Person:

Missmer, Stacey

Background: Hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) are persistent chlorinated pesticides with endocrine activity that may adversely affect the early stages of human reproduction. Objective: Our goal was to determine the association of serum levels of HCB, DDT, and DDE with implantation failure, chemical pregnancy, and spontaneous abortion in women undergoing in vitro fertilization (IVF) from 1994 to 2003. Methods: Levels of HCB and congeners of DDT and DDE were measured in serum collected during the follicular phase. Multivariable-adjusted statistical models accommodating multiple outcomes and multiple cycles per woman were used to estimate the relation between serum pesticide levels and IVF outcomes. Results: A total of 720 women with a mean (\pm) SD age 35.4 (\pm) 4.2 years at enrollment contributed 774 IVF cycles. All samples had detectable levels of HCB, DDT, and DDE, with median levels of 0.087 ng/g serum for HCB, 1.12 ng/g serum for total DDT, and 1.04 ng/g serum for p,p´-DDE. Compared with the lowest quartile (Q1) of HCB, the lipid- and multivariable-adjusted odds ratio (OR) for failed implantation was significantly elevated for those with higher HCB quartiles [Q2–Q4; adjusted ORs: for Q2, 1.71; 95% confidence interval (CI): 1.03, 2.82; for Q3, 2.30; 95% CI: 1.39, 3.81; for Q4, 2.32; 95% CI: 1.38, 3.90] and showed a significantly increasing trend (p = 0.001). No statistically significant associations were observed between DDT/DDE and IVF outcomes or between HCB and chemical pregnancy or spontaneous abortion. Conclusions: Serum HCB concentrations were on average lower than that of the general U.S. population and associated with failed implantation among women undergoing IVF.

Background: Human exposure to polychlorinated biphenyls (PCBs) remains widespread. PCBs have been associated with adverse reproductive health outcomes including reduced fecundability and increased risk of pregnancy loss, although the human data remain largely inconclusive.

Objective: Our goal was to explore the relationship between serum PCB concentrations and early pregnancy loss among a large cohort of women undergoing in vitro fertilization (IVF) between 1994 and 2003.

Methods: Concentrations of 57 PCB congeners were measured in serum samples collected during 827 IVF/intracytoplasmic sperm injection cycles from 765 women. Joint statistical models that accommodate multiple outcomes and multiple cycles per woman were used to assess the relationship between serum PCB quartiles and implantation failure, chemical pregnancies (human chorionic gonadotropin level > 5.0 mIU/mL) that did not result in clinical pregnancy, or spontaneous abortion, while also adjusting for confounders.

Results: PCB-153 was the congener present in the highest concentration (median, 46.2 ng/g lipid). Increasing quartiles of PCB-153 and the sum of all measured PCB congeners (ΣPCBs) were associated with significantly elevated dose-dependent odds of failed implantation. Adjusted odds ratios (95% confidence interval) for highest versus lowest quartile were 2.0 (1.2–3.4) for PCB-153 and 1.7 (1.0–2.9) for ΣPCBs. There were suggestive trends for increased odds of implantation failure for PCB-118 and cytochrome P450–inducing congeners (p-values for trend = 0.06). No statistically significant associations between PCBs and chemical pregnancy or spontaneous abortion were found.

Conclusions: Serum PCB concentrations at levels similar to the U.S. general population were associated with failed implantation among women undergoing IVF. These findings may help explain previous reports of reduced fecundability among women exposed to PCBs.

OBJECTIVE

To examine the association between regular physical activity and semen quality.

DESIGN

Prospective cohort study.

SETTING

Couples attending one of three IVF clinics in the greater Boston area during 1993–2003. At study entry, male participants completed a questionnaire about their general health, medical history, and physical activity. Odds ratios (OR) and 95% confidence intervals (CI) were derived using generalized estimating equations models, accounting for potential confounders and multiple samples per man.

PATIENTS

A total of 2,261 men contributing 4,565 fresh semen samples were enrolled before undergoing their first IVF cycle.

INTERVENTION

None.

MAIN OUTCOME MEASURES

Semen volume, sperm concentration, sperm motility, sperm morphology, and total motile sperm (TMS).

RESULTS

Overall, none of the semen parameters was materially associated with regular exercise. Compared with no regular exercise, bicycling ≥5 hours per week was associated with low sperm concentration (OR=1.92, 95%CI=1.03–3.56) and low TMS (OR=2.05, 95%CI=1.19–3.56). These associations did not vary appreciably by age, body mass index, or history of male factor infertility.

CONCLUSIONS

While the present study suggests no overall association between regular physical activity and semen quality, bicycling at levels of ≥5 hours per week was associated with lower sperm concentration and TMS.

