Preterm birth with placental evidence of malperfusion is associated with cardiovascular risk factors after pregnancy: a prospective cohort study.

OBJECTIVE: Preterm birth (PTB) is associated with excess maternal cardiovascular disease risk. We considered that women with PTB and placental evidence of maternal malperfusion would be particularly affected. DESIGN: Pregnancy cohort study. SETTING: Pittsburgh, PA, USA. POPULATION: Women with PTB (n = 115) and term births (n = 210) evaluated 4-12 years after pregnancy. METHODS: Cardiometabolic risk markers were compared in women with prior PTB versus term births; pre-eclampsia and growth restriction cases were excluded. Placental evidence of maternal vascular malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, intervillous fibrin deposition), acute infection/inflammation (chorioamnionitis, funisitis, deciduitus) and villitis of unknown aetiology (chronic inflammation) was used to classify PTBs. MAIN OUTCOME MEASURES: Carotid artery intima-media thickness (IMT), fasting lipids, blood pressure (BP) and inflammatory markers measured after delivery. RESULTS: Women with PTB and malperfusion lesions had higher total cholesterol (+13.5 mg/dl) and systolic BP (+4.0 mmHg) at follow up compared with women with term births, accounting for age, race, pre-pregnancy BMI, and smoking (P < 0.05). Women with PTB and malperfusion accompanied by inflammatory lesions had the most atherogenic profile after pregnancy (cholesterol +18.7, apolipoprotein B + 12.7 mg/dl; all P < 0.05), adjusted for pre-pregnancy features. Carotid IMT was higher in this group (+0.037 cm, P = 0.031) accounting for pre-pregnancy factors; differences were attenuated after adjusting for BP and atherogenic lipids at follow up (+0.027, P = 0.095). CONCLUSION: PTBs with placental malperfusion were associated with an excess maternal cardiometabolic risk burden in the decade after pregnancy. The placenta may offer insight into subtypes of PTB related to maternal cardiovascular disease. TWEETABLE ABSTRACT: Preterm births with placental malperfusion may mark women at higher cardiovascular disease risk.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Is there an association between coronary atherosclerosis and carcinoma of the prostate in men aged 50 years and older? An autopsy and coroner based post-mortem study.

BACKGROUND: Atherosclerotic disease is the most common cause of death in the United States and prostate cancer has the highest incidence among males in the United States. Reports have indicated that atherosclerosis and cancers my share common pathoetiologic and pathogenetic cascades. If atherosclerosis and cancers have common pathoetiologic and pathogenetic cascades, both diseases will co-occur and patients may represent a potential target group for cancer screening interventions. MATERIALS AND METHODS: Prostates and coronary vessels were examined from 37 deceased men, aged 50 years and older, who died unexpectedly and suddenly from traumatic causes. Tissue sections of the entire prostate were examined for benign and malignant lesions. Analysis of Variance was used to compare mean coronary artery atherosclerosis scores among groups of men with diagnosis of adenocarcinoma, intraepithelial neoplasm, benign hyperplasia and normal prostate glands. RESULTS: Twelve prostates (32.5%) showed adenocarcinoma of the prostate, four with Gleason score 7 and eight with Gleason score 6. After adjustment for age and race, there remained no statistical difference between prostate pathology groups and atherosclerosis score (F = 0.72; P = 0.55). CONCLUSIONS: To our knowledge, ours is the first study to use direct pathological examination of tissues for definitive identification of atherosclerosis and prostate cancer. In our case series, the occurrence and progression of coronary atherosclerotic disease and cancer of the prostate were not associated.

The demographic, sexual health and behavioural correlates of Mycoplasma genitalium infection among women with clinically suspected pelvic inflammatory disease.

