Publications by authors named "Ilkka Kalliala"

40 Publications

The Relation between Caffeine Consumption and Endometriosis: An Updated Systematic Review and Meta-Analysis.

Nutrients 2021 Sep 29;13(10). Epub 2021 Sep 29.

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London W12 0NN, UK.

While the contributing factors leading to endometriosis remain unclear, its clinical heterogeneity suggests a multifactorial causal background. Amongst others, caffeine has been studied extensively during the last decade as a putative contributing factor. In this systematic review and meta-analysis, we provide an overview/critical appraisal of studies that report on the association between caffeine consumption and the presence of endometriosis. In our search strategy, we screened PubMed and Scopus for human studies examining the above association. The main outcome was the relative risk of endometriosis in caffeine users versus women consuming little or no caffeine (<100 mg/day). Subgroup analyses were conducted for different levels of caffeine intake: high (>300 mg/day) or moderate (100-300 mg/day). Ten studies were included in the meta-analysis (five cohort and five case-control studies). No statistically significant association was observed between overall caffeine consumption and risk for endometriosis (RR 1.12, 95% confidence interval (CI) 0.97-1.28, I = 70%) when compared to little or no (<100 mg/day) caffeine intake. When stratified according to level of consumption, high intake was associated with increased risk of endometriosis (RR 1.30, 95%CI 1.04-1.63, I = 56%), whereas moderate intake did not reach nominal statistical significance (RR 1.18, 95%CI 0.99-1.40, I = 37%). In conclusion, caffeine consumption does not appear to be associated with increased risk for endometriosis. However, further research is needed to elucidate the potential dose-dependent link between caffeine and endometriosis or the probable role of caffeine intake as a measurement of other unidentified biases.
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http://dx.doi.org/10.3390/nu13103457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538723PMC
September 2021

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology.

Syst Rev 2021 10 8;10(1):264. Epub 2021 Oct 8.

Central Finland Central Hospital, Department of Surgery, Jyväskylä, Finland.

Background: Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries.

Methods: We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty.

Discussion: This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach.

Systematic Review Registration: PROSPERO CRD42021234119.
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http://dx.doi.org/10.1186/s13643-021-01814-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499502PMC
October 2021

Invasive cervical cancer following treatment of pre-invasive lesions: A potential theory based on a small case series.

Eur J Obstet Gynecol Reprod Biol 2021 Sep 3;264:56-59. Epub 2021 Jul 3.

Institute or Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

Purpose: The aim of this study is to present a single department's experience on cervical cancer cases following previous excision of cervical intraepithelial neoplasia (CIN) and to discuss potential pathogenesis.

Methods: Nine cervical cancer cases meeting the inclusion criteria, with available pathological and follow-up data, were considered eligible for this study.

Results: The majority (7/9) have had clear excisional margins. The interval between initial treatment and cancer diagnosis ranged from 7 to 17 years. In all cases cancer diagnosis was "unexpected", as the prior cytological and/or colposcopic evaluation was not suggestive of significant cervical pathology. All cancers were squamous, and 5/9 at stage I.

Conclusion: The long interval between initial CIN treatment and final diagnosis as well as the normal post-treatment follow-up may suggest a 'de novo' underlying but 'hidden' carcinogenesis process. It might be that dysplastic cells entrapped within crypts (or normal metaplastic affected by the same predisposing factors) continue undergoing their evolution, undetectable by cytology and colposcopy until they invade stroma and surfaces (endo- and/or ectocervical) approximately a decade later. Heavy cauterisation of cervical crater produced post excision might be a potential culprit of this entrapment.
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http://dx.doi.org/10.1016/j.ejogrb.2021.06.049DOI Listing
September 2021

Distribution of HPV Genotypes Differs Depending on Behavioural Factors among Young Women.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, 33100 Tampere, Finland.

Risk factors for the different human papillomavirus (HPV) genotypes are not well understood, although the risk of cancer is known to vary among them. Our aim was to evaluate the association of diverse behavioral and reproductive factors with genotype-specific HPV prevalence among 879 unvaccinated women aged 18-75 years referred to the colposcopy clinic at Helsinki University Hospital in Finland. Cervical swabs for HPV genotyping were collected in the first visit and assessed for 34 high-risk (hr) and low-risk (lr) HPV genotypes. Participants completed a questionnaire on behavioral, reproductive, and lifestyle factors. Differences in genotype-specific HPV prevalence were analyzed overall and in age groups using binary logistic regression. Smoking was associated with higher prevalence in HPV16 compared with other hrHPV genotypes together with decreasing age, being highest among younger women <30 years old, odds ratio (OR) 3.74 (95% CI 1.42-9.88). The later the sexual debut, the more it seemed to protect from HPV16 infection. The best protection was achieved when the sexual debut took place at >20 years of age, with an OR of 0.43 (95% CI 0.23-0.83). This association was not seen with other hrHPV genotypes. Methods of contraception seemed not to have an effect on hrHPV positivity, regardless of the HPV genotype. The genotype specific hrHPV prevalence differs, depending on behavioral factors, especially among younger women referred to colposcopy.
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http://dx.doi.org/10.3390/microorganisms9040750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066411PMC
April 2021

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

J Urol 2021 09 27;206(3):679-687. Epub 2021 Apr 27.

