring, or infertility; in oral contraceptive contraindications, indications, or complications; or in measures of breast cancer detection such as mammography or breast biopsy.Long-term oral contraceptive use among young women or use beginning near menarche may be associated with a small excess breast cancer risk, possibly due to susceptibility to genetic damage in breast epithelial cells at ages of high breast cell proliferative activity.Future studies should investigate whether the patterns of risk we reported are present as this cohort ages.A case control study was conducted in Washington among 21-45 year old white women from King, Pierce, and Snohomish counties (i.e., Seattle metropolitan area) to examine the relationship between oral contraceptive (OC) use and breast cancer. The 747 cases were diagnosed with invasive breast cancer between January 1983 and April 1990. The researchers combined short term OC users with never users since just 8% of all subjects had never used OCs. They controlled for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. Longterm use (i.e., =or 10 years) of OCs was associated with a small increased risk of breast cancer (odds ratio [OR] = 1.3; p for trend = 0.03), especially among women not older than 35 years (OR = 1.7). This finding was consistent with results of other studies. OC use early in reproductive life (i.e., within 5 years of menarche) was also associated with a moderate increase in breast cancer (OR = 1.3; p for trend = 0.04). Breast cancer risk was also elevated among women who used high progestin potency OCs (as defined by the Dickey method for classifying OC potency) for at least 1 year (OR = 1.5). Case control differences in education, religion, breast feeding of children, or infertility; in OC contraindications, indications, complications; or in measures of breast cancer detection (e.g., mammography or breast biopsy) did not confound the associations. An association between breast cancer and long term OC use among young women and OC use beginning close to menarche suggest that puberty, a time when breast epithelial cells are undergoing considerable proliferative activity, are susceptible to genetic damage. Further research is needed to determine whether the aforementioned patterns of breast cancer risk continues as the cohort becomes older.

At present, sudden infant death syndrome (SIDS) is the third leading cause of infant deaths in the United States. The declining incidence of SIDS in the past decade is ascribed mainly to recognizing the risk of infants sleeping while prone. This population-based case-control study examined the hypothesis that the drop in SIDS correlates closely with the timing of an American Academy of Pediatrics recommendation for nonprone sleep positions. Cases were 1515 singleton infants born in Washington State in 1985-1995 (excluding 1991) who died of SIDS. The control group comprised 6060 randomly selected singleton infants born in the same period who did not die of SIDS. The average incidence of infant deaths ascribed to SIDS decreased from 2.4% per 1000 live births in 1985-1990 to 1.2% per 1000 in 1992 to 1998. The proportion of all infant deaths attributed to SIDS peaked at 30% in 1989 and fell gradually to a low of 20.9% in 1996. All features associated with an increased risk of SIDS in the earlier cohort were similarly associated in the later one. They included low birth weight (

While evidence on the association between oral contraceptive (OC) use and breast cancer generally suggests little or no increased risk, the question of whether breast cancer risk varies by OC formulation remains controversial. Few studies have examined this issue because large samples and extensive OC histories are required.We used data from a multicenter, population-based, case-control investigation. Women aged 35-64 years were interviewed. To explore the association between OC formulation and breast cancer risk, we used conditional logistic regression to derive adjusted odds ratios, and we used likelihood ratio tests for heterogeneity to assess whether breast cancer risk varied by OC formulation. Key OC exposure variables were ever use, current or former use, duration of use and time since last use. To strengthen inferences about specific formulations, we restricted most analyses to the 2282 women with breast cancer and the 2424 women without breast cancer who reported no OC use or exclusive use of one OC.Thirty-eight formulations were reported by the 2674 women who used one OC; most OC formulations were used by only a few women. We conducted multivariable analyses on the 10 formulations that were each used by at least 50 women and conducted supplemental analyses on selected formulations of interest based on recent research. Breast cancer risk did not vary significantly by OC formulation, and no formulation was associated with a significantly increased breast cancer risk.These results add to the small body of literature on the relationship between OC formulation and breast cancer. Our data are reassuring in that, among women 35-64 years of age, we found no evidence that specific OC formulations increase breast cancer risk.