OBJECTIVE: Mycoplasma genitalium has been identified as a cause of pelvic inflammatory disease (PID), a clinical syndrome associated with inflammation of the female upper genital tract and serious reproductive sequelae. As the demographic, behavioural and sexual risk profile of women with M genitalium-associated PID is not well understood, the characteristics of M genitalium-infected women presenting with clinically suspected PID were investigated. METHODS: Data from 586 participants in the PID Evaluation and Clinical Health Study were analysed. Demographic, sexual history and behavioural characteristics, including age, race, marital status, education level, sexual activity, number of sexual partners, history of sexually transmitted infection (STI), bacterial vaginosis and PID, contraception use, oral and anal sex, age at sexual debut, douching practices and drug, alcohol and tobacco use, were compared between 88 women testing positive and 498 women testing negative for M genitalium by PCR in the cervix and/or endometrium. Twenty-two women with M genitalium mono-infections were compared with 172 women who tested positive for Neisseria gonorrhoeae by culture and/or Chlamydia trachomatis by PCR. RESULTS: Age under 25 years, douching two or more times per month and smoking were independently associated with M genitalium. Women with M genitalium mono-infections were significantly less likely to be African-American (59.1% vs 86.0%, p = 0.001) than women with N gonorrhoeae and/or C trachomatis. CONCLUSIONS: Women infected with M genitalium had some characteristics commonly associated with PID and other STI. The demographic, sexual and behavioural characteristics of M genitalium-positive women were similar to women with chlamydial and/or gonococcal PID.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Clinical characteristics of bacterial vaginosis among women testing positive for fastidious bacteria.

OBJECTIVES: As the aetiology of bacterial vaginosis (BV) is not well understood, this study sought to determine the relationships between several fastidious microbes, BV and selected clinical characteristics of BV. METHODS: Endometrial and cervical specimens from 50 women with non-gonococcal, non-chlamydial endometritis were tested for Leptotrichia sanguinegens/amnionii, Atopobium vaginae, bacterial vaginosis-associated bacteria 1 (BVAB1), Ureaplasma urealyticum biovar 2 (UU-2) and Ureaplasma parvum using PCR. BV was categorised using Nugent's and Amsel's criteria. Odds ratios (OR) adjusted for age and race were estimated using multivariable logistic regression. RESULTS: Although elevated pH was a universal feature, other BV characteristics differed by pathogen, suggesting variable clinical presentation. Only UU-2 was strongly associated with vaginal discharge, but a positive whiff test and a 20% or greater classification of epithelial cells as clue cells were more common among women with L sanguinegens/amnionii, A vaginae and BVAB1. For each of these bacteria, there were trends towards associations with BV defined by Amsel's criteria (L sanguinegens/amnionii OR 2.9, 95% CI 0.5 to 15.7; A vaginae OR 2.6, 95% CI 0.6 to 11.4; BVAB1 OR 5.7, 95% CI 1.0 to 31.1) and significant associations with BV defined by Gram stain (L sanguinegens/amnionii OR 17.7, 95% CI 2.8 to 113.0; A vaginae OR 19.2, 95% CI 3.7 to 98.7; BVAB1 OR 21.1, 95% CI 2.2 to 198.5). CONCLUSIONS: L sanguinegens/amnionii, A vaginae and BVAB1 are associated with clinical characteristics consistent with BV and BV defined by Nugent's and Amsel's criteria. These fastidious bacteria may cause unrecognised infection, as none was associated with abnormal vaginal discharge.

Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease.

OBJECTIVES: As Mycoplasma genitalium is associated with pelvic inflammatory disease (PID), we examined the efficacy of a commonly used PID antimicrobial in treating M genitalium upper genital tract infection. METHODS: In the PID Evaluation and Clinical Health study of inpatient versus outpatient treatment, 682 women treated with cefoxitin and doxycycline for clinically suspected PID had stored cervical and endometrial specimens available for analysis. In the current sub study, we compared baseline endometritis, short term treatment failure (continued endometritis and pelvic pain 30 days following treatment) and sequelae among women with and without M genitalium, identified using PCR. RESULTS: Endometrial M genitalium was associated with baseline endometritis (adjusted OR 3.0, 95% CI 1.5 to 6.1). Among women with a positive baseline M genitalium test, 41% tested positive again 30 days following treatment. Women testing positive compared to those testing negative for M genitalium at baseline had an increased risk of short-term treatment failure (RR 4.6, 95% CI 1.1 to 20.1). Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline. There was a non-significant trend towards increased infertility, chronic pelvic pain and recurrent PID, and decreased pregnancy and live birth following M genitalium infection. CONCLUSIONS: M genitalium is associated with endometritis and short-term PID treatment failure. Cefoxitin and doxycycline, a Centers for Disease Control and Prevention recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection.

Possible role of ovarian epithelial inflammation in ovarian cancer.