Institute for Reproductive and Developmental Biology (IRDB), Imperial College London, UK.

Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence.

Materials And Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction.

Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure () gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 () gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001).

Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 (), associated with urgency incontinence, and macrophage receptor with collagenous structure (), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
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http://dx.doi.org/10.1097/JU.0000000000001822DOI Listing
September 2021

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

Lancet Oncol 2021 04;22(4):548-557

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

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 × 10) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10). 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 × 10), and HLA-DQA1 (rs9272050; p=7·90 × 10). 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.

Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.
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http://dx.doi.org/10.1016/S1470-2045(21)00028-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008734PMC
April 2021

Preterm birth rate after bivalent HPV vaccination: Registry-based follow-up of a randomized clinical trial.

Prev Med 2021 05 24;146:106473. Epub 2021 Feb 24.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland. Electronic address:

A registry-based follow-up of pregnancy data until the end of 2014 was conducted based on a community-randomized trial to assess human papillomavirus (HPV) vaccination strategies and a reference cohort from the same community with no intervention. Our objective was to determine whether prophylactic HPV vaccination (three doses of Cervarix® (AS04-HPV-16/18)-vaccine) affects preterm birth (PTB) rates. All identified 80,272 residents in 1992-95 birth cohorts in Finland were eligible for the trial and 20,513 of 39,420 (51.9%) females consented to participate. The final study population consisted of age-aligned 6226 HPV16/18 vaccinated females and 1770 HBV vaccinated (Engerix® B, hepatitis B-virus vaccine) females that did not receive HPV vaccine at the age of 18 from the 1992-93 birth cohorts, and 19,849 females from the 1990-91 non-vaccinated reference birth cohorts. We compared the rates of preterm (22 + 0-36 + 6 pregnancy weeks) and early preterm (22 + 0-31 + 6) per term (at least 37 + 0) singleton births among the HPV- and non-HPV-vaccinated women, using nationwide Medical Birth Registry data. We observed 409 singleton first pregnancies lasting at least 22 + 0 weeks among 6226 HPV-vaccinated and 1923 among 21,619 non-HPV-vaccinated women. In the first pregnancy the PTB rate was 13/409 (3.2%) among the HPV-vaccinated and 98/1923 (5.1%) among the non-HPV-vaccinated (OR 0.61, 95% CI 0.34-1.09). Early preterm birth rate was 0/409 (0%) in the HPV-vaccinated women and 20/1923 (1.0%) in the non-HPV-vaccinated women (p = 0.04). PTB rate, especially early PTB rate, was lower among the HPV-vaccinated women. Reduction of PTB incidence after prophylactic HPV vaccination would lead to public health benefits globally. Trial Registration:NCT00534638.
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http://dx.doi.org/10.1016/j.ypmed.2021.106473DOI Listing
May 2021

Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery.

Front Immunol 2020 11;11:563073. Epub 2021 Jan 11.

Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

Background: Human pregnancy alters profoundly the immune system. The local involvement and mechanisms of activation of the complement system in the cervicovaginal milieu during pregnancy and delivery remain unexplored.

Objectives: To determine whether normal pregnancy and delivery are associated with local activation of complement or changes in the immunoglobulin profile in the cervix.

Study Design: This study was designed to assess IgA, IgG, and complement activation in the cervicovaginal area in three groups of patients: i) 49 pregnant women (week 41+3-42+0) not in active labor, ii) 24 women in active labor (38+4-42+2), and iii) a control group of nonpregnant women (n=23) at child-bearing age. We collected mucosal samples from the lateral fornix of the vagina and external cervix during routine visits and delivery. The Western blot technique was used to detect complement C3 and its activation products. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and analyzed. IgA and IgG were analyzed by Western blotting and quantified by ELISA. One-way ANOVA and Tukey's Multiple Comparison tests were used for statistical comparisons.

Results: A higher abundance but lower activation level of C3 in both the external cervix (P<0.001) and lateral fornix of the vagina (P<0.001) was observed during delivery (58 ± 22, n= 24) in comparison to the groups of nonpregnant (72 ± 13%; mean ± SD, n=23) and pregnant women (78 ± 22%, n=49). Complement activating IgG was detected in higher abundance than IgA in the cervicovaginal secretions of pregnant women. In a small proportion samples also C3-IgG complexes were detected.

Conclusions: Our results reveal an unexpectedly strong activation of the complement system and the presence IgG immunoglobulins in the cervicovaginal area during pregnancy, active labor, and among nonpregnant women. In contrast to the higher amounts of C3 in the cervicovaginal secretions during labor, its activation level was lower. Complement activating IgG was detected in higher concentrations than IgA in the mucosal secretions during pregnancy and labor. Taken together our results imply the presence a locally operating humoral immune system in the cervicovaginal mucosa.
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http://dx.doi.org/10.3389/fimmu.2020.563073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829332PMC
May 2021

Fostering Prevention of Cervical Cancer by a Correct Diagnosis of Precursors: A Structured Case-Based Colposcopy Course in Finland, Norway and UK.

