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Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk., (© 2013 UICC.)

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40., (Copyright © 2011 UICC.)

Licensed human papillomavirus (HPV) vaccines are expected to prevent high-risk (hr) HPV-infections (most notably types 16 and 18). Whether HPV vaccination will change the distribution of hrHPVs at the population level is open, since competition between HPV types is not well understood. Two stratified random subcohorts (1983-1997 and 1995-2003) of 7,815 and 3,252 women with a minimum of 2 pregnancies (<32 years) were selected from the Finnish Maternity Cohort. Using ELISA based on virus-like particles (VLP), we determined antibodies to HPV11, 16, 18 and 31 in paired sera of the women and used Poisson regression models to estimate the risk of further infection with other HPV types in those positive for HPV16 or HPV18 at baseline. Baseline HPV16 seropositivity was associated with increased risk of later infections with HPV18 (3.1, 95% CI: 1.7, 5.6). HPV18 seropositivity was associated with increased risk of HPV16 (3.9, 95% CI: 2.5, 6.1). Our observations favor a coinfection rather than superinfection model for the different HPV types and are not suggestive for type-replacement following HPV vaccination., ((c) 2009 UICC.)

According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring., (Copyright 2008 UICC.)

Vaccines against high-risk (hr) human papillomaviruses (HPVs) causing cervical cancer may soon be licensed. Thus, nature of HPV epidemics needs to be studied now. Random sampling for studies on HPV epidemiology was done from all 230,998 women belonging to the population-based Finnish Maternity Cohort and having a minimum of 2 pregnancies between 1983 and 1994. First pregnancy serum specimens were retrieved for 7,805 subjects, and were analyzed for antibodies to HPV6/11, 16 and 18 with standard ELISAs. HPV16 seroprevalence almost doubled from the 1980s to the 1990s, and the epidemic spread to new areas in 23-31 year olds, i.e. the bulk of pregnant female population in the southwest part of the country. The HPV16 epidemic in the 14-22 year olds in 1983-1988 (1961-1974 birth cohorts) and in the 23-31 year olds in 1989-1994 (1958-1971 birth cohorts) overlapped with strong clustering of HPV16 and HPV18 infections in the latter (odds ratio 8.0, 95% confidence interval 6.6-9.7). Similar clustering of HPV16 and HPV6/11 infections was not found. The epidemic and the clustering may be due to high transmission probability of the hrHPV types and increase in sexual activity of the index birth cohorts.

To investigate if polyomavirus infection during pregnancy is linked to development of neuroblastoma in the child, serum samples of 115 index mothers from the pregnancy where the child eventually developed neuroblastoma were identified and matched with serum samples from 8 control mothers per index mother. The samples were tested for specific IgG and IgM antibodies to BK and JC virus using enzyme immunoassays based on purified yeast-expressed virus-like particles (VLPs). The serum samples as well as 10 neuroblastoma cell lines were also analyzed using Real Time (TaqMan) PCR for detection and quantification of BK virus DNA. The BK virus IgG seroprevalence was similar among index mothers (80%) and control mothers (83%) [OR 0.8; 95% confidence interval (95% CI): 0.5-1.3]. BK virus IgM was also not associated with neuroblastoma risk (OR was OR = 0.6; 95% with CI, 0.2-1.9). Also JC virus had no association, neither for IgG (OR = 0.9; 95% CI, 0.6-1.4) nor for IgM (OR = 0.9; 95% CI, 0.4-1.9). All serum samples and all neuroblastoma cell lines were negative for BKV DNA. In summary, a comprehensive cohort using both serology and polyomavirus DNA detection found no evidence for association between BKV or JCV polyomaviruses and neuroblastoma.

Persistent human papillomavirus (HPV) infection is an established cause of cervical cancer, but the role of other sexually transmitted agents, most notably Chlamydia trachomatis, has not been well defined. The women participating in the population-based cervical cancer screening program in Västerbotten county of Northern Sweden were followed up for up to 26 years to identify 118 women who developed cervical cancer after having had a normal Pap smear (on average 5.6 years later; range 0.5 months-26 years). As controls, we selected another 118 women who were matched by birth cohort, time-point of sampling of the baseline normal smear and who had a normal smear at the time when the corresponding case was diagnosed with cancer. The Pap smears and cervical cancer biopsies were analyzed by PCR for C. trachomatis DNA and for HPV DNA. At baseline, C. trachomatis DNA was present in 8% of cases but not among any one of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6-infinity). The presence of C. trachomatis and of HPV were not interrelated. Whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short lag time before cancer diagnosis. Whereas most women who were HPV DNA-positive in the prediagnostic smear were also positive for the same virus in the cervical cancer biopsy, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the subsequent cervical cancer. In conclusion, a prior cervical C. trachomatis infection was associated with an increased risk for development of invasive cervical cancer., (Copyright 2002 Wiley-Liss, Inc.)

Cervical carcinoma is a sexually transmitted disease most strongly linked with human-papillomavirus (HPV) infection. We conducted a prospective sero-epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case-control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow-up of 5 years after serum sampling. The serum samples of the cases and matched cancer-free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous-cell carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3-3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and -seropositive cases (OR, 3.0; 95% CI, 1.8-5.1; OR, 2.3, 95% CI, 0. 8-7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero-epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous-cell carcinoma of the uterine cervix., (Copyright 2000 Wiley-Liss, Inc.)