Background: Prior studies indicate that women with menopausal symptoms have lower estrogen levels because they go through menopause as compared with women who do not experience them. Given the central role of hormones in the etiology of breast cancer, a link between menopausal symptoms and breast cancer is plausible. However, no prior studies have evaluated the association between menopausal symptoms and breast cancer risk. Methods: Utilizing data from a population-based case–control study we examined associations between menopausal symptoms and risks of different histologic types of breast cancer among postmenopausal women. We calculated multivariate adjusted odds ratios (OR) using polytomous logistic regression and evaluated several potential effect modifiers. Results: Women who ever experienced menopausal symptoms had lower risks of invasive ductal carcinoma [(IDC) OR = 0.5; 95% CI: 0.3–0.7], invasive lobular carcinoma (ILC, OR = 0.5; 95% CI: 0.3–0.8), and invasive ductal-lobular carcinoma (IDLC, OR = 0.7; 95% CI: 0.4–1.2), and these reductions in risk were independent of recency and timing of hormone therapy use, age at menopause, and body mass index. Increasing intensity of hot flushes among women who ever experienced hot flushes was also associated with decreasing risks of all three breast cancer subtypes (P values for trend all ≤0.017). Conclusion: This is the first study to report that women who ever experienced menopausal symptoms have a substantially reduced risk of breast cancer, and that severity of hot flushes is also inversely associated with risk. Impact: If confirmed, these findings could enhance our understanding of breast cancer etiology and factors potentially relevant to prevention. Cancer Epidemiol Biomarkers Prev; 20(2); 379–88. ©2011 AACR.

To determine whether pelvic damage is associated with positive Chlamydia trachomatis serology in women with tubal ectopic pregnancy.Cross-sectional retrospective study.A prepaid health maintenance organization.Two-hundred eighty-one women admitted with confirmed tubal ectopic pregnancy were interviewed for history of sexually transmitted diseases. Chlamydia serology was obtained for 135 subjects, and operative findings were available for 121 of these.None.Pelvic damage, as determined by review of operative findings of the pelvis at the time of ectopic surgery.Pelvic damage was associated with positive chlamydia serology with an adjusted odds ratio of 4.2 (95% confidence interval: 1.8 to 9.7). Moderate and severe pelvic damage were more strongly associated with positive serology than mild damage.Women with ectopic pregnancies and antibodies to C. trachomatis are more likely to have damaged pelves than women with ectopic pregnancies without such antibodies. Prevention or early treatment of C. trachomatis infection may reduce pelvic damage and, therefore, reduce incidence of ectopic pregnancy.

Using data from a population-based, case-control study, we assessed risk of tubal pregnancy associated with use of an intrauterine device (IUD) at the time of conception. Cases were 249 members of Group Health Cooperative of Puget Sound who experienced a tubal pregnancy between 1981 and 1986. Controls were 831 members at risk of ectopic pregnancy who were similar to cases with respect to age and county of residence, but otherwise selected at random. Risk of tubal pregnancy associated with current IUD use was compared separately to that among users of various other (or no) contraceptive methods. Tubal pregnancy was more likely to occur among IUD users than among women using oral contraceptives [relative risk (RR) = 3.8, 95% confidence interval (CI) = 1.5-9.9] or barrier methods (RR = 3.6, 95% CI = 1.6-8.1), or, to a lesser extent, among women who had been surgically sterilized (RR = 1.6, 95% CI = 0.8-3.5). In contrast, IUD users were much less likely to experience a tubal pregnancy (RR = 0.2, 95% CI = 0.1-0.4) than were women who were currently not contracepting. For most women, the decision to use an IUD occurs within the context of choosing among various contraceptive methods. Our results indicate that, for these women, the decision to use an IUD results in increased risk of ectopic pregnancy while the device is in use.In King County, Washington, health workers interviewed 249 members of Group Health Cooperative of Puget Sound who had had an ectopic pregnancy between October 1981 and September 1986 and 831 randomly selected, age- and county-matched controls who were at risk of ectopic pregnancy. Researchers wanted to examine the risk of ectopic pregnancy associated with IUD use at time of conception. The Copper 7 IUD was the most common IUD used (66.7% of cases and 65% of controls). Cases were more likely to have a positive titer for C. trachomatis than controls (33.8% vs. 17.6%). In comparison with users of oral contraceptives, barrier methods, and tubal sterilization, IUD use increased the risk of ectopic pregnancy (relative risk [RR] = 3.8, 3.6, and 1.6, respectively). On other hand, IUD users were less likely to experience ectopic pregnancy than women not using any contraception or using other contraceptive methods (RR = 0.2 and 0.6, respectively). All the aforementioned results did not change when the researchers only considered women using the Copper 7 IUD. The risk of ectopic pregnancy fell with increasing duration of IUD use among current users, but the numbers of women were small (e.g., odds ratio for 36-72 months = 0.6 and for 72 months = 0.4). These findings suggest that, for women in the midst of choosing a contraceptive, the risk of ectopic pregnancy is high when an IUD is in situ.