Cancers (Basel) 2020 Oct 30;12(11). Epub 2020 Oct 30.

Department of Obstetrics and Gynaecology, Helsinki University Hospital and Helsinki University, 00290 Helsinki, Finland.

High-quality colposcopy is essential in cervical cancer prevention. We performed a multicentre prospective interventional pilot-study, evaluating the effect of a six-hour case-based colposcopy course on short- and long-term learning of colposcopy-related knowledge, diagnostic accuracy levels and confidence. We recruited 213 colposcopists participating in three European Federation of Colposcopy (EFC) basic colposcopy courses (Finland, Norway, UK). The study consisted of three tests with identical content performed before, after and 2 months after the course, including ten colposcopic images, ten patient cases and scales for marking confidence in the answers. Outcome measures where mean scores in correct case-management, diagnosis (including high-grade lesion recognition), transformation-zone recognition and confidence in answers. Results were compared between the three tests and stratified according to experience. Mean test scores improved after the course for all participants. The increase was highest for beginners. Confidence in answers improved and the number of colposcopists showing high confidence with low scores decreased. A structured case-based course improves skills and confidence especially for inexperienced colposcopists; however, trainers should be aware of the risk of overconfidence. To complement theoretical training, further hands-on training including high-quality feedback is recommended. Conclusions drawn from long-term learning are limited due to the low participation in the follow-up test.
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http://dx.doi.org/10.3390/cancers12113201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692698PMC
October 2020

Role of Colposcopy after Treatment for Cervical Intraepithelial Neoplasia.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.

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.
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http://dx.doi.org/10.3390/cancers12061683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352967PMC
June 2020

The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease.

Proc Natl Acad Sci U S A 2020 03 16;117(13):7338-7346. Epub 2020 Mar 16.

Department of Gut, Metabolism and Reproduction, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London SW7 2DD, United Kingdom;

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.
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http://dx.doi.org/10.1073/pnas.1916960117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132269PMC
March 2020

The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: A systematic review and meta-analysis.

EBioMedicine 2019 Dec 12;50:246-259. Epub 2019 Nov 12.

Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust, UK. Electronic address:

Background: Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN).

Methods: We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates.

Findings: 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8-92·2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0-74·1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3% (95%CI:6·5-16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5-8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (95%CI:63-87), specificity 64% (95%CI:55-71), area under the curve (0·73 (95%CI:0·69-0·77)).

Interpretation: Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing.

Funding: NIHR, Genesis Research Trust, Imperial Healthcare Charity, Wellcome Trust NIHR Imperial BRC, European Union's Horizon 2020.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921230PMC
December 2019

Vaginal microbiota in pregnancy: Role in induction of labor and seeding the neonate''s microbiota?

J Biosci 2019 Oct;44(5)

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Compared to other human microbiota, vaginal microbiota is fairly simple with low bacterial diversity and high relative abundance of Lactobacillus species. Lactobacillus dominance is even more pronounced during pregnancy. Genetic factors, such as ethnicity, along with environmental, individual and lifestyle factors all have an impact on vaginal microbiota composition. The composition of the vaginal microbiota appears to play an important role in pregnancy as recent studies have linked it to adverse obstetric outcomes such as preterm birth, a leading cause of neonatal morbidity and mortality worldwide. However, the same vaginal microbiota does not seem to cause the same response in all women, calling for future research to fully understand the complex host-microbiota interplay in normal and complicated pregnancies.
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October 2019

Comparative fertility and pregnancy outcomes after local treatment for cervical intraepithelial neoplasia and stage 1a1 cervical cancer: protocol for a systematic review and network meta-analysis from the CIRCLE group.

BMJ Open 2019 10 21;9(10):e028009. Epub 2019 Oct 21.

Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK

Introduction: There are several local treatment methods for cervical intraepithelial neoplasia that remove or ablate a cone-shaped part of the uterine cervix. There is evidence to suggest that these increase the risk of preterm birth (PTB) and that this is higher for techniques that remove larger parts of the cervix, although the data are conflicting. We present a protocol for a systematic review and network meta-analysis (NMA) that will update the evidence and compare all treatments in terms of fertility and pregnancy complications.

Methods And Analysis: We will search electronic databases (CENTRAL, MEDLINE, EMBASE) from inception till October 2019, in order to identify randomised controlled trials (RCTs) and cohort studies comparing the fertility and pregnancy outcomes among different excisional and ablative treatment techniques and/or to untreated controls. The primary outcome will be PTB (<37 weeks). Secondary outcomes will include severe or extreme PTB, prelabour rupture of membranes, low birth weight (<2500 g), neonatal intensive care unit admission, perinatal mortality, total pregnancy rates, first and second trimester miscarriage. We will search for published and unpublished studies in electronic databases, trial registries and we will hand-search references of published papers. We will assess the risk of bias in RCTs and cohort studies using tools developed by the Cochrane collaboration. Two investigators will independently assess the eligibility, abstract the data and assess the risk of bias of the identified studies. For each outcome, we will perform a meta-analysis for each treatment comparison and an NMA once the transitivity assumption holds, using the OR for dichotomous data. We will use CINeMA (Confidence in Network meta-analysis) to assess the quality of the evidence for the primary outcome.

