Cancer incidence, mortality, and pregnancy outcome among women treated for cervical intraepithelial neoplasia

Cervical cancer develops through precursor lesions, i.e. cervical intraepithelialneoplasms (CIN). These can be detected and treated before progression to invasive cancer. The major risk factor for developing cervical cancer or CIN is persistent or recurrent infection with high-risk human papilloma virus (hrHPV). Other associated risk factors include low socioeconomic status, smoking, sexually transmitted infections, and high number of sexual partners, and these risk factors can predispose to some other cancers, excess mortality, and reproductive health complications as well. The aim was to study long-term cancer incidence, mortality, and reproductive health outcomes among women treated for CIN. Based on the results, we could evaluate the efficacy and safety of CIN treatment practices and estimate the role of the risk factors of CIN patients for cancer incidence, mortality, and reproductive health. We collected a cohort of 7 599 women treated for CIN at Helsinki University Central Hospital from 1974 to 2001. Information about their cancer incidence, cause of death, birth of children and other reproductive endpoints, and socio-economic status were gathered through registerlinkages to the Finnish Cancer Registry, Finnish Population Registry, and Statistics Finland. Depending on the endpoints in question, the women treated were compared to the general population, to themselves, or to an age- and municipality-matched reference cohort. Cervical cancer incidence was increased after treatment of CIN for at least 20 years, regardless of the grade of histology at treatment. Compared to all of the colposcopically guided methods, cold knife conization (CKC) was the least effective method of treatment in terms of later CIN 3 or cervical cancer incidence. In addition to cervical cancer, incidence of other HPV-related anogenital cancers was increased among those treated, as was the incidence of lung cancer and other smoking-related cancers. Mortality from cervical cancer among the women treated was not statistically significantly elevated, and after adjustment for socio-economic status, the hazard ratio (HR) was 1.0. In fact, the excess mortality among those treated was mainly due to increased mortality from other cancers, especially from lung cancer. In terms of post-treatment fertility, the CIN treatments seem to be safe: The women had more deliveries, and their incidence of pregnancy was similar before and after treatment. Incidence of extra-uterine pregnancies and induced abortions was elevated among the treated both before and after treatment. Thus this elevation did not occur because they were treated rather to a great extent was due to the other known risk factors these women had in excess, i.e. sexually transmitted infections. The purpose of any cancer preventive activity is to reduce cancer incidence and mortality. In Finland, cervical cancer is a rare disease and death from it even rarer, mostly due to the effective screening program. Despite this, the women treated are at increased risk for cancer; not just for cervical cancer. They must be followed up carefully and for a long period of time; general health education, especially cessation of smoking, is crucial in the management process, as well as interventions towards proper use of birth control such as condoms.Kohdunkaulan syöpä kehittyy todettavien ja hoidettavien esiasteiden kautta. Tunnetuin ja tärkein riskitekijä sekä kohdunkaulan syövän, että kohdunkaulan syövän esiasteiden kehittymiselle on suuren riskin ihmisen papilloomavirusinfektio (hrHPV). Muita merkittäviä riskitekijöitä ovat mm. sukupuoliteitse välittyvät taudit sekä tupakointi, jotka ovat riskitekijöitä myös tietyille muille syöville, lisääntyneelle kuolleisuudelle sekä lisääntymisterveyteen liittyville komplikaatioille. Väitöskirjatutkimuksen tavoitteena oli selvittää pitkän aikavälin syöpäilmaantuvuutta, -kuolleisuutta sekä lisääntymisterveystapahtumia kohdunkaulan syövän esiasteesta hoidetuilla naisilla. Tulosten perusteella oli tarkoitus arvioida esiastehoitojen vaikuttavuutta ja turvallisuutta, sekä kartoittaa muiden tässä joukossa lisääntyneiden riskitekijöiden vaikutusta yleiseen sairastavuuteen ja kuolleisuuteen. Tutkimusaineisto koostui 7599:stä HYKS Naistenklinikalla vv. 1974 2001 kohdunkaulan syövän esiasteesta hoidetusta naisesta. Tieto myöhemmästä syöpäilmaantuvuudesta, kuolinsyistä, lasten syntymäpäivistä, muista lisääntymisterveydellisistä muuttujista, sekä sosioekonomisen aseman luokitus hankittiin yhdistämällä tutkimusaineisto Suomen Syöpärekisterin, Väestörekisterin sekä STAKESin (nyk THL) kanssa. Riippuen osatutkimuksesta, hoidettuja naisia vertailtiin joko muuhun väestöön, itseensä, tai ikä- ja asuinkuntakaltaistettuun vertailuväestöön. Kohdunkaulan syövän ilmaantuvuus oli koholla kahdenkymmen vuoden ajan hoidetun levyepiteeliperäisen esiasteen jälkeen, riippumatta esiasteen vaikeusasteesta. Myös muiden HPV-riippuvaisten anogenitaalialueen syöpien (vagina-, vulva- ja anussyöpä), keuhkosyövän ja muiden tupakointiin liittyvien syöpien ilmaantuvuus oli koholla esiastehoidetuilla naisilla muuhun väestöön verrattuna. Eri hoitomuotojen keskinäisessä vertailussa CIN 3- ja kohdunkaulan syövän ilmaantuvuus oli suurinta veitsikonisaation jälkeen. Hoidon jälkeisen fertiliteetin suhteen esiastehoito on turvallinen: Esiasteesta hoidetut naiset tulivat vertailuväestöä useammin raskaaksi, sekä synnyttivät useammin hoidon jälkeen verrattuna hoitoa edeltäneeseen ajanjaksoon. Kohdunulkoisten raskauksien ja raskaudenkeskeytysten ilmaantuvuus oli hoidetuilla verrokkeja suurempaa sekä ennen että jälkeen hoidon: Kyseinen havainto ei siis liity itse hoitoon vaan pikemminkin muihin riskitekijöihin, mm. klamydiainfektioon, joita esiastepotilailla on keskimäärin muuta väestöä yleisemmin. Minkä tahansa seulontaohjelman tai muun syövänehkäisytoiminnan lopullisena päämääränä on ehkäistä syöpäkuolleisuutta. Suomessa kohdunkaulan syöpä on nykyään harvinainen sairaus ja kuolema tähän syöpään on vieläkin harvinaisempaa, ennen kaikkea tehokkaan seulontaohjelman ansiosta. Tästä huolimatta sekä kohdunkaulan että muutamien muiden syöpien riski on kohdunkaulan syövän esiasteen sairastaneilla lisääntynyt muuhun väestöön verrattuna. Hoidettuja naisia pitää seurata tarkasti ja riittävän pitkän ajan. Yleinen terveysvalistus, erityisesti kannustaminen tupakoinnin lopettamiseen ja kondomin käyttöön ovat tässä toiminnassa erityisasemassa