Objective. To examine fecundity prior to disease onset in women with rheumatoid arthritis (RA). Methods. Two hundred fifty-nine RA patients with an opportunity for pregnancy were compared with 1,258 control women as part of a prospective case-control study of recent-onset RA in women. Results. A 12-month or longer interval to pregnancy was found in 42% of RA cases compared with 34% of controls (odds ratio = 1.44, 95% confidence interval 1.10, 1.91). This difference was not accounted for by an older age when attempting to become pregnant among the RA cases compared with the controls. The result was unrelated to rheumatoid factor or HLA-DR4 status. Conclusion. Women with RA were found to have decreased fecundity prior to disease onset, compared with control women.

Purpose To examine whether smoking during first pregnancy, a time of potential vulnerability to tobacco mutagens, is associated with breast cancer. Methods We conducted a nested case-control study within a cohort of Washington State residents with first deliveries during 1984–1999, identified in birth and fetal death records. Linkage to population-based cancer registry data identified 1,099 women in the cohort aged 65 years and younger diagnosed with breast cancer in 1985–2000. Controls (N=10,922) were matched by year and age of first delivery, race/ethnicity, and birth outcome. Maternal smoking and other variables characterizing the pregnancy were obtained from birth and fetal death records. Conditional logistic regression was used to analyze the data. Results The adjusted risk ratio for breast cancer was 0.8, 95% confidence interval 0.7–0.9, among women who smoked during their pregnancy compared with similar women who did not smoke. When the sample was restricted to known state residents at the time of the matched case's diagnosis, there was no association (risk ratio 1.0; 0.8–1.1). Conclusions Our results do not suggest that cigarette smoking during first pregnancy increases the risk of breast cancer.

Breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer (CBC) compared to the risk of breast cancer among women in the general population. While data regarding the relationship between diabetes and breast cancer incidence are inconsistent, diabetes is more clearly linked to an elevated risk of all-cause mortality among breast cancer survivors. However, no prior studies have assessed its impact on CBC risk. We assessed the relationship between diabetes, and CBC risk in a population-based nested case–control study consisting of women 40–79 years of age diagnosed with a first primary ER-positive invasive breast cancer. It included 322 women who developed a second primary CBC and 616-matched control women diagnosed only with a first breast cancer. We used conditional logistic regression to quantify associations between diabetes and CBC risk. Compared to women without a history of diabetes, diabetics had a 2.2-fold [95% confidence interval (CI) 1.3–3.6] increased risk of CBC. This risk was more pronounced among women diagnosed with their first breast cancer before age 60 years (odds ratio, OR = 11.5, 95% CI 2.4–54.5), compared to those diagnosed at age 60 years or older (OR = 1.5, 95% CI 0.8–2.7, P for interaction = 0.011). Diabetics diagnosed with breast cancer appear to have an elevated risk of CBC. This is the first study to report this relationship, but if confirmed efforts to insure that diabetic breast cancer survivors are carefully screened for second breast cancers may be warranted.

OBJECTIVES. Further information is needed on modifiable factors associated with the occurrence of acute pelvic inflammatory disease (PID). Cigarette smoking has been implicated as a risk factor for PID sequelae, but the association between smoking and PID has yet to be fully examined. METHODS. We conducted a population-based case-control study to evaluate smoking as a risk factor for acute PID. The case patients (n = 131) were women health maintenance organization (HMO) enrollees between the ages of 18 and 40 years who were treated for a first episode of PID. The control patients (n = 294) were randomly selected from the HMO enrollment files. RESULTS. Relative to never smokers, current smokers were at increased risk of PID. Women who smoked 10 or more cigarettes per day had a higher risk than did those who smoked less. Available data indicate that smoking status is not serving as a marker for uncontrolled confounding by lifestyle factors. CONCLUSIONS. Our study results suggest that smoking represents a modifiable risk factor for acute PID.