Ovarian cancer is a commonly fatal disease for which prevention strategies have been limited, in part because of a lack of understanding of the underlying biology. This paper reviews the epidemiologic literature in the English language on risk factors and protective factors for ovarian cancer and proposes a novel hypothesis that a common mechanism underlying this disease is inflammation. Previous hypotheses about the causes of ovarian cancer have attributed risk to an excess number of lifetime ovulations or to elevations in steroid hormones. Inflammation may underlie ovulatory events because an inflammatory reaction is induced during the process of ovulation. Additional risk factors for ovarian cancer, including asbestos and talc exposure, endometriosis (i.e., ectopic implantation of uterine lining tissue), and pelvic inflammatory disease, cannot be directly linked to ovulation or to hormones but do cause local pelvic inflammation. On the other hand, tubal ligation and hysterectomy act as protective factors, perhaps by diminishing the likelihood that the ovarian epithelium will be exposed to environmental initiators of inflammation. Inflammation entails cell damage, oxidative stress, and elevations of cytokines and prostaglandins, all of which may be mutagenic. The possibility that inflammation is a pathophysiologic contributor to the development of ovarian cancer suggests a directed approach to future research

Multiple births and risk of epithelial ovarian cancer.

BACKGROUND AND METHODS: Prevailing hypotheses about the causes of ovarian carcinogenesis predict that women with a history of multiple births (twins, triplets, etc.) should be at increased risk of epithelial ovarian cancer. However, the scant available evidence suggests that they may actually be at lower risk. To resolve this issue, we pooled data from eight studies involving 2859 parous women with epithelial ovarian cancer (case patients) and 7434 parous women without ovarian cancer (control women). In addition to assessing their history of multiple births (and the sex of the children, where available), we obtained information on age, parity, oral contraceptive use, and other reproductive factors for each woman. Details of tumor histology were available for all case patients. We estimated the relative risks of various histologic types of ovarian cancers associated with multiple births by using multivariable logistic regression analysis, adjusting for matching and confounding variables. RESULTS: Among these parous women, 73 case patients (2. 6%) and 257 control women (3.5%) had a history of multiple births. The adjusted summary odds ratio (OR) for developing all types of epithelial ovarian cancer that are associated with multiple births was 0.81 (95% confidence interval [CI] = 0.61-1.08). We found no evidence that risks associated with multiple births differed among women with borderline or invasive tumors and among women with same-sex and opposite-sex offspring from multiple births. The risk reductions appeared specific for nonmucinous tumors (n = 2453; summary adjusted OR = 0.71 [95% CI = 0.52-0.98]); in contrast, associations with mucinous tumors (n = 406) were heterogeneous across studies. CONCLUSIONS: Parous women with nonmucinous ovarian cancer are no more likely to have a history of multiple births than other parous women, counter to the predictions of current hypotheses for causes of ovarian cancer.

Reproductive risk factors for epithelial ovarian cancer according to histologic type and invasiveness.

PURPOSE: Differences in histology among the subtypes of epithelial ovarian tumors suggest possible differences in their etiologies. We examined reproductive risk factors for epithelial ovarian cancer according to histologic subtype and tumor invasiveness. METHODS: We conducted a population-based, case-control study of associations between reproductive risk factors and epithelial ovarian cancer in the Delaware Valley from 1994 to 1998. Cases age 20 to 69 years with a recent diagnosis of epithelial ovarian cancer (n = 767) were compared to community controls (n = 1367) frequency matched by age. RESULTS: With few exceptions, we found significant risk reduction for each histologic subtype of epithelial ovarian cancer by using oral contraceptive, bearing children, and having a tubal ligation; for each subtype, there was significant increased risk associated with a family history of the disease. There were no significant differences among histologic subtypes in the magnitude of the odds ratios for OC use, parity, breastfeeding, tubal ligation, hysterectomy, family history of breast or ovarian cancer, use of noncontraceptive estrogens, age at menarche, and age at menopause. There were also few differences between invasive and borderline tumors, except that women with borderline tumors were significantly younger than women with invasive disease (44.7 years vs. 52.0 years, p < 0.001). Among serous tumors only, women with borderline tumors were more likely to use oral contraceptives than women with invasive tumors (OR = 2.28 95% CI 1.20-4.35). CONCLUSION: The results of this study suggest that reproductive risk factors do not differ among histologic subtypes of epithelial ovarian cancers.

Evaluating minority recruitment into clinical studies: how good are the data?

