Critical appraisal of clinical practice guidelines.

Ten questions to assess to what degree a clinical practice guideline is likely to be trustworthy: 1) Do the authors have conflicts of interests? 2) Is the clinical question relevant? 3) Have relevant stakeholders been involved? 4) Have methods for study selection been described? 5) Is there a link between evidence and recommendations (transparent methods)? 6) Has the certainty of evidence been assessed? 7) Have the methods for reaching recommendations been described? 8) Are the recommendations unambiguous? 9) Are the recommendations relevant in your situation? 10) Is there an implementation strategy?

Iatrogenic bladder injury following gynecologic and obstetric surgery: A systematic review and meta-analysis.

INTRODUCTION: Iatrogenic bladder injury is a rare complication following obstetric and gynecologic surgery and only sparse information is available regarding length of transurethral catheterization following injuries, suturing techniques including choice of suture, and complications. The primary aim of this systematic review was to evaluate length of transurethral catheterization in relation to complications following iatrogenic bladder injury. Second, we aimed to evaluate the number of complications following repair of iatrogenic bladder injuries and to describe suture technique and best choice of suture. MATERIAL AND METHODS: A systematic review and meta-analysis was conducted, and the results were presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, and Medline electronic databases were searched, and followed by screening from two independent reviewers. Studies published between January 2000 and March 2023 describing methods of bladder injury repair following obstetric or gynecologic benign surgery were included. Data extraction was done using Covidence. We performed a meta-analysis on complications after repair and explored this with a meta-regression analysis (Metafor package R) on length of catheterization to determine if length of catheterization influenced the risk of complication. A risk of bias tool from Cochrane was used to assess risk of bias and the study was registered in PROSPERO (CRD42021290586). RESULTS: Out of 2175 articles, we included 21 retrospective studies, four prospective studies, and one case-control study. In total, 595 bladder injuries were included. Cesarean section was the most prominent surgery type, followed by laparoscopically assisted vaginal hysterectomy. We found no statistically significant association between length of transurethral catheterization and numbers of complications following repair of iatrogenic bladder injuries. More than 90% of injuries were recognized intraoperatively. Approximately 1% had complications following iatrogenic bladder injury repair (0.010, 95% confidence interval 0.0015-0.0189, 26 studies, 595 participants, I2 = 4%). CONCLUSIONS: Our review did not identify conclusive evidence on the length of postoperative catheterization following bladder injury warranting further research. However, the rate of complications was low following iatrogenic bladder injury with a wide range of repair approaches.

Impact of COVID-19 pandemic on breast and cervical cancer screening in Denmark: A register-based study.

Background: Denmark was one of the few countries where it was politically decided to continue cancer screening during the COVID-19 pandemic. We assessed the actual population uptake of mammography and cervical screening during this period. Methods: The first COVID-19 lockdown in Denmark was announced on 11 March 2020. To investigate possible changes in cancer screening activity due to the COVID-19 pandemic, we analysed data from the beginning of 2017 until the end of 2021. A time series analysis was carried out to discover possible trends and outliers in the screening activities in the period 2017-2021. Data on mammography screening and cervical screening were retrieved from governmental pandemic-specific monitoring of health care activities. Results: A brief drop was seen in screening activity right after the first COVID-19 lockdown, but the activity quickly returned to its previous level. A short-term deficit of 43% [CI -49 to -37] was found for mammography screening. A short-term deficit of 62% [CI -65 to -58] was found for cervical screening. Furthermore, a slight, statistically significant downward trend in cervical screening from 2018 to 2021 was probably unrelated to the pandemic. Other changes, for example, a marked drop in mammography screening towards the end of 2021, also seem unrelated to the pandemic. Conclusions: Denmark continued cancer screening during the pandemic, but following the first lockdown a temporary drop was seen in breast and cervical screening activity. Funding: Region Zealand (R22-A597).

Labor augmentation with oxytocin in low- and lower-middle-income countries: a systematic review and meta-analysis.