The prevalence and determinants of primary caesarean section in Jamaica were estimated from a survey of women aged 14-49 years. Among 2328 women reporting 2395 live hospital births during the period January 1984 to May 1989, the prevalence of caesarean section was 4.1%. Repeat caesarean sections accounted for 1.3% of the hospital births during that period. Of the medical complications studied, prolonged labour and/or cephalopelvic disproportion carried the highest risks of primary caesarean section, followed by breech presentation, maternal diabetes, a high birth-weight baby, maternal hypertension, and a low birth-weight baby. The risk of primary caesarean section increased with maternal age, decreased with parity, was higher for urban than for rural residents, and was higher for births in private versus government hospitals.Researchers analyzed data on 2395 hospital births which occurred to 2328 14-49 year old women between January 1984 and May 1989 living in 7 parishes of Jamaica to determine the prevalence and factors of cesarean section. The primary cesarean section rate for the 5.5-year period was 4.1% which is lower than the rates of some developing countries and of some developed countries such as the US. The repeat cesarean section rate was 1.3%. Cephalopelvic disproportion and/or prolonged labor (abnormal labor) accounted for 17.4% of all primary cesarean sections. Abnormal labor carried the greatest risk of primary cesarean section (logistic regression model beta=1.9). Other delivery complications which posed considerable risk of cesarean section included breech presentation (beta=1.68), maternal diabetes (beta=0.84), maternal hypertension (beta=0.47), large birth weight infant (beta=0.4), and low birth weight infant (beta=-0.15). These complications made up 22.3%, 7.1%, 7.4%, and 5.3% of all primary cesarean sections, respectively. Nonmedical determinants of primary cesarean section included 30-year old women (beta=1.04), 1-2 births (beta=-1.27), urban residence (beta=0.75), and delivering in a private hospital (beta=0.59). 5.3% of 30-year old mothers underwent a cesarean section compared with 3.8% of 30-year old mothers. 5.2% of women of parity 1-2 had a cesarean section whereas only 2.3% of those of parity =or 3 did. Urban mothers were more likely to have a cesarean section than were rural mothers (5.4% vs. 3.3%). 7.6% of mothers delivering at a private hospital underwent a cesarean section compared with 3.9% of those delivering at a government hospital. Well-designed studies of infant mortality in Jamaica can determine whether the country can attain low levels of early infant mortality while keeping its current low rate of cesarean section.

Using the 1983 United States population of single live births, birthweight and gestational duration were compared for babies of these different parental racial groups: both parents White, mother White-father Black, mother Black-father White, both parents Black. The four groups differed significantly with respect to the usual sociodemographic variables. Mean birthweight and mean gestational duration decreased in that order from the White-White reference group, and conversely there were increasing trends for low birthweight and preterm delivery. Adjustment for the usual sociodemographic variables did not alter these trends appreciably. Group differences were more strongly related to the mother's race than to the father's, and the trends were related to the mother's race. Because the father's race was significant, genetic factors are probably of some importance. The evidence from this study, together with the often-demonstrated relationships between low birthweight and preterm delivery with sociodemographic variables, and the short-term downward secular trends in low birthweight, support the concept that non-genetic maternal factors are more important for these abnormal outcomes. But because neither the usually utilised sociodemographic variables nor genetic factors seem to explain much of the group differences, new approaches are necessary to understand why, irrespective of ethnic group, some women are at excess risk for suboptimal birth outcome.

Washington State reports one of the highest rates of sudden infant death syndrome (SIDS) in the United States; within the state, Native Americans have the highest rate of any racial group. To explore this apparent genetic predisposition, we conducted a population-based retrospective cohort study. Using the state's linked birth and death certificate file for 1984 to 1988, we compared infants whose mothers were coded as "American Indian" with infants whose mothers were coded as "white." Native American infants were more than three times more likely than white infants to die of SIDS (crude relative risk = 3.25; 95% confidence interval = 2.41 to 4.38). However, this elevated risk diminished after adjustment for differences between Native American and white mothers in age, marital status, parity, and smoking status during pregnancy (adjusted relative risk = 1.82; 95% confidence interval = 1.28 to 2.58). The high SIDS rate of Washington's Native Americans appears to be due to the high prevalence of SIDS risk factors among Native American mothers, rather than to a genetic predisposition in the infants. Because many of these maternal factors are related to socioeconomic status, it is likely that programs to improve the overall health of Native Americans might lessen both the impact of SIDS and that of other causes of infant morbidity and death.

A population-based case-control study was conducted in western Washington state to examine the relations between infection with human papilloma viruses (HPV), herpes simplex viruses (HSV), and risk of oral squamous cell cancer in men. Interviews were completed on 131 oral cancer cases diagnosed between January 1985 and December 1989 and 136 controls frequency matched to cases on age and date of diagnosis who were obtained by random digit dialing. The risk for oral cancer among men with 30 or more sexual partners was 2.4 times that of men with four or fewer partners (95% confidence interval (CI) 1.0-5.9). Men who ever practiced oral sex had lower risk for oral cancer relative to men who never practiced oral sex (relative risk (RR) = 0.4, 95% CI 0.2-0.8). Analyses of exfoliated oral cavity cells for the presence of HPV-6 DNA with polymerase chain reaction revealed that men with an oral HPV-6 infection had 2.9 times the risk for oral cancer of noninfected men (95% CI 1.1-7.3), whereas men with an oral HPV-16 infection had 6.2 times the risk for oral cancer of noninfected men (crude RR = 6.2, 95% CI 0.7-52.2). Relative risks associated with serologically detected HSV-1 and HSV-2 infections were 0.8 (95% CI 0.3-1.7) and 1.8 (95% CI 0.7-4.6), respectively. The authors conclude that HPV-6 is associated with oral cancer. Although men infected with HPV-16 and HSV-2 were at elevated risk, these associations may have been due to chance. The role of specific sexual practices in the transmission of viruses to the oral cavity remains unclear.

