Treatment methods for cervical intraepithelial neoplasia in England: A cost-effectiveness analysis.

OBJECTIVE: To compare the cost-effectiveness of different treatments for cervical intraepithelial neoplasia (CIN). DESIGN: A cost-effectiveness analysis based on data available in the literature and expert opinion. SETTING: England. POPULATION: Women treated for CIN. METHODS: We developed a decision-analytic model to simulate the clinical course of 1000 women who received local treatment for CIN and were followed up for 10 years after treatment. In the model we considered surgical complications as well as oncological and reproductive outcomes over the 10-year period. The costs calculated were those incurred by the National Health Service (NHS) of England. MAIN OUTCOME MEASURES: Cost per one CIN2+ recurrence averted (oncological outcome); cost per one preterm birth averted (reproductive outcome); overall cost per one adverse oncological or reproductive outcome averted. RESULTS: For young women of reproductive age, large loop excision of the transformation zone (LLETZ) was the most cost-effective treatment overall at all willingness-to-pay thresholds. For postmenopausal women, LLETZ remained the most cost-effective treatment up to a threshold of £31,500, but laser conisation became the most cost-effective treatment above that threshold. CONCLUSIONS: LLETZ is the most cost-effective treatment for both younger and older women. However, for older women, more radical excision with laser conisation could also be considered if the NHS is willing to spend more than £31,500 to avert one CIN2+ recurrence.

Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies.

BACKGROUND: Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear. METHODS: In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995). RESULTS: We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89-2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27-1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40-1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation. CONCLUSIONS: Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

Terminology for cone dimensions after local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer: 2022 consensus recommendations from ESGO, EFC, IFCPC, and ESP.

Local cervical treatment for squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN) removes or ablates a cone-shaped or dome-shaped part of the cervix that contains abnormal cells. This Series paper introduces the 2022 terminology for cone dimensions after local conservative treatment for SIL, CIN, or early invasive cervical cancer. The terminology was prepared by the Nomenclature Committee of the European Society of Gynaecologic Oncology, the European Federation for Colposcopy, the International Federation of Cervical Pathology and Colposcopy, and the European Society of Pathology. Cone length should be tailored to the type of transformation zone. Treatment of SIL or CIN is associated with an increased risk of preterm birth, which escalates with increasing cone length. There is a lack of agreement regarding terms used to report excised specimen dimensions both intraoperatively and in the pathology laboratory. Consensus is needed to make studies addressing effectiveness and safety of SIL or CIN treatment comparable, and to facilitate their use to improve accuracy of antenatal surveillance and management. This Series paper summarises the current terminology through a review of existing literature, describes new terminology as agreed by a group of experts from international societies in the field of cervical cancer prevention and treatment, and recommends use of the new terminology that will facilitate communication between clinicians and foster more specific treatment guidelines that balance obstetrical harm against therapeutic effectiveness.

Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis.

BACKGROUND: The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508. FINDINGS: 7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low. INTERPRETATION: More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning. FUNDING: National Institute for Health and Care Research: Research for Patient Benefit.

Minimally invasive oesophagectomy in the prone versus lateral decubitus position: a systematic review and meta-analysis.