Ethics And Dissemination: Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.

Prospero Registration Number: CRD42018115495.
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http://dx.doi.org/10.1136/bmjopen-2018-028009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803140PMC
October 2019

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Nat Commun 2019 09 2;10(1):3927. Epub 2019 Sep 2.

Center for Craniofacial and Dental Genetics, Department of Oral Biology School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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http://dx.doi.org/10.1038/s41467-019-11881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718389PMC
September 2019

Comparative efficacy and complication rates after local treatment for cervical intraepithelial neoplasia and stage 1a1 cervical cancer: protocol for a systematic review and network meta-analysis from the CIRCLE Group.

BMJ Open 2019 08 2;9(8):e028008. Epub 2019 Aug 2.

Department of Surgery and Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK

Introduction: Local treatments for cervical intraepithelial neoplasia (CIN) and microinvasive disease remove or ablate a cone-shaped part of the uterine cervix containing the abnormal cells. A trend toward less radical techniques has raised concerns that this may adversely impact the rates of precancerous and cancerous recurrence. However, there has been no strong evidence to support such claims. We hereby describe a protocol of a systematic review and network meta-analysis that will update the evidence and compare all relevant treatments in terms of efficacy and complications.

Methods And Analysis: Literature searches in electronic databases (CENTRAL, MEDLINE, EMBASE) or trial registries will identify published and unpublished randomised controlled trials (RCTs) and cohort studies comparing the efficacy and complications among different excisional and ablative techniques. The excisional techniques include cold knife, laser or Fischer cone, large loop or needle excision of the transformation zone and the ablative radical point diathermy, cryotherapy, cold coagulation or laser ablation. The primary outcome will be residual/recurrent disease defined as abnormal histology or cytology of any grade, while secondary outcomes will include treatment failure rates defined as high-grade histology or cytology, histologically confirmed CIN1+ or histologically confirmed CIN2+, human papillomavirus positivity rates, involved margins rates, bleeding and cervical stenosis rates. We will assess the risk of bias in RCTs and observational studies using tools developed by the Cochrane Collaboration. Two authors will independently assess study eligibility, abstract the data and assess the risk of bias. Random-effects meta-analyses and network meta-analyses will be conducted using the OR for dichotomous outcomes and the mean difference for continuous outcomes. The quality of the evidence for the primary outcome will be assessed using the CINeMA (Confidence In Network Meta-Analysis) tool.

Ethics And Dissemination: Ethical approval is not required. We will disseminate findings to clinicians, policy-makers, patients and the public.

Prospero Registration Number: CRD42018115508.
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http://dx.doi.org/10.1136/bmjopen-2018-028008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687014PMC
August 2019

Methylation in Predicting Progression of Untreated High-grade Cervical Intraepithelial Neoplasia.

Clin Infect Dis 2020 06;70(12):2582-2590

Center for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.

Background: There is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2).

Methods: Baseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance.

Results: Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4-49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9-91.8) than of cytology (62.3%; 95% CI, 49.0-74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621-0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information.

Conclusions: The S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2.
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http://dx.doi.org/10.1093/cid/ciz677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286376PMC
June 2020

Age-specific HPV type distribution in high-grade cervical disease in screened and unvaccinated women.

Gynecol Oncol 2019 08 5;154(2):354-359. Epub 2019 Jun 5.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland. Electronic address:

Background And Aim: Age-specific type-distribution of high-risk human papillomavirus (hrHPV) in cervical precancerous lesions is subject to change in the HPV vaccination era. Knowing the pre-vaccination type-distribution helps to anticipate changes induced by mass vaccination and optimize screening.

Methods: We recruited 1279 women referred to colposcopy for abnormal cytology into a population-based study on HPV type distribution in diagnostic cervical samples (ISRCTN10933736). The HPV genotyping findings were grouped as: HPV16/18+, other hrHPV+ (HPV31/33/35/39/45/51/52/56/58/59/66/68), non-vaccine targeted hrHPV+ (HPV35/39/51/56/59/66/68), low-risk HPV, and HPV negative. We estimated the HPV group-specific prevalence rates according to diagnostic histopathological findings in the age groups of <30 (n = 339), 30-44.9 (n = 614), and ≥45 (n = 326).

Results: Altogether 503 cases with high grade squamous intraepithelial lesion or worse (HSIL+) were diagnosed. More than half, 285 (56.7%) of HSIL+ cases were associated with HPV16/18: 64.3% (101/157) in women <30 years (reference group), 58.4% (157/269) in women 30-44.9 years (risk ratio (RR) 0.91, 95% confidence interval (95% CI) 0.78-1.06), and 35.1% (27/77) in women ≥45 years of age (RR 0.55, 95% CI 0.39-0.75). Conversely, other hrHPV's were associated with 191 (38.0%) of HSIL+: 31.9% (50/157) in women <30, 36.8% (99/269) in women 30-44.9 years, 54.6% (42/77) and in women ≥45 (RR 1.71, 95% CI 1.26-2.33). The proportion of non-vaccine targeted hrHPV and HPV negative HSIL+ increased with advancing age.