The association between fetal marijuana and/or alcohol exposure and facial features resembling fetal alcohol syndrome was investigated in a sample of 80 children. Standardized lateral and frontal facial photographs were taken of 40 children, 5 to 7 years of age, whose mothers reported frequent use of marijuana during the first trimester of pregnancy and 40 children whose mothers reported no use of marijuana during pregnancy. The marijuana-exposed and unexposed children were group-matched on alcohol exposure prior to and during pregnancy, sex, race, and age at the time of assessment. The photographs were assessed clinically by a study staff dysmorphologist and morphometrically by computerized landmark analysis. Fetal alcohol syndrome-like facial features were not associated with prenatal marijuana exposure in this study sample. No consistent patterns of facial features were identified among the marijuana-exposed group. Maternal consumption of two or more ounces of alcohol per day, on average, in early gestation was found to be associated with fetal alcohol syndrome-like facial features identified both clinically and morphometrically. Cocaine use reported by 13 of the 80 women was independently associated with mild facial dysmorphic features of hypertelorism and midfacial flattening. The results demonstrate the usefulness of this diagnostic technique for quantifying anomalies apparently unique to fetal alcohol syndrome and for targeting clusters of anomalies in new conditions for future evaluation.

Combined estrogen-progesterone therapy (EPT) is a well-established risk factor for breast cancer (1–5). Multiple observational studies document 1.6- to 3.0-fold elevated risks of breast cancer associated with current, long-term use of EPT (4, 6–11). In the Women's Health Initiative randomized trial, investigators observed a 1.3-fold (95% confidence interval (CI): 1.00, 1.59) increased risk of breast cancer associated with EPT use after a mean follow-up period of 5.2 years (2, 12). In contrast, use of unopposed estrogen therapy was not related to breast cancer risk in the Women's Health Initiative trial, which is consistent with several recent observational studies (6, 9, 13–15). The mechanisms by which EPT, particularly progestogen, influences the risk of breast cancer remain unclear. With progesterone appearing to exhibit both anticarcinogenic and procarcinogenic qualities in the female body (16–21), there is a potential for mechanisms involved in this duality to be involved in breast carcinogenesis. First, the progesterone receptor (PGR) gene codes for 2 PGR isoforms, PGR-A and PGR-B, which have opposing transcriptional targets (17). Additionally, several enzymes involved in the prereceptor metabolism of progesterone, including the enzymes steroid 5-α reductase (SRD5A) and aldo-keto reductase 1C (AKR1C), metabolize progesterone into the 5α-pregnanes and 4-pregnenes, respectively (16). These metabolites have opposing effects within breast tissue: The 5α-pregnanes have been observed to increase cellular proliferation and detachment, while the 4-pregnenes are associated with weak activation of PGR (16, 22–24). Lastly, the cytochrome P-450 3A4 (CYP3A4) enzyme is included in this pathway because the vast majority of EPT used in the United States contains a synthetic progestogen, medroxyprogesterone acetate, which is predominantly metabolized in the liver by the CYP3A4 enzyme (25, 26). Thus, single nucleotide polymorphisms (SNPs) in the AKR1C1, AKR1C2, AKR1C3, CYP3A4, PGR, SRD5A1, and SRD5A2 genes could influence progesterone's regulation and carcinogenic potential. On the basis of evidence accumulated to date, we hypothesized that the presence of 1 or more specific alleles in polymorphic genes that regulate PGR or lie within the progestogen metabolism pathway influence the risk of developing breast cancer and, more specifically, interact with EPT to affect breast cancer risk.

Objective To compare birth outcomes among female survivors of childhood and adolescent cancer who subsequently bear children, relative to those of women without a history of cancer. Design Retrospective cohort study. Setting Four US regions. Participants Cancer registries identified girls younger than 20 years who were diagnosed as having cancer from 1973 through 2000. Linked birth records identified the first live births after diagnosis (n = 1898). Comparison subjects were selected from birth records (n = 14 278). Survivors of genital tract carcinomas underwent separate analysis. Main Exposure Cancer diagnosis at younger than 20 years. Main Outcome Measures Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, and delivery method, and maternal diabetes, anemia, and preeclampsia. Results Infants born to childhood cancer survivors were more likely to be preterm (relative risk [RR], 1.54; 95% confidence interval [CI], 1.30-1.83) and to weigh less than 2500 g (1.31; 1.10-1.57). For the offspring of genital tract carcinoma survivors, RRs were 1.33 (95% CI, 1.13-1.56) and 1.29 (1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR, 4.92; 95% CI, 1.60-15.13), and anemia was more common among brain tumor survivors (3.05; 1.16-7.98) and childhood cancer survivors whose initial treatment was chemotherapy only (2.45; 1.16-5.17). Conclusions Infants born to female survivors of childhood and adolescent cancer were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest that close monitoring is warranted. Increased diabetes and anemia among subgroups have not been reported, suggesting areas for study.