OBJECTIVE: Despite its worldwide use, reviews of oxytocin for labor augmentation include mainly studies from high-income countries. Meanwhile, oxytocin is a potentially harmful medication and risks may be higher in low-resource settings. We conducted a systematic review and meta-analysis of practices, benefits, and risks of oxytocin for labor augmentation in low- and lower-middle-income countries. DATA SOURCES: PubMed, Embase, PsycINFO, Index Medicus, Cochrane, and Google Scholar were searched for publications until January 1, 2022. STUDY ELIGIBILITY CRITERIA: All studies evaluating oxytocin augmentation rates were included. To investigate benefits and risks, randomized and quasi-randomized trials comparing oxytocin augmentation with placebo or no oxytocin were included. To explore risks more broadly, cohort and case-control studies were also included. METHODS: Data were extracted and quality-assessed by 2 researchers using a modified Newcastle-Ottawa scale. Generic inverse variance outcome and a random-effects model were used. Adjusted or crude effect measures with 95% confidence intervals were used. RESULTS: In total, 42 studies were included, presenting data from 885 health facilities in 25 low- and lower-middle-income countries (124,643 women). Rates of oxytocin for labor augmentation varied from 0.7% to 97.0%, exceeding 30% in 14 countries. Four studies investigated timing of oxytocin for augmentation and found that 89.5% (2745) of labors augmented with oxytocin did not cross the partograph's action line. Four cohort and 7 case-control studies assessed perinatal outcomes. Meta-analysis revealed that oxytocin was associated with: stillbirth and day-1 neonatal mortality (relative risk, 1.45; 95% confidence interval, 1.02-2.06; N=84,077; 6 studies); low Apgar score (relative risk, 1.54; 95% confidence interval, 1.21-1.96; N=80,157; 4 studies); neonatal resuscitation (relative risk, 2.69; 95% confidence interval, 1.87-3.88; N=86,750; 3 studies); and neonatal encephalopathy (relative risk, 2.90; 95% confidence interval, 1.87-4.49; N=1383; 2 studies). No studies assessed effects on cesarean birth rate and uterine rupture. CONCLUSION: This review discloses a concerning level of oxytocin use, including in labors that often did not fulfill criteria for dystocia. Although this finding is limited by confounding by indication, oxytocin seems associated with increased perinatal risks, which are likely mediated by inadequate fetal monitoring. We call for cautious use on clear indications and robust implementation research to support evidence-based guidelines for labor augmentation, particularly in low-resource settings.

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. DATA SOURCES: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. STUDY ELIGIBILITY CRITERIA: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. METHODS: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. RESULTS: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. CONCLUSION: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta-analysis.

INTRODUCTION: In this review and meta-analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+). MATERIAL AND METHODS: We performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta-analysis was performed using fixed and random-effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2-tool for RCTs and ROBINS-I for observational studies. The protocol was registered in PROSPERO (CRD42021238257). RESULTS: A total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed-effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16-0.53). Due to considerable heterogeneity in observational studies, the random-effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18-0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21-1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included. CONCLUSIONS: HPV vaccination post-treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well-designed randomized placebo-controlled trials are needed to determine whether post-treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

Multivitamin use and risk of preeclampsia: A systematic review and meta-analysis.

INTRODUCTION: Preeclampsia is associated with adverse maternal and neonatal outcomes. It is unclear whether multivitamin use reduces the risk of preeclampsia. This systematic review and meta-analysis aimed to evaluate the association between multivitamin use and the risk of preeclampsia. MATERIAL AND METHODS: We searched PubMed, Embase and the Cochrane Library from database inception to July 2021. Randomized controlled trials (RCTs), case-control and cohort studies assessing the association between multivitamin use and risk of preeclampsia were eligible. Studies of treatment with a single micronutrient were excluded. Relative risks and 95% confidence intervals (95% CI) were calculated using random-effects models. RoB2, the Newcastle Ottawa Scale and GRADE were used to assess risk of bias and quality of evidence. The protocol was registered in PROSPERO (no. CRD42021214153). RESULTS: Six studies were included (33 356 women). Only two RCTs were found, both showing a significantly decreased risk of preeclampsia in multivitamin users. These studies were not compatible for meta-analysis due to clinical heterogeneity. A meta-analysis of observational studies using a random-effects model showed an unchanged risk of preeclampsia following multivitamin use (relative risk 0.85, 95% CI 0.69-1.03). The quality of evidence according to GRADE was very low. CONCLUSIONS: Very weak evidence suggests that multivitamin use might reduce the risk of preeclampsia; however, more research is needed. Large RCTs should be prioritized. The results of this review do not allow any final conclusions to be drawn regarding a preventive effect of multivitamin use in relation to preeclampsia.