Conclusions: Pre-vaccination HPV type distribution in HSIL+ was distinctly polarised by age with HPV16/18 attributed disease being markedly more prevalent in women aged <30. In the older women the other hrHPV types, however, dominated suggesting a need for more age-dependent screening strategies.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.024DOI Listing
August 2019

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

Sci Rep 2019 05 23;9(1):7750. Epub 2019 May 23.

Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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.
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http://dx.doi.org/10.1038/s41598-019-44157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533281PMC
May 2019

Risk factors for endometrial cancer: An umbrella review of the literature.

Int J Cancer 2019 10 20;145(7):1719-1730. Epub 2019 Feb 20.

Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom.

Although many risk factors could have causal association with endometrial cancer, they are also prone to residual confounding or other biases which could lead to over- or underestimation. This umbrella review evaluates the strength and validity of evidence pertaining risk factors for endometrial cancer. Systematic reviews or meta-analyses of observational studies evaluating the association between non-genetic risk factors and risk of developing or dying from endometrial cancer were identified from inception to April 2018 using PubMed, the Cochrane database and manual reference screening. Evidence was graded strong, highly suggestive, suggestive or weak based on statistical significance of random-effects summary estimate, largest study included, number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, excess significance bias and sensitivity analysis with credibility ceilings. We identified 171 meta-analyses investigating associations between 53 risk factors and endometrial cancer incidence and mortality. Risk factors were categorised: anthropometric indices, dietary intake, physical activity, medical conditions, hormonal therapy use, biochemical markers, gynaecological history and smoking. Of 127 meta-analyses including cohort studies, three associations were graded with strong evidence. Body mass index and waist-to-hip ratio were associated with increased cancer risk in premenopausal women (RR per 5 kg/m 1.49; CI 1.39-1.61) and for total endometrial cancer (RR per 0.1unit 1.21; CI 1.13-1.29), respectively. Parity reduced risk of disease (RR 0.66, CI 0.60-0.74). Of many proposed risk factors, only three had strong association without hints of bias. Identification of genuine risk factors associated with endometrial cancer may assist in developing targeted prevention strategies for women at high risk.
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http://dx.doi.org/10.1002/ijc.31961DOI Listing
October 2019

Fertility-sparing Surgery for Presumed Early-stage Invasive Cervical Cancer: A Survey of Practice in the United Kingdom.

Anticancer Res 2018 06;38(6):3641-3646

Institute of Reproductive and Developmental Biology, Surgery and Cancer, Imperial College London, London, U.K.

Aim: To explore current practice in fertility-sparing surgery for cervical cancer in the UK.

Materials And Methods: A web-based structured questionnaire was designed and circulated to all members of the British Gynaecological Cancer Society.

Results: From 111 recipients, a total of 49 responses were collected. The majority of centres treated between 20-29 cases of invasive cervical cancer surgically (21/49, 42.9%) and performed between 0-5 cases of radical trachelectomy annually (29/49, 59.2%). The vaginal approach was the one most commonly used and was offered by almost half of the centres (21/49, 42.9%); laparoscopic techniques were offered in 13 (13/49, 26.6%). The responses were divided as to whether these cases should have been referred to supra-regional centres (25/49, 51.0%).

Conclusion: With the use of Human Papillomavirus vaccination leading to a projected decrease in the number of cervical cancer incidence, patients may need to be referred to supraregional centres in the future.
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http://dx.doi.org/10.21873/anticanres.12639DOI Listing
June 2018

Chlamydia trachomatis-induced cell-mediated and humoral immune response in women with unexplained infertility.

Am J Reprod Immunol 2018 07 25;80(1):e12865. Epub 2018 Apr 25.

Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Problem: What is the role of past Chlamydia trachomatis infection in unexplained infertility?

Method Of Study: This is a prospective study of the impact of past C. trachomatis infection on pregnancy rates in 96 women with unexplained infertility. Both humoral and cell-mediated immune responses (CMI) against C. trachomatis were studied. Serum C. trachomatis IgG antibodies were analyzed using major outer membrane protein (MOMP) peptide-based ELISA. CMI was studied by lymphocyte proliferation (LP) assay in vitro. Data on given fertility treatment, time to pregnancy, and pregnancy outcome were collected.

Results: Altogether, 11.5% of the 96 women had C. trachomatis IgG antibodies. LP response to C. trachomatis was positive in 62.9% women. The overall pregnancy rate or live birth rate did not differ by the presence of antichlamydial antibodies or CMI against C. trachomatis. Time to spontaneous pregnancy was longer among C. trachomatis sero-positive women than among sero-negative women (2.9 years vs 2.0 years, P = .03).