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

Purpose An outcome of considerable concern among breast cancer survivors is the development of second primary breast cancer. However, evidence regarding how potentially modifiable lifestyle factors modulate second breast cancer risk is limited. We evaluated the relationships between obesity, alcohol consumption, and smoking on risk of second primary invasive contralateral breast cancer among breast cancer survivors. Methods Utilizing a population-based nested case-control study design, we enrolled 365 patients diagnosed with an estrogen receptor–positive (ER+) first primary invasive breast cancer and a second primary contralateral invasive breast cancer, and 726 matched controls diagnosed with only an ER+ first primary invasive breast cancer. Obesity, alcohol use, and smoking data were ascertained from medical record reviews and participant interviews. Using conditional logistic regression we evaluated associations between these three exposures and second primary contralateral breast cancer risk. Results Obesity, consumption of ≥ 7 alcoholic beverages per week, and current smoking were all positively related to risk of contralateral breast cancer (odds ratio [OR], 1.4; 95% CI, 1.0 to 2.1; OR, 1.9; 95% CI, 1.1 to 3.2; and OR, 2.2; 95% CI, 1.2 to 4.0, respectively). Compared with women who consumed fewer than seven alcoholic beverages per week and were never or former smokers, women who consumed ≥ 7 drinks per week and were current smokers had a 7.2-fold (95% CI, 1.9 to 26.5) elevated risk of contralateral breast cancer. Conclusion Our population-based study adds to the limited available literature and suggests that obesity, smoking, and alcohol consumption influence contralateral breast cancer risk, affording breast cancer survivors three means of potentially reducing this risk.

Compared with the breast cancer risk women in the general population have, breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer. Adjuvant hormonal therapy reduces this risk, but preliminary data indicate that it may also increase risk of hormone receptor–negative contralateral tumors. We conducted a population-based nested case-control study including 367 women diagnosed with both first primary estrogen receptor (ER)–positive invasive breast cancer and second primary contralateral breast cancer and 728 matched control women diagnosed only with a first breast cancer. Data on adjuvant hormonal therapy, other treatments, and breast cancer risk factors were ascertained through telephone interviews and medical record abstractions. Two-sided statistical tests using conditional logistic regression were conducted to quantify associations between adjuvant hormonal therapy and risk of hormone receptor–specific subtypes of contralateral breast cancer (n = 303 ER+ and n = 52 ER− cases). Compared with women not treated with hormonal therapy, users of adjuvant tamoxifen for ≥5 years had a reduced risk of ER+ contralateral breast cancer [odds ratio, 0.4; 95% confidence interval (CI), 0.3–0.7], but a 4.4-fold (95% CI, 1.03–19.0) increased risk of ER− contralateral breast cancer. Tamoxifen use for

Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle–Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use ≥1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (Pheterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (Pheterogeneity = 0.02 and 0.01, respectively). Among women ≤40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use ≥1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women ≤40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1157–66)

To determine whether maternal infertility treatment is associated with adverse outcomes.Population-based cohort study using linked birth certificate-hospital discharge data.Washington State.Live-born singleton infants conceived with infertility treatment between 2003 and 2006 (n = 2,182) and a random sample of live-born singleton infants conceived spontaneously, frequency matched by birth year (n = 10,989).None.Mantel-Haenszel adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed for low birth weight, delivery at37 weeks, small for gestational age infants, any malformation, placenta previa, and placenta abruptio.Women with infertility treatment were at increased risk of placental abnormalities, including placenta abruptio (RR, 1.6; 95% CI, 1.1-2.5) and placenta previa (RR, 3.0; 95% CI, 2.0-4.7). Their infants were more likely to be delivered at37 weeks (RR, 1.7; 95% CI, 1.4-1.9) or weigh2500 g (RR, 1.4; 95% CI, 1.1-1.7); however, they were not at increased risk of being small for gestational age. An increased risk of malformations was observed in infants born to older women with infertility treatment, but not to younger women.Women using infertility treatment are at increased risk for delivering preterm, placenta previa, and placenta abruptio. Studies with measurement of specific infertility treatments will help identify the mechanisms.

