Immunological Markers of Chlamydia trachomatis Infection in Epithelial Ovarian Cancer.

BACKGROUND/AIM: Pelvic inflammatory disease (PID) is a risk factor for epithelial ovarian cancer (EOC). Chlamydia trachomatis infection, a major cause of PID, may persist in some women. Serum IgG antibodies to chlamydial TroA and HtrA are more common in ascending or repeat chlamydial infection than in uncomplicated infection. The aim of this study was to explore the role of C. trachomatis infection in EOC by analyzing chlamydial TroA, HtrA and major outer membrane protein (MOMP) IgG serum antibody responses. PATIENTS AND METHODS: The study is based on the review of Oulu University Hospital medical records of 162 women diagnosed with EOC between March 2008 and May 2018. Serum IgG antibody responses to recombinant C. trachomatis TroA, HtrA and MOMP were analyzed using enzyme-linked immunoassay. Complete response to the first line therapy and the three-year survival were the study endpoints. RESULTS: Altogether, 16.7%, 11.1% and 12.3% women were C. trachomatis TroA, HtrA and MOMP IgG positive, respectively. Women with these antibodies were more likely to have a complete response to the first-line treatment, compared to women without these antibodies (63.0% vs. 34.1% for TroA IgG, 50.0% vs. 37.5% for HtrA IgG and 50% vs. 37.3% for MOMP IgG, respectively). The presence of these antibodies predicted better three-year survival. CONCLUSION: Women with EOC and positive markers of persistent C. trachomatis infection have better response to the first-line treatment and seem to have better three-year survival.

Effectiveness of various human papillomavirus vaccination strategies: A community randomized trial in Finland.

INTRODUCTION: We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine. METHODS: Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination. RESULTS: Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes. CONCLUSIONS: This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

Chlamydia trachomatis, Pelvic Inflammatory Disease, and Epithelial Ovarian Cancer.

Epidemiologic, clinical, molecular and translational research findings support an interrelationship between Chlamydia trachomatis, pelvic inflammatory disease (PID), and epithelial ovarian cancer (EOC). Overall, the link between C. trachomatis, PID, and EOC seems to be relatively weak, although nondifferential misclassification bias may have attenuated the results. The predominant tubal origin of EOC and the role of chronic inflammation in tumorigenesis suggest that the association is biologically plausible. Thus, C. trachomatis and PID may represent potential risk factors or risk markers for EOC. However, many steps in this chain of events are still poorly understood and need to be addressed in future studies. Research gaps include time of exposure in relation to the long-term consequences and lag time to EOC. Data of differential risk for EOC between chlamydial and nonchlamydial PID is also needed. Another major research gap has been the absence of high-performance biomarkers for C. trachomatis, PID, and EOC, as well as EOC precursors. Biomarkers for C. trachomatis and PID leading to increased risk of EOC should be developed. If the association is confirmed, C. trachomatis and PID prevention efforts may play a role in reducing the burden of EOC.

Genital Tract GAS Infection ISIDOG Guidelines.

There has been an increasing worldwide incidence of invasive group A streptococcal (GAS) disease in pregnancy and in the puerperal period over the past 30 years. Postpartum Group A streptococci infection, and in particular streptococcal toxic shock syndrome (TSS) and necrotizing fasciitis, can be life threatening and difficult to treat. Despite antibiotics and supportive therapy, and in some cases advanced extensive surgery, mortality associated with invasive group A streptococcal postpartum endometritis, necrotizing fasciitis, and toxic shock syndrome remains high, up to 40% of postpartum septic deaths. It now accounts for more than 75,000 deaths worldwide every year. Postpartum women have a 20-fold increased incidence of GAS disease compared to non-pregnant women. Despite the high incidence, many invasive GAS infections are not diagnosed in a timely manner, resulting in potentially preventable maternal and neonatal deaths. In this paper the specific characteristics of GAS infection in the field of Ob/Gyn are brought to our attention, resulting in guidelines to improve our awareness, early recognition and timely treatment of the disease. New European prevalence data of vaginal GAS colonization are presented, alongside two original case histories. Additionally, aerobic vaginitis is proposed as a supplementary risk factor for invasive GAS diseases.

