Roberta B. Ness

Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications.

The cause of preeclampsia remains elusive in spite of many attempts to understand its biologic characteristics and to characterize its predictors. We suggest that there are distinct origins of preeclampsia, each with its own pathologic characteristics and natural history. One genesis is the result of reduced placental perfusion, which we will call placental, and another results from maternal disorders preexisting (but sometimes not evident before) pregnancy. These preexisting maternal disorders comprise predisposing factors for cardiovascular disease such as hypertension, renal disease, overweight, and diabetes. A critical review of the epidemiologic and pathologic literature is presented, which supports the hypothesis that preeclampsia is the result of heterogeneous causes. The implications of this hypothesis are discussed, particularly its impact on the development of rules to predict the occurrence of preeclampsia.

Risk of sequelae after Chlamydia trachomatis genital infection in women.

Chlamydia trachomatis infection, the most common reportable disease in the United States, can lead to pelvic inflammatory disease (PID), infertility, ectopic pregnancy, and chronic pelvic pain. Although C. trachomatis is identified among many women who receive a diagnosis of PID, the incidence and timing of PID and long-term sequelae from an untreated chlamydial infection have not been fully determined. This article examines evidence reviewed as part of the Centers for Disease Control and Prevention Chlamydia Immunology and Control Expert Advisory Meeting; 24 reports were included. We found no prospective studies directly assessing risk of long-term reproductive sequelae, such as infertility, after untreated C. trachomatis infection. Several studies assessed PID diagnosis after untreated chlamydial infection, but rates varied widely, making it difficult to determine an overall estimate. In high-risk settings, 2%-5% of untreated women developed PID within the approximately 2-week period between testing positive for C. trachomatis and returning for treatment. However, the rate of PID progression in the general, asymptomatic population followed up for longer periods appeared to be low. According to the largest studies, after symptomatic PID of any cause has occurred, up to 18% of women may develop infertility. In several studies, repeated chlamydial infection was associated with PID and other reproductive sequelae, although it was difficult to determine whether the risk per infection increased with each recurrent episode. The present review critically evaluates this body of literature and suggests future research directions. Specifically, prospective studies assessing rates of symptomatic PID, subclinical tubal damage, and long-term reproductive sequelae after C. trachomatis infection; better tools to measure PID and tubal damage; and studies on the natural history of repeated chlamydial infections are needed.

Bone lead levels in adjudicated delinquents: A case control study

BACKGROUND Lead exposure shares many risk factors with delinquent behavior, and bone lead levels are related to self-reports of delinquent acts. No data exist as to whether lead exposure is higher in arrested delinquents. The goal of this study is to evaluate the association between lead exposure, as reflected in bone lead levels, and adjudicated delinquency. METHODS This is a case-control study of 194 youths aged 12-18, arrested and adjudicated as delinquent by the Juvenile Court of Allegheny County, PA and 146 nondelinquent controls from high schools in the city of Pittsburgh. Bone lead was measured by K-line X-ray fluorescence (XRF) spectroscopy of tibia. Logistic regression was used to model the association between delinquent status and bone lead concentration. Covariates entered into the model were race, parent education and occupation, presence of two parental figures in the home, number of children in the home and neighborhood crime rate. Separate regression analyses were also conducted after stratification on race. RESULTS Cases had significantly higher mean concentrations of lead in their bones than controls (11.0+/-32.7 vs. 1.5+/-32.1 ppm). This was true for both Whites and African Americans. The unadjusted odds ratio for a lead level > or =25 vs. <25 ppm was 1.9 (95% CL: 1.1-3.2). After adjustment for covariates and interactions and removal of noninfluential covariates, adjudicated delinquents were four times more likely to have bone lead concentrations >25 ppm than controls (OR=4.0, 95% CL: 1.4-11.1). CONCLUSION Elevated body lead burdens, measured by bone lead concentrations, are associated with elevated risk for adjudicated delinquency.

Factors Related to Inflammation of the Ovarian Epithelium and Risk of Ovarian Cancer

Previous epidemiologic observations consistently suggest that suppression of ovulation, tubal ligation, and hysterectomy reduce the risk of ovarian cancer and that perineal talc use increases the risk. We examined these and other risk factors in the context of a new hypothesis: that inflammation may play a role in ovarian cancer risk. Ovulation entails ovarian epithelial inflammation; talc, endometriosis, cysts, and hyperthyroidism may be associated with inflammatory responses of the ovarian epithelium; gynecologic surgery may preclude irritants from reaching the ovaries via ascension from the lower genital tract. We evaluated these risk factors in a population-based case-control study. Cases 20-69 years of age with a recent diagnosis of epithelial ovarian cancer (767) were compared with community controls (1,367). We found that a number of reproductive and contraceptive factors that suppress ovulation, including gravidity, breast feeding, and oral contraception, reduced the risk of ovarian cancer. Environmental factors and medical conditions that increased risk included talc use, endometriosis, ovarian cysts, and hyperthyroidism. Gynecologic surgery including hysterectomy and tubal ligation were protective. Tubal ligation afforded a risk reduction even 20 or more years after the surgery. The spectrum of associations provides support for the hypothesis that inflammation may mediate ovarian cancer risk.

Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae.

Context Can nucleic acid amplification tests on urine samples replace cervical and urethral samples to screen for chlamydia and gonorrhea? Contribution Pooled data from 29 studies showed that 3 commercially available nucleic acid amplification tests had high specificity (>95%) for detecting chlamydia and gonorrhea. Sensitivity was reasonably high (approximately 80% to 93%), except for polymerase chain reaction (PCR) for gonococcal infections in women (approximately 56%). Limitations Few studies tested transcription-mediated amplification and strand displacement amplification assays. Implications Nucleic acid amplification tests are easily obtainable non-invasive tests on urine samples that detect chlamydia and gonorrhea reasonably well. However, negative results on PCR assays on urine samples are not useful to rule out gonococcal infections in women. The Editors Chlamydia trachomatis and Neisseria gonorrhoeae infections are among the most common bacterial sexually transmitted infections worldwide (1). In the United States, experts estimate an annual incidence of 2.8 million new chlamydial infections and 720000 new gonococcal infections, the majority of which are asymptomatic (2). Nearly every major U.S. public health organization now recommends routine screening of sexually active young women for chlamydial infection (3-5). Screening young women for chlamydia has been shown to be a cost-effective method of preventing pelvic inflammatory disease, which is a major cause of infertility and chronic pelvic pain (6). Although the proportion of women who are screened appears to be increasing, 60% or fewer women at risk undergo screening (7, 8). In many settings, the prevalence of chlamydial infection in asymptomatic young men is around 3% to 5% (9-11). The screening of young men may be needed as part of a strategy to prevent chlamydial infection in young women, but little evidence is available to support recommendations for or against screening of men. Nonetheless, in both men and women, chlamydial and gonococcal infections are associated with a 3-fold to 6-fold increase in the risk for transmission or acquisition of HIV (12). Traditional methods of screening for chlamydial infection require a speculum examination in women and insertion of 1 or more swabs into the urethra in men. Not only are these screening methods embarrassing and uncomfortable, but they also require a clinic visit and use of an examination room, sterile equipment, gowns, and trained clinicians. Noninvasive screening options, such as urine testing or self-collected vaginal swabs, could eliminate some of the barriers to screening for chlamydial infection. Noninvasive methods are clearly preferred by patients (13, 14) and could substantially increase the acceptability and convenience of screening in a variety of settings. Urine-based screening has been used to identify infections in young women in primary care settings who are not receiving pelvic examinations (15) and can increase the proportion of sexually active young persons who receive chlamydial screening in clinical practices (16). Therefore, replacing invasive screening procedures with noninvasive screening procedures might improve adherence with screening guidelines. Several newly developed nucleic acid amplification tests that use noninvasive samples have been evaluated. Previous reviews of various types of tests for chlamydia concluded that nucleic acid amplification tests have superior sensitivity (17-19) but did not specifically address the question of whether tests on noninvasively obtained samples are as accurate as those obtained with cervical or urethral samples. No widely accepted guidelines exist for screening for gonorrhea. However, each of the commercially available nucleic acid amplification tests can evaluate for C. trachomatis and N. gonorrhoeae in the same specimen. This combination testing option makes it convenient for many clinicians to test for chlamydial infection and gonorrhea simultaneously. The literature on these assays can be confusing because the study samples and reference standards used differ greatly. We conducted a systematic review of the literature on the sensitivity and specificity of urine-based nucleic acid amplification tests for C. trachomatis and N. gonorrhoeae. We specifically sought to compare the results obtained with urine samples to those obtained with cervical and urethral samples and to further analyze the results according to type of assay, sample characteristics, and reference standard used. Methods We based our review strategy on several articles that outline procedures for conducting systematic reviews and meta-analyses, including the QUORUM guidelines for reporting of meta-analyses (20) and general guidelines for systematic reviews of diagnostic tests (21-24). Literature Search We searched the MEDLINE database for articles published from 1 January 1991 to 31 December 2004. We specifically sought articles that contained the Medical Subject Headings Chlamydia trachomatis, chlamydial infections (not pneumoniae), or Neisseria gonorrhoeae and also included the terms nucleic acid amplification techniques or polymerase chain reaction or the text words strand displacement, transcription-mediated, or polymerase. Additional articles were identified through references of relevant articles and a hand search through January 2005 of the 3 journals in which articles on these topics most commonly appeared (Journal of Clinical Microbiology, Sexually Transmitted Diseases, and Sexually Transmitted Infections). Study Selection We selected studies that evaluated 1 of 3 commercially available nucleic acid amplification tests, presented data separately by sex, included data obtained from the same assay on both a urine sample and a traditional sample (obtained from the cervix or urethra), and used an appropriate reference standard. We excluded studies that used a nucleic acid amplification test that is not commercially available, including studies that evaluated the ligase chain reaction assay (which was removed from the commercial market in 2002). We also excluded some studies in which data were obtained from urine samples only because one of our main objectives was to determine whether such results were similar to those obtained from cervical or urethral samples. The choice of an appropriate reference standard is complicated because the nucleic acid amplification tests under evaluation are generally more sensitive than the other diagnostic methods that could be used for reference standards. The choice is also complicated by the fact that both C. trachomatis and N. gonorrhoeae can simultaneously infect multiple anatomic sites. In some women, chlamydia can be detected only in the cervix. In others, it can be detected only in the urethra or urine. The diagnostic test must therefore be able to detect the maximum number of infected persons who require treatment. In evaluating reference standards, we included studies in which 2 conditions were met. First, samples must have been collected from at least 2 anatomic sites, including the cervix in women or the urethra in men. In addition, the reference standard required confirmation by culture (which most experts consider to be 100% specific) or by at least 1 additional nucleic acid amplification test that differed from the test under evaluation (to ensure acceptable sensitivity of the reference standard). Examples of reference standards that did not meet our site and test criteria included urine tests that were compared only with other urine tests, nucleic acid amplification tests that were compared only with culture or other less-sensitive assays, and nucleic acid amplification tests that were confirmed by the same test under evaluation but at a different anatomic site. Data Extraction and Validity Assessment Two of the authors independently read each eligible article and extracted detailed information on the study sample, test characteristics, reference standard, and results. If a study included results from both symptomatic and asymptomatic patients, we included both sets of results. If a study presented data obtained by using more than 1 reference standard, we selected the results that were most consistent with the reference standard criteria outlined earlier. Several guidelines suggest criteria to evaluate validity and report results of diagnostic test studies, although there is no consensus on which criteria are most important for study validity (21-24). We abstracted information that was consistently noted in these reports, including whether the study sample was clearly defined and not already known to have the condition, whether the reference standard tests were conducted without knowledge of the test under evaluation, whether all participants received the same diagnostic evaluation, and whether the reference standard was clearly defined. For each study, we calculated 95% CIs for sensitivity and specificity by using the binomial distribution. We calculated positive likelihood ratios by using the following formula: sensitivity/(1corresponding specificity). We calculated negative likelihood ratios by using the following formula: (1sensitivity)/specificity. To calculate likelihood ratios, we converted sensitivities or specificities of 1.0 to 0.9999. Data Synthesis Studies were assessed qualitatively and quantitatively. The qualitative assessment identified potential sources of heterogeneity, which included different types of assays, sex of study participants, and presence or absence of symptoms in the sample. We therefore aimed to stratify studies into groups with clinically similar tests, participants, and infections (25). Our initial intent was to synthesize study results by constructing a summary receiver-operating characteristic curve (26, 27). This method is a particularly robust way of synthesizing diagnostic test information across studies because it is relatively insensitive to the particular test threshold t