Conclusion: Past chlamydial infection does not play a major role in unexplained infertility. Women with unexplained infertility and positive immune response to C. trachomatis do not have reduced pregnancy rates, but time to spontaneous pregnancy is longer among C. trachomatis IgG sero-positive women than among sero-negative women.
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http://dx.doi.org/10.1111/aji.12865DOI Listing
July 2018

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis.

BMJ 2018 02 27;360:k499. Epub 2018 Feb 27.

Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols.

Design: Systematic review and meta-analysis.

Data Sources: Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016.

Eligibility Criteria: Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months.

Data Synthesis: Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I statistics.

Main Outcome Measures: Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months).

Results: 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I=0%), 23% (two studies, 226/938 women, 20% to 26%; I=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%.

Conclusions: Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.

Systematic Review Registration: PROSPERO 2014: CRD42014014406.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826010PMC
http://dx.doi.org/10.1136/bmj.k499DOI Listing
February 2018

Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease.

Cochrane Database Syst Rev 2017 11 2;11:CD012847. Epub 2017 Nov 2.

Surgery and Cancer - West London Gynaecological Cancer Centre, Imperial College London - Queen Charlotte's & Chelsea, Hammersmith Hospital, Imperial NHS Healthcare Trust, Du Cane Road, London, UK, W12 0NN.

Background: The mean age of women undergoing local treatment for pre-invasive cervical disease (cervical intra-epithelial neoplasia; CIN) or early cervical cancer (stage IA1) is around their 30s and similar to the age of women having their first child. Local cervical treatment has been correlated to adverse reproductive morbidity in a subsequent pregnancy, however, published studies and meta-analyses have reached contradictory conclusions.

Objectives: To assess the effect of local cervical treatment for CIN and early cervical cancer on obstetric outcomes (after 24 weeks of gestation) and to correlate these to the cone depth and comparison group used.

Search Methods: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 5), MEDLINE (up to June week 4, 2017) and Embase (up to week 26, 2017). In an attempt to identify articles missed by the search or unpublished data, we contacted experts in the field and we handsearched the references of the retrieved articles and conference proceedings.

Selection Criteria: We included all studies reporting on obstetric outcomes (more than 24 weeks of gestation) in women with or without a previous local cervical treatment for any grade of CIN or early cervical cancer (stage IA1). Treatment included both excisional and ablative methods. We excluded studies that had no untreated reference population, reported outcomes in women who had undergone treatment during pregnancy or had a high-risk treated or comparison group, or both DATA COLLECTION AND ANALYSIS: We classified studies according to the type of treatment and the obstetric endpoint. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model and inverse variance. Inter-study heterogeneity was assessed with I statistics. We assessed maternal outcomes that included preterm birth (PTB) (spontaneous and threatened), preterm premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage and cervical stenosis. The neonatal outcomes included low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, perinatal mortality and Apgar scores.

Main Results: We included 69 studies (6,357,823 pregnancies: 65,098 pregnancies of treated and 6,292,725 pregnancies of untreated women). Many of the studies included only small numbers of women, were of heterogenous design and in their majority retrospective and therefore at high risk of bias. Many outcomes were assessed to be of low or very low quality (GRADE assessment) and therefore results should be interpreted with caution. Women who had treatment were at increased overall risk of preterm birth (PTB) (less than 37 weeks) (10.7% versus 5.4%, RR 1.75, 95% CI 1.57 to 1.96, 59 studies, 5,242,917 participants, very low quality), severe (less than 32 to 34 weeks) (3.5% versus 1.4%, RR 2.25, 95% CI 1.79 to 2.82), 24 studies, 3,793,874 participants, very low quality), and extreme prematurity (less than 28 to 30 weeks) (1.0% versus 0.3%, (RR 2.23, 95% CI 1.55 to 3.22, 8 studies, 3,910,629 participants, very low quality), as compared to women who had no treatment.The risk of overall prematurity was higher for excisional (excision versus no treatment: 11.2% versus 5.5%, RR 1.87, 95% CI 1.64 to 2.12, 53 studies, 4,599,416 participants) than ablative (ablation versus no treatment: 7.7% versus 4.6%, RR 1.35, 95% CI 1.20 to 1.52, 14 studies, 602,370 participants) treatments and the effect was higher for more radical excisional techniques (less than 37 weeks: cold knife conisation (CKC) (RR 2.70, 95% CI 2.14 to 3.40, 12 studies, 39,102 participants), laser conisation (LC) (RR 2.11, 95% CI 1.26 to 3.54, 9 studies, 1509 participants), large loop excision of the transformation zone (LLETZ) (RR 1.58, 95% CI 1.37 to 1.81, 25 studies, 1,445,104 participants). Repeat treatment multiplied the risk of overall prematurity (repeat versus no treatment: 13.2% versus 4.1%, RR 3.78, 95% CI 2.65 to 5.39, 11 studies, 1,317,284 participants, very low quality). The risk of overall prematurity increased with increasing cone depth (less than 10 mm to 12 mm versus no treatment: 7.1% versus 3.4%, RR 1.54, 95% CI 1.09 to 2.18, 8 studies, 550,929 participants, very low quality; more than 10 mm to 12 mm versus no treatment: 9.8% versus 3.4%, RR 1.93, 95% CI 1.62 to 2.31, 8 studies, 552,711 participants, low quality; more than 15 mm to 17 mm versus no treatment: 10.1 versus 3.4%, RR 2.77, 95% CI 1.95 to 3.93, 4 studies, 544,986 participants, very low quality; 20 mm or more versus no treatment: 10.2% versus 3.4%, RR 4.91, 95% CI 2.06 to 11.68, 3 studies, 543,750 participants, very low quality). The comparison group affected the magnitude of effect that was higher for external, followed by internal comparators and ultimately women with disease, but no treatment. Untreated women with disease and the pre-treatment pregnancies of the women who were treated subsequently had higher risk of overall prematurity than the general population (5.9% versus 5.6%, RR 1.24, 95% CI 1.14 to 1.34, 15 studies, 4,357,998 participants, very low quality).pPROM (6.1% versus 3.4%, RR 2.36, 95% CI 1.76 to 3.17, 21 studies, 477,011 participants, very low quality), low birth weight (7.9% versus 3.7%, RR 1.81, 95% CI 1.58 to 2.07, 30 studies, 1,348,206 participants, very low quality), NICU admission rate (12.6% versus 8.9%, RR 1.45, 95% CI 1.16 to 1.81, 8 studies, 2557 participants, low quality) and perinatal mortality (0.9% versus 0.7%, RR 1.51, 95% CI 1.13 to 2.03, 23 studies, 1,659,433 participants, low quality) were also increased after treatment.