Sustainability of neutralising antibodies induced by bivalent or quadrivalent HPV vaccines and correlation with efficacy: a combined follow-up analysis of data from two randomised, double-blind, multicentre, phase 3 trials.

BACKGROUND: Quadrivalent and bivalent vaccines against oncogenic human papillomavirus (HPV) are used worldwide with different reported overall efficacies against HPV infections. Although protective concentrations of vaccine-induced antibodies are still not formally defined, we evaluated the sustainability of neutralising antibodies in vaccine trial participants 2-12 years after vaccination and the correlation with reported vaccine efficacy. METHODS: We did a follow-up analysis of data from the Finnish cohorts of two international, randomised, double-blind, phase 3 trials of HPV vaccines, PATRICIA (bivalent, HPV16 and 18) and FUTURE II (quadrivalent, HPV6, 11, 16, and 18). In 2002 and 2004-05, respectively, Finnish girls aged 16-17 years participated in one of these two trials and consented to health registry follow-up with the Finnish Cancer Registry. The cohorts were also linked with the Finnish Maternity Cohort (FMC) that collects first-trimester serum samples from nearly all pregnant Finnish women, resulting in 2046 post-vaccination serum samples obtained during up to 12 years of follow-up. We obtained serum samples from the FMC-based follow-up of the FUTURE II trial (from the quadrivalent vaccine recipients) and the PATRICIA trial (from corresponding bivalent vaccine recipients who were aligned by follow-up time, and matched by the number of pregnancies). We assessed neutralising antibody concentrations (type-specific seroprevalence) to HPV6, 16, and 18, and cross-neutralising antibody responses to non-vaccine HPV types 31, 33, 45, 52, and 58 from 2 to 12 years after vaccination. FINDINGS: Up to Dec 31, 2016, we obtained and analysed 577 serum samples from the quadrivalent vaccine recipients and 568 from the bivalent vaccine recipients. In 681 first-pregnancy serum samples, neutralising antibodies to HPV6, 16, and 18 were generally found up to 12 years after vaccination. However, 51 (15%) of 339 quadrivalent vaccine recipients had no detectable HPV18 neutralising antibodies 2-12 years after vaccination, whereas all 342 corresponding bivalent vaccine recipients had HPV18 neutralising antibodies.. In seropositive quadrivalent vaccine recipients, HPV16 geometric mean titres (GMT) halved by years 5-7 (GMT 3679, 95% CI 2377 to 4708) compared with years 2-4 (6642, 2371 to 13 717). Between 5 and 12 years after vaccination, GMT of neutralising antibodies to HPV16 and 18 were 5·7 times and 12·4 times higher, respectively, in seropositive bivalent vaccine recipients than in the quadrivalent vaccine recipients. Cross-neutralising antibodies to HPV31, 33, 45, 52, and 58 were more prevalent in the bivalent vaccine recipients but, when measurable, sustainable up to 12 years after vaccination with similar GMTs in both vaccine cohorts. Seroprevalence for HPV16, 31, 33, 52, and 58 significantly correlated with vaccine efficacy against persistent HPV infections in the bivalent vaccine recipients only (rs=0·90, 95% CI 0·09 to 0·99, p=0·037, compared with rs=0·62, 95% CI -0·58 to 0·97, p=0·27 for the quadrivalent vaccine recipients). Correlation of protection with prevalence of neutralising or cross-neutralising HPV antibodies was not significant in the quadrivalent vaccine recipients. INTERPRETATION: The observed significant differences in the immunogenicity of the two vaccines are in line with the differences in their cross-protective efficacy. Protective HPV vaccine-induced antibody titres can be detected up to 12 years after vaccination. FUNDING: Academy of Finland and Finnish Cancer Foundation.

Reproductive system infections in women: upper genital tract, fetal, neonatal and infant syndromes.