The thoracic phase of minimally invasive esophagectomy was initially performed in the lateral decubitus position (LDP); however, many experts have gradually transitioned to a prone position (PP) approach. The aim of the present systematic review and meta-analysis is to quantitatively compare the two approaches. A systematic literature search of the MEDLINE, Embase, Google Scholar, Web of Knowledge, China National Knowledge Infrastructure and ClinicalTrials.gov databases was undertaken for studies comparing outcomes between patients undergoing minimally invasive esophageal surgery in the PP versus the LDP. In total, 15 studies with 1454 patients (PP; n = 710 vs. LDP; n = 744) were included. Minimally invasive esophagectomy in the PP provides statistically significant reduction in postoperative respiratory complications (Risk ratios 0.5, 95% confidence intervals [CI] 0.34-0.76, P < 0.001), blood loss (weighted mean differences [WMD] -108.97, 95% CI -166.35 to -51.59 mL, P < 0.001), ICU stay (WMD -0.96, 95% CI -1.7 to -0.21 days, P = 0.01) and total hospital stay (WMD -2.96, 95% CI -5.14 to -0.78 days, P = 0.008). In addition, prone positioning increases the overall yield of chest lymph node dissection (WMD 2.94, 95% CI 1.54-4.34 lymph nodes, P < 0.001). No statistically significant difference in regards to anastomotic leak rate, mortality and 5-year overall survival was encountered. Subgroup analysis revealed that the protective effect of prone positioning against pulmonary complications was more pronounced for patients undergoing single-lumen tracheal intubation. A head to head comparison of minimally invasive esophagectomy in the prone versus the LDP reveals superiority of the former method, with emphasis on the reduction of postoperative respiratory complications and reduced length of hospitalization. Long-term oncologic outcomes appear equivalent, although validation through prospective studies and randomized controlled trials is still necessary.

Minimally invasive surgical management of spontaneous esophageal perforation (Boerhaave's syndrome).

BACKGROUND: Spontaneous esophageal perforation (Boerhaave's syndrome) is a highly morbid condition traditionally associated with poor outcomes. The Pittsburgh perforation severity score (PSS) accurately predicts risk of morbidity, length of stay (LOS) and mortality. Operative management is indicated among patients with medium (3-5) or high (> 5) PSS; however, the role of minimally invasive surgery remains uncertain. METHODS: Consecutive patients presenting with Boerhaave's syndrome with intermediate or high PSS managed via a thoracoscopic and laparoscopic approach from 2012 to 2018 were reviewed. Demographics, clinical presentation, management, and outcomes were analyzed. RESULTS: Ten patients (80% male) with a mean age of 61.3 years (range 37-81) were included. Two patients had intermediate and eight had high PSS (7.9 ± 2.8, range 4-12). The mean time from onset of symptoms to diagnosis was 27 ± 12 h and APACHE II score was 13.6 ± 4.9. Thoracoscopic debridement and primary repair was performed in eight cases, with two perforations repaired primarily over a T-tube. Laparoscopic feeding jejunostomy was performed in all patients. Critical care LOS was 8.7 ± 6.8 days (range 3-26), while inpatient LOS was 23.1 ± 12.5 days (range 14-46). Mean comprehensive complications index was 42.1 ± 26.2, with grade IIIa and IV morbidity in 60% and 10%, respectively. One patient developed dehiscence at the primary repair, which was managed non-operatively. In-hospital and 90-day mortality was 10%. CONCLUSION: Minimally invasive surgical management of spontaneous esophageal perforation with medium to high perforation severity scores is feasible and safe, with outcomes which compare favorably to the published literature.

The beneficial role of simultaneous splenectomy after extended hepatectomy: experimental study in pigs.

BACKGROUND: The role of hepatic hemodynamic modulation in the development of "small-for-size" syndrome (SFSS) after extended hepatectomy (EH) or living-donor liver transplantation is still controversial. We have designed an experimental study to investigate the effect of hemodynamic parameters of the liver circulation on the development of SFSS after EH in a porcine model. METHODS: Eighteen pigs were randomly divided into two groups: group A has received EH (75%-80%) without splenectomy, and group B with EH and simultaneous splenectomy was carried out. Portal hemodynamics, liver function tests, histologic findings, injury and survival rates were compared between groups A and B. RESULTS: The 7-d survival rate in the splenectomy group was significantly improved compared with group A (88.9% versus 44.4%, P < 0.05). Portal vein pressure, portal vein flow, and liver function tests in the splenectomy group were significantly lower than in group A immediately after splenectomy and postoperatively until the day of sacrifice. Histologic findings in group A clearly illustrate severe inflammation, bridging necrosis, ischemic cholangitis, and severe congestion, while in group B there were less serious histologic changes. CONCLUSIONS: Our experimental study indicates that perioperative portal modulation can successfully prevent the manifestation of SFSS after EH. Therefore, by focusing on "flow" rather than on "size," researchers may understand better the pathophysiology of this syndrome.