Authors' Conclusions: Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment appears to further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than it is for ablation. However, the results should be interpreted with caution as they were based on low or very low quality (GRADE assessment) observational studies, most of which were retrospective.
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http://dx.doi.org/10.1002/14651858.CD012847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486192PMC
November 2017

Obesity and gynaecological and obstetric conditions: umbrella review of the literature.

BMJ 2017 Oct 26;359:j4511. Epub 2017 Oct 26.

Department of Surgery and Cancer, IRDB, Faculty of Medicine, Imperial College, London W12 0NN, UK.

 To study the strength and validity of associations between adiposity and risk of any type of obstetric or gynaecological conditions. An umbrella review of meta-analyses. PubMed, Cochrane database of systematic reviews, manual screening of references for systematic reviews or meta-analyses of observational and interventional studies evaluating the association between adiposity and risk of any obstetrical or gynaecological outcome. Meta-analyses of cohort studies on associations between indices of adiposity and obstetric and gynaecological outcomes. Evidence from observational studies was graded into strong, highly suggestive, suggestive, or weak based on the significance of the random effects summary estimate and the largest study in the included meta-analysis, the number of cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. Interventional meta-analyses were assessed separately. 156 meta-analyses of observational studies were included, investigating associations between adiposity and risk of 84 obstetric or gynaecological outcomes. Of the 144 meta-analyses that included cohort studies, only 11 (8%) had strong evidence for eight outcomes: adiposity was associated with a higher risk of endometrial cancer, ovarian cancer, antenatal depression, total and emergency caesarean section, pre-eclampsia, fetal macrosomia, and low Apgar score. The summary effect estimates ranged from 1.21 (95% confidence interval 1.13 to 1.29) for an association between a 0.1 unit increase in waist to hip ratio and risk endometrial cancer up to 4.14 (3.61 to 4.75) for risk of pre-eclampsia for BMI >35 compared with <25. Only three out of these eight outcomes were also assessed in meta-analyses of trials evaluating weight loss interventions. These interventions significantly reduced the risk of caesarean section and pre-eclampsia, whereas there was no evidence of association with fetal macrosomia. Although the associations between adiposity and obstetric and gynaecological outcomes have been extensively studied, only a minority were considered strong and without hints of bias.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656976PMC
http://dx.doi.org/10.1136/bmj.j4511DOI Listing
October 2017

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

PLoS One 2017 19;12(7):e0181477. Epub 2017 Jul 19.

Immunobiology Research Programme, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.

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® 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® 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517051PMC
September 2017

Adiposity and cancer at major anatomical sites: umbrella review of the literature.

BMJ 2017 Feb 28;356:j477. Epub 2017 Feb 28.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