Lower genital tract infection and bloodborne spread of infection are the two principal modes for infection of the upper genital tract or for infection of the fetus, neonate or infant. Treponema pallidum and human immunodeficiency virus (HIV) are the two most common bloodborne pathogens that infect the fetus, neonate or infant. Most infections of the upper genital tract, however, spread along epithelial surfaces from the vagina or cervix to the upper genital tract or chorioamnion, fetus, neonate or infant. These infections are caused by either pathogens associated with a dysbiotic vaginal microbiome or those that are sexually transmitted. The clinical syndromes that these pathogens produce in the lower genital tract were discussed in part one of this review. We now discuss the syndromes and pathogens that affect the upper genital tract of both non-pregnant and pregnant women as well as fetus, neonate and infant.

Reproductive system infections in women: lower genital tract syndromes.

Gynecological and obstetrical infectious diseases are an important component of women's health. A system approach to gynecological and obstetrical infection helps unify and classify microbial etiology and pathogenesis within a clinical anatomical framework of lower and upper genital tract syndromes. The reproductive system of women includes the vulva, vagina, cervix, uterus, fallopian tubes and ovaries. During pregnancy, additional tissues include the chorioamnion and placenta together with the fetus and amniotic fluid. We review in two parts reproductive system infection syndromes in women using selected research results to illustrate the clinical utility of the system approach in terms of diagnosis, treatment and prevention. We conclude that a reproductive system perspective will lead to improvements in understanding, management and prevention of these diseases.

Vaccination With Moderate Coverage Eradicates Oncogenic Human Papillomaviruses If a Gender-Neutral Strategy Is Applied.

BACKGROUND: Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, the herd effect (HE) depends both on the HPV type and the vaccination strategy. METHODS: We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007-2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010-2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication. RESULTS: The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy. CONCLUSIONS: Gender-neutral vaccination is superior for eradication of oncogenic HPVs.

The Prevalence of HSV, HHV-6, HPV and Mycoplasma genitalium in Chlamydia trachomatis positive and Chlamydia trachomatis Negative Urogenital Samples among Young Women in Finland.

Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) and human papillomavirus (HPV) cause sexually transmitted infections. In addition, human herpesvirus 6 (HHV-6) may be a genital co-pathogen. The prevalence rates of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes were investigated by PCR in urogenital samples of the C. trachomatis nucleic acid amplification test positive (n = 157) and age-, community- and time-matched negative (n = 157) women. The prevalence of HPV DNA was significantly higher among the C. trachomatis positives than the C. trachomatis negatives (66% vs. 25%, p < 0.001). The prevalence of HSV (1.9% vs. 0%), HHV-6 (11% vs. 14%), and M. genitalium DNA (4.5% vs. 1.9%) was not significantly different between the C. trachomatis-positive and -negative women. Thirteen per cent of test-of-cure specimens tested positive for C. trachomatis. The prevalence of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes did not significantly differ between those who cleared the C. trachomatis infection (n = 105) and those who did not (n = 16). The higher prevalence of HPV DNA among the C. trachomatis positives suggests greater sexual activity and increased risk for sexually transmitted pathogens.

High risk in the first-trimester combined screening: Long-term outcomes of the children.

OBJECTIVE: To bring new accuracy to the prognosis of outcomes of euploid fetuses with an extremely high risk in the first-trimester combined screening when compared to the low-risk group. STUDY DESIGN: The data included pregnancies with a trisomy 21 risk ≥ 1:50 in the combined first-trimester screening but normal fetal chromosomes. The control group had a risk value ≤ 1:300. Miscarriage, termination of pregnancy, stillbirth, premature delivery, and delivery of an unhealthy child were considered adverse outcomes. The impact of each component in the combined first-trimester screening was analyzed separately. Statistical comparisons were made by using the chi-square test, Fisher-Freeman-Halton test, Mann-Whitney test or t-test. RESULTS: The study comprised 483 women (161 cases and 322 controls). The mean follow-up time of children born alive was 61.4 months. An adverse outcome was detected in 11.8% of the cases and in 5.9% of the controls. After adjusting the values of mother´s age, parity, and smoking habit the odds ratio for an adverse outcome was 2.1 (95% CI: 1.0-4.5, p = 0.05) for cases. When evaluating the effect of 1 SD increase in MOM of PAPP-A or 1 SD decrease in MOM of NT or ß-hCG to any adverse outcome, 1 SD increase in PAPP-A MOM decreased the risk of adverse outcome by OR 0.48 (95% CI: 0.3 - 0.8, p = 0.05) while the others were not significant. CONCLUSION: Euploid fetuses with a high risk in the combined first-trimester screening have a twofold risk for adverse outcomes when compared to those with a low risk.