Number of Pregnancies and the Subsequent Risk of Cardiovascular Disease

BACKGROUND Whether increasing parity or gravidity is a risk factor for coronary heart disease has been debated, but the question remains unresolved. METHODS We tested the association between the number of pregnancies and a variety of cardiovascular end points in two groups of women who had completed childbearing. One group comprised 2357 women who were followed for 28 years through the Framingham Heart Study, and the other 2533 women followed for at least 12 years through the first National Health and Nutrition Examination Survey National Epidemiologic Follow-up Study (NHEFS). RESULTS The rates of coronary heart disease were higher among multigravid women than among women who had never been pregnant, in both the Framingham Heart Study and the NHEFS, but in both studies, the higher rates were statistically significant only in women with six or more pregnancies. For the women in the Framingham Study, the rate ratio adjusted for age and educational level in the group with six or more pregnancies (as compared with women who had never been pregnant) was 1.6 (95 percent confidence interval, 1.1 to 2.2). For the women in the NHEFS, the same adjusted rate ratio was 1.5 (95 percent confidence interval, 1.1 to 1.9). Adjustments for other known cardiovascular risk factors, including weight, did not markedly alter this risk. The rate of total cardiovascular disease was also significantly higher among multigravid women in the Framingham Study than in the women who had never been pregnant. CONCLUSIONS In two prospective American studies, having six or more pregnancies was associated with a small but consistent increase in the risk of coronary heart disease and cardiovascular disease. Whether gravidity itself or some other unmeasured factor accounts for the increase in risk that we observed requires further investigation.