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

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 I2 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.

Results of the modified bi-pectoral muscle flap procedure for post-sternotomy deep wound infection.

PURPOSE: Post-sternotomy deep sternal wound infection (DSWI) is a severe complication of cardiac surgery. The introduction of omental and muscle flaps has resulted in a significant decrease in morbidity and mortality. In this article, we present the findings for a series of 55 consecutive patients with DSWI treated using an alternative bi-pectoral musculofascial flap technique. METHODS: The patients were stratified into two groups (one-or two-stage intervention). Patients with septic wounds initially underwent debridement and wound treatment, while vacuum therapy was used in a subset of the subjects. All patients were treated with wound debridement and bi-pectoral advancement flap reconstruction. RESULTS: 30-day mortality was 5.4%. Most patients (72%) were treated in two stages, while vacuum therapy was used in 20% of the patients. The mean number of hospitalization days was 8 and 12 for the one- and the two-stage groups, respectively. Reconstruction was successful in all but three patients, each of whom developed recurrent infection. No major morbidity was reported at a mean follow-up of 82 months with excellent functional and aesthetic outcomes. CONCLUSIONS: Pectoralis-major muscle flaps remain relevant in the modern management of post-sternotomy mediastinitis. The addition of an omental flap should be considered in cases in which the lower sternum is involved. Prompt diagnosis and a meticulous surgical technique ensure favorable results for the majority of patients.

Extended hepatectomy using the bipolar tissue sealer: an experimental model of small-for-size syndrome in pigs.

PURPOSE: After liver transplantation with a small-for-size liver graft or after extensive hepatectomy for liver malignancies or other non malignant conditions with an insufficient liver volume, the survival of patients depends on liver regeneration. This study was carried out in order to create a new porcine model for the study of small-for-size syndrome (SFSS) after extensive hepatectomy. METHODS: In the present study we used 23 domestic Landrace pigs weighing 28.3±3 kg and aged 19-21 weeks. We describe our detailed surgical procedure for 75% partial hepatectomy a in porcine model, using the saline-coupled bipolar sealing device (Aquamantys®) for hepatectomy. RESULTS: The Aquamantis 2.3 bipolar sealer was connected to the Aquamantis generator and was adjusted to produce 150 watts at a medium flow rate of 20 ml/min. The device temperature was programmed to remain at approximately 100° C and, as a consequence, it produced a tissue ablation without charring. The mean operating time was 153.8 min and the mean blood loss 81.9 ml. The estimated residual liver weight (ERL) was 177 g, whereas the mean proportion of ERL was 24.5%. There was no perioperative mortality. CONCLUSIONS: A large animal model, such as pig, is extremely useful in order to reproduce and understand the SFSS. Our simple technique for successful resection of 75% of the liver in pigs, using the Aquamantys system, achieves effective and safe liver parenchymal transection with significant decrease of intraoperative blood loss and can provide useful information for researchers.

The value of calprotectin S100A8/A9 complex as a biomarker in colorectal cancer: A systematic review.

PURPOSE: Associations between inflammation and carcinogenesis have been reported for many years, as originally postulated by Virchow in his studies, but the results from prospective cohort studies remain controversial. We evaluated the role of calprotectin as a biomarker for colorectal cancer (CRC). METHODS: The MEDLINE/PubMed database was thoroughly searched using the keywords: "inflammation", "colorectal cancer, "calprotectin", "carcinogenesis" and/or "biomarkers". We focused on human and animal (rodent) studies of CRC and the role of calprotectin as a new biomarker and its potential value to the diagnosis, follow-up and CRC prognosis. RESULTS: According to the literature, calprotectin seems to be a reliable sensitive marker in the diagnosis and postoperative evaluation of CRC patients at the cost of low specificity and no correlation with the progress and stage of disease. CONCLUSIONS: Calprotectin stands for a novel but well-evaluated biomarker in CRC. The experimental studies focus on the CRC microenvironment and suggest that malignant cells and tissues overexpress S100A8 and S100A9 and the heterodimer S100A8/A9.

Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia.

BACKGROUND: Cervical intra-epithelial neoplasia (CIN) typically occurs in young women of reproductive age. Although several studies have reported the impact that cervical conservative treatment may have on obstetric outcomes, there is much less evidence for fertility and early pregnancy outcomes. OBJECTIVES: To assess the effect of cervical treatment for CIN (excisional or ablative) on fertility and early pregnancy outcomes. SEARCH METHODS: We searched in January 2015 the following databases: the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 12, 2014), MEDLINE (up to November week 3, 2014) and EMBASE (up to week 52, 2014). SELECTION CRITERIA: We included all studies reporting on fertility and early pregnancy outcomes (less than 24 weeks of gestation) in women with a history of CIN treatment (excisional or ablative) as compared to women that had not received treatment. DATA COLLECTION AND ANALYSIS: Studies were classified according to the treatment method used and the fertility or early pregnancy endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model and inter-study heterogeneity was assessed with I(2). Two review authors (MK, AM) independently assessed the eligibility of retrieved papers and risk of bias. The two review authors then compared their results and any disagreements were resolved by discussion. If still unresolved, a third review author (MA) was involved until consensus was reached. MAIN RESULTS: Fifteen studies (2,223,592 participants - 25,008 treated and 2,198,584 untreated) that fulfilled the inclusion criteria for this review were identified from the literature search. The meta-analysis demonstrated that treatment for CIN did not adversely affect the chances of conception. The overall pregnancy rate was higher for treated (43%) versus untreated women (38%; RR 1.29, 95% CI 1.02 to 1.64; 4 studies, 38,050 participants, very low quality), although the inter-study heterogeneity was considerable (P < 0.01). The pregnancy rates in treated and untreated women with an intention to conceive (88% versus 95%, RR 0.93, 95% CI 0.80 to 1.08; 2 studies, 70 participants, very low quality) and the number of women requiring more than 12 months to conceive (14% versus 9%, RR 1.45, 95% CI 0.89 to 2.37; 3 studies, 1348 participants, very low quality) were no different. Although the total miscarriage rate (4.6% versus 2.8%, RR 1.04, 95% CI 0.90 to 1.21; 10 studies, 39,504 participants, low quality) and first trimester miscarriage rate (9.8% versus 8.4%, RR 1.16, 95% CI 0.80 to 1.69, 4 studies, 1103 participants, low quality) was similar for treated and untreated women, CIN treatment was associated with an increased risk of second trimester miscarriage, (1.6% versus 0.4%, RR 2.60, 95% CI 1.45 to 4.67; 8 studies, 2,182,268 participants, low quality). The number of ectopic pregnancies (1.6% versus 0.8%, RR 1.89, 95% CI 1.50 to 2.39; 6 studies, 38,193 participants, low quality) and terminations (12.2% versus 7.4%, RR 1.71, 95% CI 1.31 to 2.22; 7 studies, 38,208 participants, low quality) were also higher in treated women.The results should be interpreted with caution. The included studies were often small with heterogenous design. Most of these studies were retrospective and of low or very low quality (GRADE assessment) and were therefore prone to bias. Subgroup analyses for the individual treatment methods and comparison groups and analysis to stratify for the cone length was not possible. AUTHORS' CONCLUSIONS: This meta-analysis suggests that treatment for CIN does not adversely affect fertility, although treatment was associated with an increased risk of miscarriage in the second trimester. These results should be interpreted with caution as the included studies were non-randomised and many were of low or very low quality and therefore at high risk of bias. Research should explore mechanisms that may explain the increase in mid-trimester miscarriage risk and stratify this impact of treatment by the length of the cone and the treatment method used.