Eradication of human papillomavirus and elimination of HPV-related diseases - scientific basis for global public health policies.

INTRODUCTION: Infections with oncogenic human papillomaviruses (HPV) globally cause about 9% of cancers in females and 1% of cancers in males. HPV disease burden can be effectively controlled by prophylactic HPV-vaccination provided it has high impact. AREAS COVERED: A unique series of biobank-based and health registry-based studies that exploit randomized intervention cohorts has provided data on population-level safety of HPV vaccination, duration of vaccine-induced protection and impact of gender-neutral HPV vaccination, providing a scientific basis for policies to eradicate oncogenic HPV types and associated diseases worldwide. EXPERT COMMENTARY: The ultimate goal of HPV vaccination is the eradication of high-risk (hr) HPVs. Seventy-five percent coverage gender-neutral vaccination of early adolescents will rapidly eradicate also HPV16 from the general population.

Cervical and Amniotic Fluid Matrix Metalloproteinase-8 and Interleukin-6 Concentrations in Preterm Pregnancies with or without Preterm Premature Rupture of Membranes.

INTRODUCTION: Intra-amniotic inflammation is defined by elevated inflammatory biomarkers in the amniotic fluid (AF), either due to microbial invasion of the amniotic cavity (MIAC) or sterile inflammation. Amniocentesis being an invasive procedure, we wanted to investigate whether elevated matrix metalloproteinase-8 (MMP-8) or interleukin-6 (IL-6) concentrations could be detected from cervical fluid samples. MATERIALS AND METHODS: This prospective study included 67 women with singleton nondiabetic pregnancies with or without preterm premature rupture of membranes (PPROM) between 22+0 and 37+0 weeks of gestation. Simultaneous AF and cervical samples were obtained. RESULTS: In women without PPROM, cervical MMP-8 concentrations correlated with AF MMP-8 concentrations (rS = 0.466, p = 0.002), but cervical IL-6 did not correlate with AF IL-6 (rS = 0.277, p = 0.076). In PPROM cases no correlations were found. Women with MIAC had higher concentrations of AF MMP-8 and AF IL-6 compared to women without MIAC regardless of membrane status. However, only women without PPROM had higher concentrations of cervical MMP-8 in proven MIAC. CONCLUSION: In women without PPROM, cervical MMP-8 concentration reflects the magnitude of AF MMP-8, thus potentially guiding the selection of patients benefitting from amniocentesis.

Subsequent risk of cancer among women with a history of placental abruption.

BACKGROUND: Placentation is characterized by extensive cell proliferation and neovascularization, which is similar to the processes observed in the development of cancer. Nonetheless, little is known about the relation between abnormal placentation, such as placental abruption, and cancer. MATERIAL AND METHODS: Data on women with placental abruption in a singleton pregnancy between 1971 and 2005 (n = 7804) were collected from the Finnish Hospital Discharge Registry and the Finnish Medical Birth Registry. The cohort was then linked with the Finnish Cancer Registry records until the end of 2013. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by those expected. The expected numbers were based on national cancer incidence rates. RESULTS: During follow-up, 597 cancers were found among women with a history of placental abruption. The overall risk of cancer was not increased (SIR 0.95, 95% CI 0.88-1.02). However, the history of placental abruption was associated with an increased risk of lung cancer (SIR 1.51, 95% CI 1.05-2.10) and thyroid cancer (SIR 1.47, 95% CI 1.04-2.02). A decreased risk was found for breast cancer (SIR 0.85, 95% CI 0.75-0.96). The risk of rectal cancer was also decreased, although these numbers were small (SIR 0.49, 95% CI 0.20-1.01). CONCLUSIONS: Overall, the risk of lung cancer was increased, and the risk of breast cancer decreased, in women with a history of placental abruption. These observations can be explained to some extent by risk factors or risk markers for placental abruption. The increased risk of thyroid cancer may be explained by surveillance bias.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Gender-neutral vaccination provides improved control of human papillomavirus types 18/31/33/35 through herd immunity: Results of a community randomized trial (III).