Comparative analysis of vaginal microbiota sampling using 16S rRNA gene analysis

Background Molecular methods such as next-generation sequencing are actively being employed to characterize the vaginal microbiota in health and disease. Previous studies have focused on characterizing the biological variation in the microbiota, and less is known about how factors related to sampling contribute to the results. Our aim was to investigate the impact of a sampling device and anatomical sampling site on the quantitative and qualitative outcomes relevant for vaginal microbiota research. We sampled 10 Finnish women representing diverse clinical characteristics with flocked swabs, the Evalyn (R) self-sampling device, sterile plastic spatulas and a cervical brush that were used to collect samples from fornix, vaginal wall and cervix. Samples were compared on DNA and protein yield, bacterial load, and microbiota diversity and species composition based on Illumina MiSeq sequencing of the 16S rRNA gene. We quantified the relative contributions of sampling variables versus intrinsic variables in the overall microbiota variation, and evaluated the microbiota profiles using several commonly employed metrics such as alpha and beta diversity as well as abundance of major bacterial genera and species. Results The total DNA yield was strongly dependent on the sampling device and to a lesser extent on the anatomical site of sampling. The sampling strategy did not affect the protein yield or the bacterial load. All tested sampling methods produced highly comparable microbiota profiles based on MiSeq sequencing. The sampling method explained only 2% (p-value = 0.89) of the overall microbiota variation, markedly surpassed by intrinsic factors such as clinical status (microscopy for bacterial vaginosis 53%, p = 0.0001), bleeding (19%, p = 0.0001), and the variation between subjects (11%, p-value 0.0001). Conclusions The results indicate that different sampling strategies yield comparable vaginal microbiota composition and diversity. Hence, past and future vaginal microbiota studies employing different sampling strategies should be comparable in the absence of other technical confounders. The Evalyn (R) self-sampling device performed equally well compared to samples taken by a clinician, and hence offers a good-quality microbiota sample without the need for a gynecological examination. The amount of collected sample as well as the DNA and protein yield varied across the sampling techniques, which may have practical implications for study design.Peer reviewe

Milloin HPV-rokote aikuiselle?