[Phased implementation of HPV-based cervical cancer screening in Denmark].

Studies have shown, that HPV-based screening is more sensitive than cytology-based screening, but local factors will influence the performance. From January 2021 phased implementation of HPV-based screening was introduced in the Danish cervical cancer screening programme to women between 30 and 59 years. Women with even birth dates will remain on the current cytology-based screening, whereas women with odd birth dates will receive HPV-based screening. The aim of the implementation is to provide guidance to the National Health Authority on the future Danish cervical screening, as argued in this review.

Human Papillomavirus Testing in the Last Cervical Screening Round at Age 60-64 Years.

OBJECTIVE: To compare the real-life screening outcomes after cytology was replaced by human papillomavirus (HPV) testing for women aged 60-64 years. METHODS: Using the Danish national pathology register, we compared screening outcomes during two consecutive calendar periods, one where women were screened with cytology and one where most women were screened with HPV testing. Our primary outcomes were the proportions of women with positive test results, high-grade cervical intraepithelial neoplasia (CIN 2 or worse), and cervical cancer. RESULTS: Women screened during the HPV testing period were more likely to have a positive screening test result than were women screened during the cytology period (relative proportion 2.80, 95% CI 2.65-2.96). The detection of CIN 2 or worse was also increased (relative proportion 1.54, 95% CI 1.31-1.80), whereas there was no increase in screen-detected cervical cancer diagnoses (relative proportion 1.27, 95% CI 0.76-2.12). Within the first 4 years after a negative screening test result, including 168,477 woman-years at risk after a negative screen result in the HPV period and 451,421 woman-years after a negative screen result in the cytology period, the risk of a cervical cancer diagnosis was approximately 4 per 100,000 woman-years and was similar for both screening tests (relative risk 0.99, 95% CI 0.41-2.35). CONCLUSION: Human papillomavirus testing led to more positive screening test results and diagnoses of high-grade CIN lesions. Few women were diagnosed with cervical cancer after a negative screening test result.

[Christmas article: Coitus is not recommended - a systematic review].

The overall positive effects of coitus have not been estimated before. A systematic review and meta-analysis was conducted for coitus versus everything. A search was made in MEDLINE resulting in 1,121 hits. The authors screened studies and conducted a meta-analysis. Thirty publications randomising to coitus or something else were included. Pooled results showed a relative risk of 0.91 (95% CI: 0.86-0.96) favouring "everything else" over coitus. Subjective pleasure is not a primary outcome in any of the included studies, and trialists must have regarded this outcome as less important. In conclusion, coitus cannot be recommended based on the published randomised studies. Evaluation by evidence-based methodology makes it clear, that better alternatives exist.

Systematic review of the limited evidence for different surgical techniques at benign hysterectomy: A clinical guideline initiated by the Danish Health Authority.