With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective effectiveness (PE) against high-risk HPV infections by HPV type and vaccination strategy in a community-randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender-neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Entire 1992-1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20-30% and 45% coverage in 2007-2010. During 2010-2014, 11,396 cervicovaginal samples were collected from 13,545 18.5-year-old attendees. HPV typing was performed by a high-throughput PCR. VE was calculated for HPV vaccinated women and HE for non-HPV-vaccinated women, using the HBV vaccinated, for HE all non-HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate-weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86-94% and 30-66%, respectively. Only the gender-neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort-increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender-neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender-neutral vaccination-enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.

Evaluation of HPV type-replacement in unvaccinated and vaccinated adolescent females-Post-hoc analysis of a community-randomized clinical trial (II).

Efficacy of human papillomavirus (HPV) vaccines promises to control HPV infections. However, HPV vaccination programs may lay bare an ecological niche for non-vaccine HPV types. We evaluated type-replacement by HPV type and vaccination strategy in a community-randomized trial executed in HPV vaccination naïve population. Thirty-three communities were randomized to gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Resident 1992-95 born boys (40,852) and girls (39,420) were invited. 11,662 boys and 20,513 girls were vaccinated with 20-30% and 45-48% coverage, respectively. HPV typing of 11,396 cervicovaginal samples was performed by high throughput PCR. Prevalence ratios (PR) between arms and ranked order of HPV types and odds ratio (OR) for having multiple HPV types in HPV16 or 18/45 positive individuals were calculated. The ranked order of HPV types did not significantly differ between arms or birth cohorts. For the non-HPV vaccinated 1992-1993 birth cohorts increased PR, between the gender-neutral intervention versus control arms for HPV39 (PRA 1.84, 95% CI 1.12-3.02) and HPV51 (PRA 1.56, 95% CI 1.11-2.19) were observed. In the gender-neutral arm, increased clustering between HPV39 and the vaccine-covered HPV types 16 or 18/45 (ORA16 = 5.1, ORA18/45 = 11.4) was observed in the non-HPV vaccinated 1994-1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (ORB16 = 4.7, ORB18/45 = 4.3), in the girls-only arm. In conclusion, definitively consistent postvaccination patterns of HPV type-replacement were not observed. Future occurrence of HPV39 and HPV51 warrant investigation.

Risk of preterm birth in women with cervical intraepithelial neoplasia grade one: a population-based cohort study.

INTRODUCTION: In this population-based register study our objective was to explore the association of cervical intraepithelial neoplasia, grade 1 and loop electrosurcigal excision procedure with preterm birth. MATERIAL AND METHODS: Our population consisted of 4759 women diagnosed with cervical intraepithelial neoplasia, grade 1 during 1997-2009 and their 3021 subsequent deliveries analyzed by loop electrosurcigal excision procedure and parity. Hospital Discharge Register was used to identify women diagnosed for cervical intraepithelial neoplasia, grade 1 and these data were linked with the Medical Birth Register data. We calculated odds ratios with 95% confidence intervals. RESULTS: Cervical intraepithelial neoplasia, grade 1 patients with loop electrosurcigal excision procedure had 54 (6.7%) subsequent preterm births and the corresponding figure among cervical intraepithelial neoplasia, grade 1 patients without loop electrosurcigal excision procedure was 116 (5.2%). This results in odds ratios 1.31 (95% confidence interval 0.94-1.83). We assessed the risk before and after diagnosis of cervical intraepithelial neoplasia, grade 1 both for patients with loop electrosurcigal excision procedure (odds ratios 1.47, 95% confidence interval 1.05-2.06) and without loop electrosurcigal excision procedure (odds ratios 0.90, 95% confidence interval 0.71-1.13). An increased risk for preterm birth after diagnosis of cervical intraepithelial neoplasia, grade 1 and loop electrosurcigal excision procedure was observed. We also compared both groups to the background population in the Medical Birth Register. For cervical intraepithelial neoplasia, grade 1 patients without loop electrosurcigal excision procedure the risk for preterm birth was not increased (odds ratios 0.95, 95% confidence interval 0.76-1.21) whereas for cervical intraepithelial neoplasia, grade 1 patients treated with loop electrosurcigal excision procedure the risk for preterm birth was increased (odds ratios 1.45, 95% confidence interval 1.02-1.92). CONCLUSIONS: Loop electrosurcigal excision procedure itself increases the risk for preterm birth. Cervical intraepithelial neoplasia, grade 1 as such does not increase the risk for preterm birth.