To determine whether the occurrence of one or more histologic types of uterine sarcoma is related to events in a woman's reproductive life, a population-based case-control study was conducted. One-hundred sixty-seven women newly diagnosed with uterine sarcoma among residents of 6 geographic regions were compared to 208 women selected at random from the same populations with regard to histories of menstruation, pregnancy and childbearing, and breast feeding, as reported during a telephone interview. Compared to women whose menstrual periods began at age 13, women whose menses began earlier were at increased risk of leiomyosarcoma (OR = 2.0, 95% CI 0.9, 4.3); other histologic types were less strongly associated with early age at menarche. Women with leiomyosarcoma and endometrial stromal sarcoma, but not malignant mixed Müllerian tumors, tended to have ceased menstruating 2-3 years later than controls. None of the histologic types was clearly related to parity or to age at first live birth, but each was inversely related to age at last live birth. Associations were observed between leiomyosarcoma and histories of an induced abortion (OR = 4.2, 95% CI 1.2, 14.2) and of breast feeding after a live birth (OR = 0.5, 95% CI 0.3, 1.0); these relationships were not observed for other morphologic variants. These results suggest possible similarities and differences in menstrual and reproductive risk factors among histologic types of uterine sarcoma, and between these malignancies and the more common breast, endometrial and ovarian carcinomas.

In a population-based study of ectopic pregnancy, a card-back system of initial subject contact yielded a positive response from 85.1% of potential cases and 65.0% of potential controls. We subsequently recontacted by telephone potential controls who had declined to participate and offered them $10 compensation for participation. We recontacted 205 of the 330 control women who had refused to participate. Twenty-eight were found to be ineligible, and 75.7% of the remaining 177 agreed to participate on recontact. The additional 125 women were not recontacted, 9 because of firm initial refusals and 116 because the study ended before contact could be sought or made. Controls who initially declined to participate but subsequently agreed differed from those who initially agreed on a number of demographic and reproductive characteristics, and estimates of ectopic pregnancy risk associated with induced abortion and tubal sterilization changed slightly with the inclusion of initial nonparticipants. We conclude that use of a card-back system of subject contact yields a low level of positive response among reproductive-aged women and that many initial nonparticipants can be converted into participants by personal contact and the offer of compensation.

Data from a population-based case-control study of chronic lymphocytic leukemia were analyzed to assess the possible etiologic role of chronic antigenic stimulation. The study, conducted in four geographic areas of the United States (the metropolitan areas surrounding Seattle, Washington, Salt Lake City, Utah, Detroit, Michigan, and Atlanta, Georgia) sought to identify all incident cases (n = 430) among residents diagnosed between July 1, 1977 and December 31, 1981. The responses of these cases to questions about possible sources of antigenic stimulation were compared with the responses of controls selected from the populations of these areas. Little difference between cases and controls was present for a history of most forms of viral and bacterial infection and for a history of allergies or allergy treatment. However, a relation was observed with antecedent syphilis infection (odds ratio (OR) = 5.0, 95% confidence interval (Cl) 2.0-12.9). Associations of smaller magnitude were observed with a history of tuberculosis (OR = 1.9, 95% Cl 1.0-3.7) and of urinary tract infection (OR = 1.4, 95% Cl 1.1-1.9). Overall, however, the authors found little evidence of a relation between chronic antigenic stimulation and the occurrence of chronic lymphocytic leukemia. Nonetheless, because the measure of prior antigenic stimulation was restricted to that obtained through interviews and undoubtedly was an insensitive one, these negative results should not be interpreted as ruling out antigenic stimulation as a possible cause of some cases of chronic lymphocytic leukemia.

A population-based case-control study was conducted utilizing linked cancer registry and birth certificate data to examine potential associations between selected birth characteristics and the occurrence of brain tumors in children. Cases ( n = 157) were those children ages 10 and under who were born in Washington state and who were diagnosed with a primary brain tumor between 1974 and 1986. Controls were randomly selected from the Washington State birth files and were matched 5:1 to cases on year and county of birth. A limited number of positive findings emerged from the study. Results suggested that high birthweight may be related to an increased risk of childhood brain tumor (odds ratio (OR) = 1.4, 95% CI 1.0–2.0 for all histologies combined; OR=1.9, 95% CI 1.1–3.1 for astrocytomas). The risk of astrocytoma was also observed to be associated with older maternal age (OR = 2.2, 95% CI 1.2–4.0) and a history of prior fetal death(s) (OR = 1.9, 95% CI 1.0–3.8).