Vertaisarvioitu.Kattavampi rokottaminen ja kohdunkaulasyövän seulonnan samanaikainen muutos pian tarpee

Genetic variation in cervical preinvasive and invasive disease : a genome-wide association study

Background Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls. Methods We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer. Findings We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0.87, 95% CI 0.84-0.91; p=1.07 x 10(-9)) and rs27069 (CLPTM1L; 0.88, 0.84-0.92; p=2.51 x 10(-9)), and previously reported signals at rs9272050 (HLA-DQA1; 1.27, 1.21-1.32; p=2.51 x 10(-28)), rs6938453 (MICA; 0.79, 0.75-0 .83; p=1.97 x 10-(17)), rs55986091 (HLA-DQB1; 0.66, 0 .60-0.72; p=6.42 x 10-(22)), and rs9266183 (HLA-B; 0.73, 0.64-0.83; p=1.53 x 10(-6)). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0.015), CLPTM1L (rs27069; p=2.54 x 10(-7)), and HLA-DQA1 (rs9272050; p=7.90 x 10(-8)). Mendelian randomisation further supported the complementary role of smoking (OR 2.46, 95% CI 1.64-3.69), older age at first pregnancy (0.80, 0.68-0.95), and number of sexual partners (1.95, 1.44-2.63) in the risk of developing cervical cancer. Interpretation Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Busy day effect on the use of obstetrical interventions and epidural analgesia during labour : a cross-sectional register study of 601 247 deliveries

Background Daily delivery volume might affect the quality of obstetric care. We explored the busy day effect on selected obstetrical interventions and epidural analgesia performed during labour in different sized delivery hospitals and on the Finnish obstetric ecosystem. Methods We conducted a cross-sectional study on Finnish Medical Birth Register data of singleton pregnancies (N = 601,247) from 26 delivery hospitals from 2006 to 2016. Delivery hospitals were stratified by annual delivery volume: C (category) 1: = 3000, and C5: university hospitals. The exposure variables were defined as quiet, optimal, and busy days determined based on daily delivery volume distribution in each hospital category. Quiet and busy days included approximately 10% of the lowest and highest delivery volume days, while the rest were defined as optimal. Outcome measures were unplanned caesarean section (CS), instrumental delivery, induction of labour, and epidural analgesia. We compared the incidence of outcomes in quiet vs. optimal, busy vs. optimal, and busy vs. quiet days using logistic regression. The statistical significance level was set at 99% to reduce the likelihood of significant spurious findings. Results In the total population, the incidence of instrumental delivery was 8% (99% CI 2-15%) lower on quiet than on optimal days. In smaller hospitals (C1 and C2), unplanned caesarean sections were performed up to one-third less frequently on busy than optimal and quiet days. More (27%, 99% CI 12-44%) instrumental deliveries were performed in higher delivery volume hospitals (C4) on busy than quiet days. In C1-C3, deliveries were induced (12-35%) less often and in C5 (37%, 99% CI 28-45%) more often on busy than optimal delivery days. More (59-61%) epidural analgesia was performed on busy than optimal and quiet days in C4 and 8% less in C2 hospitals. Conclusions Pooled analysis showed that busyness had no effect on outcomes at the obstetric ecosystem level, but 10% fewer instrumental deliveries were performed in quiet than on busy days overall. Furthermore, dissecting the data shows that small hospitals perform less, and large non-tertiary hospitals perform more interventions during busy days.Peer reviewe

Vaginal Microbiota Composition Correlates Between Pap Smear Microscopy and Next Generation Sequencing and Associates to Socioeconomic Status

Recent research on vaginal microbiota relies on high throughput sequencing while microscopic methods have a long history in clinical use. We investigated the correspondence between microscopic findings of Pap smears and the vaginal microbiota composition determined by next generation sequencing among 50 asymptomatic women. Both methods produced coherent results regarding the distinction between Lactobacillus-dominant versus mixed microbiota, reassuring gynaecologists for the use of Pap smear or wet mount microscopy for rapid evaluation of vaginal bacteria as part of diagnosis. Cytologic findings identified women with bacterial vaginosis and revealed that cytolysis of vaginal epithelial cells is associated to Lactobacillus crispatus-dominated microbiota. Education and socio-economic status were associated to the vaginal microbiota variation. Our results highlight the importance of including socio-economic status as a co-factor in future vaginal microbiota studies.Peer reviewe

Female reproductive tract microbiota and recurrent pregnancy loss : a nested case- control study

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Pregnancy incidence and outcome before and after cervical intraepithelial neoplasia: a retrospective cohort study,”