Impact of gender-neutral or girls-only vaccination against human papillomavirus-Results of a community-randomized clinical trial (I).

Human papillomavirus (HPV) vaccine is efficacious but the real-life effectiveness of gender-neutral and girls-only vaccination strategies is unknown. We report a community-randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (11 communities) or Arm C) gender-neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992-95 were invited in 2007-09. Virtually all (99%) 12- to 15-year-old participating males (11,662) and females (20,513) received three doses resulting in uniform 20-30% male and 50% female vaccination coverage by birth cohort. Four years later (2010-14) 11,396 cervicovaginal samples obtained from 18.5 year-old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non-vaccine types consistent with cross-protection were highest in those born 1994-95 for HPV45 (VEA 82.8%; VEB 86.1%) and for HPV31 (VEA 77.6%, VEB 84.6%). The HEs in the non HPV-vaccinated were statistically significant in those born 1994-95 for HPV18 (HEA 51.0%; 95% CI 8.3-73.8, HEB 47.2%; 6.5-70.2) and for HPV31/33 in arm A (HEA 53.7%; 22.1-72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PEA 58.1%; 45.1-69.4; PEB 55.7%; 42.9-66.6). PE estimates against HPV31/33 were higher by the gender-neutral vaccination (PEA 60.5%; 43.6-73.4; PEB 44.5%; 24.9-60.6). In conclusion, while gender-neutral strategy enhanced the effectiveness of HPV vaccination for cross-protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638.

Long-term Follow-up After Endometrial Ablation in Finland: Cancer Risks and Later Hysterectomies.

OBJECTIVE: To study the risk of endometrial cancer and breast cancer and the hysterectomy rate after endometrial ablation. METHODS: In this retrospective cohort study, records of all women with endometrial ablation at ages 30-49 years in Finland (1997-2014) were extracted from the Hospital Discharge Register and linked to the Cancer Registry and Finnish Central Population Register. The primary outcome was cancer incidences in the endometrial ablation cohort compared with those in the background population of the same age. Secondarily, the postablation hysterectomy rate was compared with that of a control cohort of similar-aged women extracted from the Finnish Central Population Register. Multivariate regression models with adjustment for age, parity, number of cesarean deliveries, history of sterilization, and the duration of follow-up were evaluated as risk factors for postablation hysterectomy. RESULTS: In total, 154 cancers (standardized incidence ratio [observed-to-expected ratio] 0.96, 95% CI 0.82-1.13) were diagnosed among 5,484 women treated with endometrial ablation during the follow-up of 39,892 women-years. The standardized incidence ratio for endometrial cancer was 0.56 (95% CI 0.12-1.64) and for breast cancer 0.86 (95% CI 0.67-1.09). A total of 1,086 (19.8%) women had postablation hysterectomy. Risk of hysterectomy was almost fourfold in the endometrial ablation cohort compared with 26,938 women in a control group (adjusted hazard ratio [HR] 3.63, 95% CI 3.32-3.96). Factors predisposing to postablation hysterectomy were leiomyomas (adjusted HR 1.78, 95% CI 1.03-3.10), age younger than 35 years (adjusted HR 1.44, 95% CI 1.15-1.81), at least two prior cesarean deliveries (adjusted HR 1.27, 95% CI 1.04-1.55), and history of sterilization (adjusted HR 1.15, 95% CI 1.01-1.32). CONCLUSION: Endometrial ablation was not associated with an elevated endometrial cancer or breast cancer risk in Finland. Leiomyomas, young age, and history of prior cesarean deliveries or sterilization were associated with an increased risk of postablation hysterectomy.