To investigate what role a man's occupation may have on his risk of testicular cancer, we conducted a case-control study among noncryptorchid white males who were between 20 and 69 years of age and resided in western Washington State. Cases were men in whom a germ cell tumor of the testis was diagnosed between 1977 and 1984 (n = 323). Their occupational histories were compared to those of controls of the same age, race, and geographic area who were selected through random-digit dialing (n = 658). Administrators/managers (relative risk (RR) = 1.5), salesmen (RR = 1.5), electricians (RR = 2.8), and sailors and fishermen (RR = 3.1) were among the jobs reported more commonly by cases than controls. The risk among farmers/farm managers was also elevated (RR = 1.9), but not that among farm workers (RR = 0.6). No consistent association between any one occupation and testicular cancer has been observed across studies of this topic. The most frequent observation has been an over-representation among cases of certain types of white collar worker; this may reflect the influence of some other aspect of socioeconomic status and not occupational exposures per se.

Using data from a case-control study conducted in Group Health Cooperative (GHC) of Puget Sound, we examined the relation between the use of electric blankets or heated water beds and the risk of prostate cancer. Cases were 175 prostate cancer patients ages 40-69 years. Controls were 258 male GHC members frequency matched to cases. The odds ratio (OR) for prostate cancer associated with the use of an electric blanket or heated water bed was 1.4 (95% confidence interval (CI) 0.9-2.2). The risk, however, did not tend to be higher with increasing months per year or years of use. This study did not provide clear evidence on the hypothesized association.

Background: Alcohol consumption has been comprehensively investigated as an etiologic risk factor for breast cancer but has received little attention in terms of its effect on prognosis after breast cancer, particularly for young women. Methods: 1,286 women diagnosed with invasive breast cancer at age ≤45 years from two population-based case-control studies in the Seattle-Puget Sound region were followed from their diagnosis of breast cancer (between January 1983 and December 1992) for survival through June 2002, during which time 364 women had died. Cox proportional hazards modeling was used to assess the effect of prediagnostic alcohol consumption on the risk of dying. Results: After adjusting for age and diagnosis year, compared with nondrinkers, women who consumed alcohol in the 5 years before diagnosis had a decreased risk of death [>0 to Conclusion: These results suggest that women who consume alcohol before a diagnosis of breast cancer have improved survival, which does not appear to be attributable to differences in stage, screening, or treatment. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1988–96)

Combined estrogen and progestin hormone therapy (CHT) increases breast cancer risk, but this risk varies by breast cancer type. Several studies indicate that CHT is more strongly related to lobular carcinoma risk than to ductal carcinoma risk, but these studies have been limited in their assessments of recency and duration of use, and none included a centralized pathology review. We conducted a population-based case-control study consisting of 324 lobular, 196 ductal-lobular, and 524 ductal cases diagnosed from 2000 to 2004 and 469 controls ages 55 to 74 years old. Tissue specimens were centrally reviewed for 83% of cases. Associations between hormone use and breast cancer risk were evaluated using polytomous logistic regression. Current CHT users had 2.7-fold [95% confidence interval (95% CI), 1.7-4.2] and 3.3-fold (95% CI, 2.0-5.7) elevated risks of lobular and ductal-lobular carcinomas, respectively, regardless of tumor stage, size, or nodal status. Elevations in risk were observed only among users of CHT for ≥3 years. Among ductal-lobular cases, CHT increased risk of tumors that were ≥50% lobular (odds ratio, 4.8; 95% CI, 2.1-11.1) but not tumors that were

The prevalence at birth of gastroschisis, a rare abnormality of the abdominal wall, appears to have increased over the past decade. To characterize risk factors that might explain this increase, birth certificates for Washington State residents were compared for 62 infants born with gastroschisis during the years 1984 to 1987 and 617 randomly selected unaffected infants matched for birth year. After simultaneously adjusting for 14 potential risk factors, 4 factors stood out. Infants born during January, February, or March were at greater risk than infants born in any other months (odds ratio 2.2, 95% confidence interval 1.1, 4.1). Mothers less than 25 years old were at greater risk than mothers 25 years and older, with the highest risk to mothers less than 20 years old (odds ratio 4.1, 95% confidence interval 1.4, 12.0). Women who smoked during pregnancy were at greater risk than women who did not smoke (odds ratio 2.0, 95% confidence interval 1.03, 3.8). Finally, mothers receiving inadequate prenatal care were at greater risk than mothers receiving adequate prenatal care (odds ratio 2.1, 95% confidence interval 0.99, 4.6). Unidentified behavioral and environmental exposures may explain the associations with month of birth, maternal age, and prenatal care. However, smoking during pregnancy is a plausible risk factor that should be examined further as an explanation of the apparently increasing prevalence at birth of gastroschisis in developed nations.