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

Duration of Lactation and Risk Factors for Maternal Cardiovascular Disease

OBJECTIVE: To examine dose–response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease. METHODS: We examined data from 139,681 postmenopausal women (median age 63 years) who reported at least one live birth on enrolling in the Women’s Health Initiative observational study or controlled trials. Multivariable models were used to control for sociodemographic (age, parity, race, education, income, age at menopause), lifestyle, and family history variables when examining the effect of duration of lactation on risk factors for cardiovascular disease, including obesity (body mass index [BMI] at or above 30), hypertension, self-reported diabetes, hyperlipidemia, and prevalent and incident cardiovascular disease. RESULTS: Dose-response relationships were seen; in fully adjusted models, women who reported a lifetime history of more than 12 months of lactation were less likely to have hypertension (odds ratio [OR] 0.88, P<.001), diabetes (OR 0.80, P<.001), hyperlipidemia (OR 0.81, P<.001), or cardiovascular disease (OR 0.91, P=.008) than women who never breast-fed, but they were not less likely to be obese. In models adjusted for all above variables and BMI, similar relationships were seen. Using multivariate adjusted prevalence ratios from generalized linear models, we estimate that among parous women who did not breast-feed compared with those who breast-fed for more than 12 months, 42.1% versus 38.6% would have hypertension, 5.3% versus 4.3% would have diabetes, 14.8% versus 12.3% would have hyperlipidemia, and 9.9% versus 9.1% would have developed cardiovascular disease when postmenopausal. Over an average of 7.9 years of postmenopausal participation in the Women’s Health Initiative, women with a single live birth who breast-fed for 7–12 months were significantly less likely to develop cardiovascular disease (hazard ratio 0.72, 95% confidence interval 0.53–0.97) than women who never breast-fed. CONCLUSION: Among postmenopausal women, increased duration of lactation was associated with a lower prevalence of hypertension, diabetes, hyperlipidemia, and cardiovascular disease. LEVEL OF EVIDENCE: II

Douching in relation to bacterial vaginosis, lactobacilli, and facultative bacteria in the vagina

OBJECTIVE To study how frequency, recentness, and reason for douching impact bacterial vaginosis‐related vaginal microflora and the occurrence of cervical pathogens. Douching has been linked to bacterial vaginosis as well as to chlamydial cervicitis in some, but not all, studies. METHODS A total of 1200 women at high risk for sexually transmitted infections were enrolled from five clinical sites around the United States. Cross‐sectional, structured interviews were conducted and vaginal swabs were self‐obtained for Gram stain, culture, and DNA amplification tests for Neisseria gonorrhoeae and Chlamydia trachomatis. RESULTS Douching at least once per month was associated with an increased frequency of bacterial vaginosis. Those who douched recently (within 7 days) were at highest risk [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3, 3.1]. Douching for symptoms (OR 1.7, 95% CI 1.1, 2.6) and for hygiene (OR 1.3, 95% CI 1.0, 1.9) both related to bacterial vaginosis risk. The associations between douching and Gardnerella vaginalis, Mycoplasma hominis, and lack of hydrogen peroxide‐producing lactobacilli were similar to those between douching and bacterial vaginosis. Gonococcal or chlamydial cervicitis was not associated with douching. CONCLUSION Douching for symptoms or hygiene, particularly frequent or recent douching, was associated with bacterial vaginosis and bacterial vaginosis‐associated vaginal microflora, but not with gonococcal or chlamydial cervicitis.

Inflammation and Endometrial Cancer: A Hypothesis

Endometrial cancer is the most common gynecologic malignancy in the United States. Substantial epidemiologic data implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a role in endometrial cancer development. Emerging laboratory data suggest that elevated levels of prostaglandin E2 may underlie the transformation of normal endometrium to neoplastic tissue and that in vitro nonsteroidal anti-inflammatory drugs may inhibit endometrial cancer cell growth. In this review, we suggest that the risk factors for endometrial cancer—unopposed estrogens, anovulation, polycystic ovary syndrome, excessive menstruation, early menarche, and late menopause—may be viewed as factors increasing the exposure of the endometrium to inflammation, whereas pregnancy and smoking, two likely protective factors, have the opposite effect. Chronic inflammation can induce rapid cell division, increasing the possibility for replication error, ineffective DNA repair, and subsequent mutations. A proinflammatory milieu can also directly increase estrogen production. Hence, inflammation may work in conjunction with or in addition to estrogen exposure in the development of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2840–7)