PURPOSE: There has been much publicized concern about difficulty with minority recruitment into research studies, particularly since minority inclusion in randomized clinical trials was mandated by the 1993 National Institutes of Health Revitalization Act. We reviewed recruitment data in published reports from clinical studies to assess the actual degree of success in recruiting minorities versus whites and to identify barriers to recruitment. METHODS: We abstracted articles published between September 1993 and February 1995 that reported detailed results of participant recruitment for studies conducted in the United States. RESULTS: Of 65 articles meeting our eligibility criteria (median sample size, 1323), only one (1.5%) reported the racial/ethnic composition of potential study participants. Only two articles (3.1%) provided information about the racial/ethnic composition of eligible subjects, and only one (1.5%) provided information about the racial/ethnic composition of refusing subjects. For enrolled subjects, race/ethnicity was less likely to be reported (58.5%) than were age (90.8%) or gender (80.0%). CONCLUSIONS: The published literature currently contains insubstantial data to either refute or prove that there are differential recruitment rates among minorities as compared with whites. Changes in reporting will be needed in order to track progress in this area.

Free leptin is increased in normal pregnancy and further increased in preeclampsia.

We measured bound and free leptin levels in preeclamptic and matched normal pregnant and never-pregnant women to determine whether the free component of leptin is increased during pregnancy and further increased in preeclampsia. Two milliliters of serum was obtained from 18 normal and 18 preeclamptic patients matched by pre-pregnancy body mass index (BMI), and from 18 never-pregnant women matched by BMI with the pregnant groups. The sample was subjected to gel filtration using Sephadex G-100. Radioimmunoassay (RIA) was performed on all fractions, and the proportions of bound and free leptin were determined by analyzing the areas under the curve of the chromatographic profile. The total maternal serum leptin concentration was significantly higher in normal pregnancy compared with the nonpregnant state and was further increased in preeclampsia (33.8 +/- 4.1 v 15.2 +/- 1.8 ng/mL, P = .002, and 48.1 +/- 5.6 ng/mL, P = .02, respectively). Free leptin was increased in normal pregnant compared with never-pregnant women (25.9 +/- 4.1 v 11.0 +/- 2.0 ng/mL, respectively, P = .01), while the increase of total leptin in preeclampsia was exclusively in the free fraction that was significantly higher versus the normal pregnant group (41.8 +/- 5.6 v25.9 +/- 4.1 ng/mL, respectively, P = .01). The bound leptin fraction, by contrast, was significantly increased in the normal pregnant group compared with the preeclamptic group and the never-pregnant group (7.9 +/- 0.56 v 6.2 +/- 0.36 and 4.1 +/- 0.36 ng/mL, respectively, P = .009 and P = <.0001). In conclusion, the free leptin concentration increases in normal pregnancy and is further increased in preeclampsia. This supports the hypothesis that biologically active leptin is elevated in normal pregnancy and is increased more in women with preeclampsia.

Physical activity and reduced risk of ovarian cancer.

OBJECTIVE: To examine the relation between leisure-time physical activity and ovarian cancer. METHODS: We used data from a population based case-control study. Cases (n = 767) were women 20-69 years of age in whom epithelial ovarian cancer was diagnosed during 1994-1998 and who resided in a defined region of Pennsylvania, New Jersey, or Delaware. Controls (n = 1367) were ascertained by using random-digit dialing and Health Care Financing Administration files and were frequency-matched to cases for age and county of residence. Information on lifetime leisure-time physical activity was obtained during in-person interviews. RESULTS: Leisure-time physical activity was significantly associated with reduced occurrence of ovarian cancer (P =.01). After adjustment for age, parity, oral contraceptive use, tubal ligation, family history of ovarian cancer, race, and body mass index, women with the highest level of activity had an odds ratio of 0.73 (95% CI 0.56, 0.94) for ovarian cancer compared with women with the lowest level of activity. When the relation was analyzed by various recalled time periods during life, the odds ratios for the highest versus the lowest category of activity at ages 14-17, 18-21, 22-29, 30-39, 40-49, and >50 years ranged from 0.64-0.78. CONCLUSION: Leisure-time physical activity is associated with reduced occurrence of epithelial ovarian cancer.

Do men become infertile after having sexually transmitted urethritis? An epidemiologic examination.