 To evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer. Umbrella review of systematic reviews and meta-analyses. PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references. Systematic reviews or meta-analyses of observational studies that evaluated the association between indices of adiposity and risk of developing or dying from cancer. Primary analysis focused on cohort studies exploring associations for continuous measures of adiposity. The evidence was graded into strong, highly suggestive, suggestive, or weak after applying criteria that included the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, the number of cancer cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. 204 meta-analyses investigated associations between seven indices of adiposity and developing or dying from 36 primary cancers and their subtypes. Of the 95 meta-analyses that included cohort studies and used a continuous scale to measure adiposity, only 12 (13%) associations for nine cancers were supported by strong evidence. An increase in body mass index was associated with a higher risk of developing oesophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma. Weight gain and waist to hip circumference ratio were associated with higher risks of postmenopausal breast cancer in women who have never used hormone replacement therapy and endometrial cancer, respectively. The increase in the risk of developing cancer for every 5 kg/m increase in body mass index ranged from 9% (relative risk 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer among men to 56% (1.56, 1.34 to 1.81) for biliary tract system cancer. The risk of postmenopausal breast cancer among women who have never used HRT increased by 11% for each 5 kg of weight gain in adulthood (1.11, 1.09 to 1.13), and the risk of endometrial cancer increased by 21% for each 0.1 increase in waist to hip ratio (1.21, 1.13 to 1.29). Five additional associations were supported by strong evidence when categorical measures of adiposity were included: weight gain with colorectal cancer; body mass index with gallbladder, gastric cardia, and ovarian cancer; and multiple myeloma mortality. Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers (oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney) were supported by strong evidence. Other associations could be genuine, but substantial uncertainty remains. Obesity is becoming one of the biggest problems in public health; evidence on the strength of the associated risks may allow finer selection of those at higher risk of cancer, who could be targeted for personalised prevention strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421437PMC
http://dx.doi.org/10.1136/bmj.j477DOI Listing
February 2017

Pain Sensation During Colposcopy and Cervical Biopsy, With or Without Local Anesthesia: A Randomized Trial.

J Low Genit Tract Dis 2017 Apr;21(2):102-107

1Obstetrics and Gynecology, University of Helsinki and University Central Hospital, Helsinki, Finland, and 2 Public Health - Cancer Policy Support, Institute for Health and Consumer Protection, European Commission, DG Joint Research Centre, Ispara, Italy.

Objective: The aim of the study was to determine whether an injection of a local anesthetic is more painful than a cervical punch biopsy without local anesthesia.

Materials And Methods: The study was a randomized controlled trial, conducted at the Helsinki University Central Hospital. It consisted of 204 women referred for colposcopic assessments. Half of them were randomized to receive local anesthesia before their cervical punch biopsies. After the injection of the local anesthetic, the cervical punch biopsy, and the endocervical curettage, the women scored their actual pain using a 10-cm visual analog scale (VAS).To measure the difference in VAS scores between two groups, a linear regression model was used. Binomial regression model was applied for comparing the probability of experiencing unbearable pain between the groups. Applying modeling approach allowed also for proper adjustment for other potential risk factors.

Results: The mean VAS score for the injection of the local anesthetic was 2.7, the VAS score for the cervical punch biopsy without local anesthesia was 3.5, and the difference was 0.8 (p = .017; 95% CI = 0.1-1.5). The mean VAS for the biopsy with local anesthesia was 0.8, which was significantly lower than the mean VAS for the biopsy without local anesthesia (difference = 2.7; p < .001; 95% CI = 2.2-3.3). The relative risk for experiencing moderate or severe pain (VAS ≥ 5) was 0.6 (p = .03; 95% CI = 0.3-0.9) for the injection of local anesthetic versus the biopsy without local anesthesia.

Conclusions: Injection of a local anesthetic for colposcopy is less painful than biopsies without local anesthesia, and local anesthesia decreases the pain perceived.
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http://dx.doi.org/10.1097/LGT.0000000000000292DOI Listing
April 2017

Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test.

Cochrane Database Syst Rev 2017 01 26;1:CD009836. Epub 2017 Jan 26.

Department of Obstetrics and Gynaecology, Ioannina University Hospital, Ioannina, Greece, 45001.

Background: A significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.

Objectives: To assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.

Search Methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).

Selection Criteria: We included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).

Data Collection And Analysis: The primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I statistics.

Main Results: We identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I greater than 60%) and we considered the evidence to be of moderate quality).The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence).Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence).

Authors' Conclusions: Based on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.
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http://dx.doi.org/10.1002/14651858.CD009836.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464319PMC
January 2017

Tracking the Impact of Excisional Cervical Treatment on the Cervix using Biospectroscopy.

Sci Rep 2016 12 15;6:38921. Epub 2016 Dec 15.

Centre for Biophotonics, LEC, Lancaster University, Lancaster, UK.

Local excisional treatment for cervical intra-epithelial neoplasia (CIN) is linked to significant adverse sequelae including preterm birth, with cone depth and radicality of treatment correlating to the frequency and severity of adverse events. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy can detect underlying cervical disease more accurately than conventional cytology. The chemical profile of cells pre- and post-treatment may differ as a result of altered biochemical processes due to excision, or treatment of the disease. Since pre-treatment cervical length varies amongst women, the percentage of cervix excised may correlate more accurately to risk than absolute dimensions. We show that treatment for CIN significantly alters the biochemistry of the cervix, compared with women who have not had treatment; this is due to the removal of cervical tissue rather than the removal of the disease. However, the spectra do not seem to correlate to the cone depth or proportion of cervical length excised. Future research should aim to explore the impact of treatment in a larger cohort.
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http://dx.doi.org/10.1038/srep38921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156919PMC
December 2016
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