Abstract We performed a retrospective cohort study of 3530 women treated for cervical intraepithelial neoplasia (CIN) in Helsinki University Central Hospital, Finland, to investigate whether CIN treatment itself affects pregnancy incidence and outcome. We estimated the incidence of live births, miscarriages, extrauterine pregnancies, molar pregnancies, and termination of pregnancies (TOPs) before and after CIN treatment using nationwide registers. Women were followed up until death, emigration, sterilization, or the end of 2004. The comparison of incidence of pregnancy outcomes before and after the treatment was estimated by calculating hazard ratios (HRs) with conditional Poisson regression. After 76,162 woman-years of follow-up, the incidence of any pregnancy remained constant over CIN-treatment, HR 1.02 and 95% confidence interval (CI) 0.97-1.08, but the incidence of the first pregnancy was significantly elevated after treatment, HR 1.13, and 95% CI 1.03-1.23. The incidence of live births was significantly elevated after treatment, HR 1.08 and 95% CI 1.01-1.15. Incidence of miscarriages, TOPs, extrauterine pregnancies, and molar pregnancies was not elevated. TOPs was significantly increased in the first pregnancy, HR 1.40, 95% CI 1.15-1.72 and after treatment by the loop electrosurgical excision procedure (LEEP), HR 1.36, 95% CI 1.15-1.60. CIN treatment did not reduce pregnancy incidence and women had more live births after than before CIN treatment. TOPs was more common in the first pregnancy or after treatment by LEEP. We encourage research on the psychosocial consequences of CIN treatment also in other countries and settings

Role of Colposcopy after Treatment for Cervical Intraepithelial Neoplasia

Colposcopy is often used in follow-up after treatment for cervical intraepithelial neoplasia (CIN) despite its marked inter-observer variability and low sensitivity. Our objective was to assess the role of colposcopy in post-treatment follow-up in comparison to hrHPV (high-risk human papillomavirus) testing, cytology, and cone margin status. Altogether, 419 women treated for histological high-grade lesion (HSIL) with large loop excision of the transformation zone (LLETZ) attended colposcopy with cytology and hrHPV test at six months. Follow-up for recurrence of HSIL continued for 24 months. Colposcopy was considered positive if colposcopic impression was recorded as high grade and cytology if HSIL, ASC-H (atypical squamous cells, cannot exclude HSIL), or AGC-FN (atypical glandular cells, favor neoplasia) were present. Overall, 10 (10/419, 2.4%) recurrent HSIL cases were detected, 5 at 6 months and 5 at 12 months. Colposcopic impression was recorded at 407/419 6-month visits and was positive for 11/407 (2.7%). None of them had recurrent lesions, resulting in 0% sensitivity and 97% specificity for colposcopy. Sensitivity for the hrHPV test at 6 months was 100% and specificity 85%, for cytology 40% and 99%, and for margin status at treatment 60% and 82%, respectively. While the hrHPV test is highly sensitive in predicting recurrence after local treatment for CIN, colposcopy in an unselected population is not useful in follow-up after treatment of CIN.Peer reviewe

Parity and gestational age are associated with vaginal microbiota composition in term and late term pregnancies

Background Vaginal microbiota and its potential contribution to preterm birth is under intense research. However, only few studies have investigated the vaginal microbiota in later stages of pregnancy or at the onset of labour. Methods We used 16S rRNA gene amplicon sequencing to analyse cross-sectional vaginal swab samples from 324 Finnish women between 37-42 weeks of gestation, sampled before elective caesarean section, at the onset of spontaneous labour, and in pregnancies lasting >= 41 weeks of gestation. Microbiota data were combined with comprehensive clinical data to identify factors associated with microbiota variation. Findings Vaginal microbiota composition associated strongly with advancing gestational age and parity, i.e. presence of previous deliveries. Absence of previous deliveries was a strong predictor of Lactobacillus crispatus dominated vaginal microbiota, and the relative abundance of L. crispatus was higher in late term pregnancies, especially among nulliparous women. Interpretation This study identified late term pregnancy and reproductive history as factors underlying high abundance of gynaecological health-associated L. crispatus in pregnant women. Our results suggest that the vaginal micro biota affects or reflects the regulation of the duration of gestation and labour onset, with potentially vast clinical utilities. Further studies are needed to address the causality and the mechanisms on how previous labour, but not pregnancy, affects the vaginal microbiota. Parity and gestational age should be accounted for in future studies on vaginal microbiota and reproductive outcomes. Funding This research was supported by EU H2020 programme Sweet Crosstalk ITN (814102), Academy of Finland, State Research Funding, and University of Helsinki. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.Peer reviewe