The association between educational level and cycle outcomes was quantified by applying multivariable logistic and linear regression within a prospective cohort of 2,569 women commencing their first in vitro fertilization (IVF) cycle. Although a woman’s educational attainment was not associated with the likelihood of implantation failure, chemical pregnancy, spontaneous abortion, or live birth, the odds of cycle cancellation before egg retrieval were 40% lower among those with an college degree and 48% lower among those with graduate school attendance compared with women who had no college degree, suggesting that educational attainment is inversely associated with the likelihood of cycle cancellation.

There is evidence of endocrine disruption and reproductive effects in animals following exposure to certain PBDEs, but human studies are limited. The goal of this study was to investigate the use of serum and follicular fluid as biomarkers of exposure to PBDEs and to explore whether a relationship between PBDE exposure and early pregnancy loss exists. We measured 8 PBDE congeners in archived serum and ovarian follicular fluid samples from 65 women undergoing in-vitro fertilization (IVF). Logistic regression models were used to predict the odds of failed embryo implantation associated with higher levels of PBDEs among the women in the study. There were moderate Kendall’s Tau-beta correlations between serum and follicular fluid concentrations of BDE 28, 47, 100 and 154 (Tβ =0.29–0.38, all p-values<0.005), but BDE 99 and 153 were not correlated between the two matrices (Tβ<0.2, p-values>0.05). Women with detectable concentrations of BDE 153 (39% had detectable levels) in follicular fluid had elevated odds of failed implantation compared with women who had non-detectable concentrations (adjusted OR=10.0; 95%CI: 1.9 to 52; p=0.006; adjusted by age and body mass index). These findings suggest that exposure to BDE 153 may be associated with failed embryo implantation. Due to our observation of only moderate correlations between matrices, serum PBDE concentrations may not be a good indicator of follicular fluid concentrations when studying early pregnancy endpoints in women undergoing IVF.

We examined the relationship between cotinine measures in follicular fluid (FF) and urine to inform our exposure assessment strategy for an ongoing epidemiological study of secondhand tobacco smoke (STS) exposure and early pregnancy loss. Among subjects undergoing in vitro fertilization (IVF), we compared cotinine levels in paired urine and FF samples from the same women and examined FF cotinine levels over time. We found a weak rank-order relationship (Spearman r <0.2) and poor agreement for classifying nonsmoking individuals as exposed to STS (sensitivity = 0.29–0.71; specificity = 0.35–0.72) between cotinine concentrations in FF and urine. We observed fair reliability (ICC = 0.42–0.52) in FF cotinine concentrations from women undergoing multiple IVF cycles. If available, FF cotinine concentrations may be desired as a biomarker of low-level tobacco smoke exposure over urinary cotinine in studies of early reproduction. Collection of multiple FF samples for cotinine analysis may be needed to accurately represent long-term STS exposure.

Differentiating ovarian tumors based on developmental pathway may further our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (NECC) and two cohort studies (NHS/NHSII) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and non-dominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid, or clear cell, whereas non-dominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis, and age were more strongly associated with dominant (RRs = 0.60, 0.83, 1.58, 1.37, respectively) than non-dominant tumors (RRs = 1.03, 0.93, 0.84, 1.14 p-difference = 0.0001, 0.01, 0.0003, 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

To estimate whether alcohol use at the initiation of an in vitro fertilization (IVF) cycle is associated with IVF outcomes.

METHODS

In this prospective cohort study, men and women completed a self-administered questionnaire before their first IVF cycle. Participants reported alcohol type, amount, and frequency consumed. Discrete survival analysis was applied to calculate the odds ratio (OR) and 95% confidence interval (CI) for live birth—the primary outcome. Secondary outcomes were cycle characteristics and points of failure in the IVF process (cycle cancellation, failed fertilization, implantation failure, and spontaneous abortion). We conducted multicycle analyses with final models adjusted for potential confounders that included cycle number, cigarette use, body mass index, and age.

RESULTS

A total of 2,545 couples contributed 4,729 cycles. Forty-one percent of women and 58% of men drank one to six drinks per week. Women drinking at least four drinks per week had 16% less odds of a live birth rate compared with those who drank fewer than four drinks per week (OR 0.84, CI 0.71–0.99). For couples in which both partners drank at least four drinks per week, the odds of live birth were 21% lower compared with couples in which both drank fewer than four drinks per week (OR 0.79; CI 0.66–0.96).

CONCLUSION

Consumption of as few as four alcoholic drinks per week is associated with a decrease in IVF live birth rate.

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.