Hysterectomy for benign gynecological conditions is a common operation that has developed extensively through the last 20 years. Methods and surgical techniques vary throughout the regions in Denmark as well as internationally. Consequently, the Danish Health Authority initiated a national clinical guideline on the subject based on a systematic review of the literature. A guideline panel of seven gynecologists formulated the clinical questions for the guideline. A search specialist performed the comprehensive literature search. The guideline panel reviewed the literature and rated the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Finally, the panel weighted the evidence and formulated the clinical recommendations. Based on the limited available literature and the corresponding quality of evidence according to GRADE, the guideline panel gave the following recommendations: ↓ Subtotal hysterectomy should only be preferred over total hysterectomy after careful consideration because there are documented disadvantages such as persistent cyclic vaginal bleeding (⊕ΟΟΟ). ↑ Consider vaginal hysterectomy rather than conventional laparoscopic hysterectomy for non-prolapsed uteri when feasible (⊕ΟΟΟ). ↓ Robot-assisted laparoscopic hysterectomy should only be preferred over conventional laparoscopic hysterectomy after careful consideration because the beneficial effect is uncertain and because of the longer operating time (⊕⊕ΟΟ). ↑ Consider concomitant bilateral salpingectomy at the time of hysterectomy if the procedure is not considered to increase the risk of complications significantly (⊕ΟΟΟ). ↑ Consider vaginal vault suspension to the cardinal and the uterosacral ligaments when performing hysterectomy for non-prolapsed uteri (⊕ΟΟΟ). Though supporting evidence is missing, the guideline panel emphasizes that it is good practice not to morcellate uteri with presumed fibroids inside the peritoneal cavity (√). The recommendations serve as professional advice in specific clinical situations. The implementation of the guideline in Denmark will be monitored through the national Danish Hysterectomy and Hysteroscopy Database.

Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.

BACKGROUND: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. METHODS AND FINDINGS: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. CONCLUSIONS: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

The Food and Drug Administration reports provided more data but were more difficult to use than the European Medicines Agency reports.

OBJECTIVES: To compare the accessibility, comprehensiveness, and usefulness of data available from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) drug reports. STUDY DESIGN AND SETTING: This is a cross-sectional study. All new molecular drugs approved between January 1, 2011 and December 31, 2012 from the FDA and EMA Web sites were eligible. RESULTS: We included 27 drug reports. Most were searchable, but the FDA table of contents did not match the file's page numbers. Several FDA documents must be searched compared with a single EMA document, but the FDA reports contain more summary data on harms. Detailed information about harms was reported for 93% of the FDA reports (25 of 27 reports) and 26% of the EMA reports (7 of 27 reports). The reports contained information about trial methodology but did not include trial registry IDs or investigator names. All reports but one contained sufficient information to be used in a meta-analysis. CONCLUSION: Detailed data on efficacy and harms are available at the two agencies. The FDA has more summary data on harms, but the documents are harder to navigate.

Searching for unpublished data for Cochrane reviews: cross sectional study.

OBJECTIVE: To describe the experiences of authors of Cochrane reviews in searching for, getting access to, and using unpublished data. DESIGN: Cross sectional study. SETTING: Cochrane reviews. PARTICIPANTS: 2184 corresponding authors of Cochrane reviews as of May 2012. MAIN OUTCOME MEASURE: Frequencies of responses to open ended and closed questions in an online survey. RESULTS: Of 5915 authors contacted by email, 2184 replied (36.9% response rate). Of those, 1656 (75.8%) had searched for unpublished data. In 913 cases (55.1% of 1656), new data were obtained and we received details about these data for 794 data sources. The most common data source was "trialists/investigators," accounting for 73.9% (n=587) of the 794 data sources. Most of the data were used in the review (82.0%, 651/794) and in 53.4% (424/794) of cases data were provided in less than a month. Summary data were most common, provided by 50.8% (403/794) of the data sources, whereas 20.5% (163/794) provided individual patient data. In only 6.3% (50/794) of cases were data reported to have been obtained from the manufacturers, and this group waited longer and had to make more contacts to get the data. The data from manufacturers were less likely to be for individual patients and less likely to be used in the review. Data from regulatory agencies accounted for 3.0% (24/794) of the obtained data. CONCLUSIONS: Most authors of Cochrane reviews who searched for unpublished data received useful information, primarily from trialists. Our response rate was low and the authors who did not respond were probably less likely to have searched for unpublished data. Manufacturers and regulatory agencies were uncommon sources of unpublished data.