OBJECTIVE: To critically assess the possibility that gonorrhea or chlamydia causes male infertility. DESIGN: Comprehensive literature review structured to evaluate the epidemiologic tenets for causality, including biologic plausibility, strength of association, dose response, consistency, temporality, and treatment effect. RESULT(S): It is biologically plausible that gonorrhea and/or chlamydia could cause male infertility. There is clinical and pathologic evidence linking these pathogens to urethritis, linking urethritis to epididymo-orchitis, and linking epididymo-orchitis to infertility. Retrospective epidemiologic results also support an association between chlamydia serologies and male infertility, which in most of these small studies does not reach the level of statistical significance. However, there is no consistent epidemiologic evidence that these pathogens alter sperm characteristics. We discuss the methodologic limitations of previous epidemiologic studies and suggest strategies for future research. CONCLUSION(S): Whether gonorrhea and/or chlamydia cause male infertility is currently unclear. Sound methodologic research strategies must be applied to future studies.

Life event stress and the association with spontaneous abortion in gravid women at an urban emergency department.

In this study, the authors hypothesized that life event stress is associated with an increased risk of spontaneous abortion. Using a nested case-control design in an emergency department (N = 970), stress was measured using a life event inventory and a sample drawn from R. B. Ness et al.'s (1999) Early Pregnancy Study. Gestational age at time of fetal loss served as a marker of chromosomal status. Women experiencing more than one life event used more alcohol and public assistance. Spontaneous abortion at 11 weeks or greater was associated with more life event stress (adjusted odds ratio 2.9, 95% confidence interval 1.4-6.2), whereas spontaneous abortion at any gestational age was not, implying that life event stress increases the risk of chromosomally normal spontaneous abortion. An analysis of confounders showed tobacco use was associated with an increased risk of spontaneous abortion, whereas prenatal care was only associated with fetal loss at 11 weeks or greater.

Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia.

OBJECTIVES: To test the hypothesis that the common missense mutation of 5,10-methylenetetrahydrofolate reductase (MTHFR) (677 C to T, ala to val) is more prevalent among nulliparous preeclamptic women compared with control and transient hypertension of pregnancy patients. The correlation of the MTHFR T677/T677 genotype in mothers and fetuses was also investigated to test for possible maternal-fetal interactions. Lastly, possible differences in serum folate concentrations between control and preeclampsia patients and the possibility of a correlation between serum folate and MTHFR genotype were investigated as well. METHODS: The MTHFR genotype was determined for 114 control subjects, 99 preeclamptic patients, and 24 patients with transient hypertension of pregnancy by a polymerase chain reaction/restriction fragment length polymorphism (PCR) method. To ensure homogeneity of ethnic background, only samples from white women were analyzed. Results were analyzed with a chi 2 test for homogeneity. Serum folate was determined by radioimmunoassay (RIA). RESULTS: The prevalence of the MTHFR T677/T677 genotype was not significantly different between the populations studied. There was no significant difference in the prevalence of the MTHFR T677/T677 genotype between the infants of preeclamptic and control mothers. Furthermore, there was no difference in serum folate concentrations between control and preeclampsia patients, and there was no correlation between serum folate and MTHFR genotype. CONCLUSION: These data suggest that contrary to previous published reports, the C677T missense mutation of MTHFR is not a risk factor for preeclampsia in this nulliparous patient population. Furthermore, this mutation is not related to serum folate status in late pregnancy.

Reproductive history in relation to plasma hormone levels in healthy post-menopausal women.

OBJECTIVES: We sought to examine the relationship between reproductive history and measures of selected gonadotrophins and steroid hormones among post-menopausal women. Previous studies have suggested that there is a negative correlation between parity and post-menopausal serum estrogens, which may be a mechanism by which pregnancies protect women from the development of breast cancer. METHODS: We analyzed women who experienced a natural menopause within the Healthy Women Study cohort both 1 and 8 years after menopause. Lifetime reproductive history was obtained and blood was assayed for estrone, estradiol, androstenedione, testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) at 1 year post-menopause and for many of these steroid hormones at 8 years post-menopause. Also at 8 years post-menopause, a hip bone mineral density measure was obtained. RESULTS: Age at menopause related to a modest increase in estrone at 1 year but a decrease in estrone and estradiol at eight years. Adjustment for body mass index (BMI), oral contraceptive use, alcohol use, cigarette smoking, and education had little impact on these findings. There were no other internally consistent relationships between reproductive variables and steroid hormones or hip-bone mineral density. CONCLUSIONS: These observations do not support the hypothesis that parity acts to diminish endogenous levels of post-menopausal estrogens.

Impact of maternal lifestyle factors on newborn HPRT mutant frequencies and molecular spectrum--initial results from the Prenatal Exposures and Preeclampsia Prevention (PEPP) Study.

Epidemiological studies have demonstrated associations between maternal tobacco smoke exposure and consumption of alcohol during pregnancy and increased risk of pediatric malignancies, particularly infant leukemias. Molecular evidence also suggests that somatic mutational events occurring during fetal hematopoiesis in utero can contribute to this process. As part of an ongoing multi-endpoint biomarker study of 2000 mothers and newborns, the HPRT T-lymphocyte cloning assay was used to determine mutant frequencies (Mf) in umbilical cord blood samples from an initial group of 60 neonates born to a sociodemographically diverse cohort of mothers characterized with respect to age, ethnicity, socioeconomic status, and cigarette smoke and alcohol exposure. Non-zero Mf (N = 47) ranged from 0.19 to 5.62 x 10(-6), median 0.70 x 10(-6), mean +/- SD 0.98 +/- 0.95 x 10(-6). No significant difference in Mf was observed between female and male newborns. Multivariable Poisson regression analysis revealed that increased HPRT Mf were significantly associated with maternal consumption of alcohol at the beginning [Relative Rate (RR) = 1.84, 95% CI = 0.99-3.40, P = 0.052) and during pregnancy (RR = 2.99, 95% CI = 1.14-7.84, P = 0.026). No independent effect of self-reported active maternal cigarette smoking, either at the beginning or throughout pregnancy, nor maternal passive exposure to cigarette smoke was observed. Although based on limited initial data, this is the first report of a positive association between maternal alcohol consumption during pregnancy and HPRT Mf in human newborns. In addition, the spectrum of mutations at the HPRT locus was determined in 33 mutant clones derived from 19 newborns of mothers with no self-reported exposure to tobacco smoke and 14 newborns of mothers exposed passively or actively to cigarette smoke. In the unexposed group, alterations leading to specific exon 2-3 deletions, presumably as a result of illegitimate V(D)J recombinase activity, were found in five of the 19 mutants (26.3%); in the passively exposed group, two exon 2-3 deletions were present among the seven mutants (28.6%); and in the actively exposed group, six of the seven mutants (85.7%) were exon 2-3 deletions. Although no overall increase in HPRT Mf was observed and the number of mutant clones examined was small, these initial results point to an increase in V(D)J recombinase-associated HPRT gene exon 2-3 deletions in cord blood T-lymphocytes in newborns of actively smoking mothers relative to unexposed mothers (P = 0.011). Together, these results add to growing molecular evidence that in utero exposures to genotoxicants result in detectable transplacental mutagenic effects in human newborns.

Homocysteine and cellular fibronectin are increased in preeclampsia, not transient hypertension of pregnancy.

OBJECTIVE: The objective of this study was to confirm that endothelial dysfunction is present in preeclampsia and absent in transient hypertension of pregnancy, and to determine whether the cardiovascular risk factor homocysteine is associated with the degree of endothelial dysfunction. METHODS: We measured cellular fibronectin (as a marker of endothelial injury) and total plasma homocysteine in samples collected at the time of admittance to labor and delivery in 17 women with preeclampsia (increased blood pressure, proteinuria, and hyperuricemia), 16 women with transient hypertension of pregnancy (only increased blood pressure), and 34 normal pregnant women. Each subject with preeclampsia was matched by prepregnancy body mass index, race, and gestational age at delivery to one subject with transient hypertension of pregnancy and two controls. RESULTS: Cellular fibronectin was found to be significantly increased in women with preeclampsia compared to subjects with transient hypertension of pregnancy or normal pregnant women (22.9 +/- 14.1 microg/mL versus 10.9 +/- 5.4 and 10.1 +/- 6.2 microg/mL, respectively, p<0.0001). Similarly, total plasma homocysteine was also significantly increased in the women with preeclampsia compared to subjects with transient hypertension of pregnancy or normal pregnant women (8.3 +/- 2.5 microM versus <5.5 +/- 2.2 and 5.4 +/- 3.4 microM respectively, p<0.01). However, contrary to our hypothesis, there was no apparent association between cellular fibronectin and homocysteine. CONCLUSIONS: The increased concentrations of homocysteine observed in preeclampsia are not a general feature of all hypertensive complications of pregnancy. Furthermore, endothelial dysfunction is present in preeclampsia and is not evident in transient hypertension of pregnancy. However, the apparent endothelial dysfunction in preeclampsia is not explained by the increase in homocysteine concentrations observed.