Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.

BACKGROUND: A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases. METHODS: In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex. FINDINGS: Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. INTERPRETATION: Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases. FUNDING: Research Foundation Flanders.

Factors associated with inappropriateness of antibiotic prescriptions for acutely ill children presenting to ambulatory care in high-income countries: a systematic review and meta-analysis.

BACKGROUND: Acutely ill children are at risk of unwarranted antibiotic prescribing. Data on the appropriateness of antibiotic prescriptions provide insights into potential tailored interventions to promote antibiotic stewardship. OBJECTIVES: To examine factors associated with the inappropriateness of antibiotic prescriptions for acutely ill children presenting to ambulatory care in high-income countries. METHODS: On 8 September 2022, we systematically searched articles published since 2002 in MEDLINE, Embase, CENTRAL, Web of Science, and grey literature databases. We included studies with acutely ill children presenting to ambulatory care settings in high-income countries reporting on the appropriateness of antibiotic prescriptions. The quality of the studies was evaluated using the Appraisal tool for Cross-Sectional Studies and the Newcastle-Ottawa Scale. Pooled ORs were calculated using random-effects models. Meta-regression, sensitivity and subgroup analysis were also performed. RESULTS: We included 40 articles reporting on 30 different factors and their association with inappropriate antibiotic prescribing. 'Appropriateness' covered a wide range of definitions. The following factors were associated with increased inappropriate antibiotic prescribing: acute otitis media diagnosis [pooled OR (95% CI): 2.02 (0.54-7.48)], GP [pooled OR (95% CI) 1.38 (1.00-1.89)] and rural setting [pooled OR (95% CI) 1.47 (1.08-2.02)]. Older patient age and a respiratory tract infection diagnosis have a tendency to be positively associated with inappropriate antibiotic prescribing, but pooling of studies was not possible. CONCLUSIONS: Prioritizing acute otitis media, GPs, rural areas, older children and respiratory tract infections within antimicrobial stewardship programmes plays a vital role in promoting responsible antibiotic prescribing. The implementation of a standardized definition of appropriateness is essential to evaluate such programmes.

Temporal trends in antibiotic prescribing and serious and nonserious infections in children presenting to general practice: a registry-based longitudinal cohort study of 162 507 individuals.

BACKGROUND: It is crucial to understand the trends in paediatric antibiotic prescribing and serious and nonserious infections to improve antibiotic prescribing practices for children in ambulatory care. OBJECTIVES: Assessing trends in paediatric antibiotic prescribing and infection incidence in general practice from 2002 to 2022. METHODS: In this retrospective cohort study using INTEGO network data from 162 507 patients in Flanders (Belgium), we calculated antibiotic prescribing rates and proportions alongside incidence rates of serious and nonserious infections, stratified by age (0-1, 2-6, 7-12 years) and municipality. We performed autoregressive moving average time-series analyses and seasonality analyses. RESULTS: From 2002 to 2022, antibiotic prescribing rate decreased significantly: 584/1000 person-years (PY) (95% CI 571-597) to 484/1000PY (95% CI 478-491); so did antibiotic overall prescribing proportion: 46.3% (95% CI 45.1-47.6) to 23.3% (95% CI 22.9-23.7) (59.3% amoxicillin and 17.8% broad spectrum). Prescribing proportions dropped significantly for nonserious (45.6% to 20.9%) and increased for serious infections (64.1% to 69.8%). Proportions significantly dropped for acute suppurative otitis media (74.7% to 64.1%), upper respiratory tract infections (44.9% to 16.6%), bronchitis/bronchiolitis (73.6% to 44.1%) and acute tonsillopharyngitis (59.5% to 21.7%), while significantly increasing for pneumonia (65.2% to 80.2%). Nonserious and serious infection incidence rates increased from 785/1000PY and 34.2/1000PY to 1223/1000PY and 64.1/1000PY, respectively. Blood and CRP testing proportions increased significantly. CONCLUSIONS: Antibiotic prescribing in general practice for children declined from 2002 to 2022. Further targeted antibiotic stewardship initiatives are needed to reduce the use of broad-spectrum antibiotics and antibiotic prescribing for conditions such as otitis media and bronchitis/bronchiolitis.

Accuracy of respiratory muscle assessments to predict weaning outcomes: a systematic review and comparative meta-analysis.

BACKGROUND: Several bedside assessments are used to evaluate respiratory muscle function and to predict weaning from mechanical ventilation in patients on the intensive care unit. It remains unclear which assessments perform best in predicting weaning success. The primary aim of this systematic review and meta-analysis was to summarize and compare the accuracy of the following assessments to predict weaning success: maximal inspiratory (PImax) and expiratory pressures, diaphragm thickening fraction and excursion (DTF and DE), end-expiratory (Tdiee) and end-inspiratory (Tdiei) diaphragm thickness, airway occlusion pressure (P0.1), electrical activity of respiratory muscles, and volitional and non-volitional assessments of transdiaphragmatic and airway opening pressures. METHODS: Medline (via Pubmed), EMBASE, Web of Science, Cochrane Library and CINAHL were comprehensively searched from inception to 04/05/2023. Studies including adult mechanically ventilated patients reporting data on predictive accuracy were included. Hierarchical summary receiver operating characteristic (HSROC) models were used to estimate the SROC curves of each assessment method. Meta-regression was used to compare SROC curves. Sensitivity analyses were conducted by excluding studies with high risk of bias, as assessed with QUADAS-2. Direct comparisons were performed using studies comparing each pair of assessments within the same sample of patients. RESULTS: Ninety-four studies were identified of which 88 studies (n = 6296) reporting on either PImax, DTF, DE, Tdiee, Tdiei and P0.1 were included in the meta-analyses. The sensitivity to predict weaning success was 63% (95% CI 47-77%) for PImax, 75% (95% CI 67-82%) for DE, 77% (95% CI 61-87%) for DTF, 74% (95% CI 40-93%) for P0.1, 69% (95% CI 13-97%) for Tdiei, 37% (95% CI 13-70%) for Tdiee, at fixed 80% specificity. Accuracy of DE and DTF to predict weaning success was significantly higher when compared to PImax (p = 0.04 and p < 0.01, respectively). Sensitivity and direct comparisons analyses showed that the accuracy of DTF to predict weaning success was significantly higher when compared to DE (p < 0.01). CONCLUSIONS: DTF and DE are superior to PImax and DTF seems to have the highest accuracy among all included respiratory muscle assessments for predicting weaning success. Further studies aiming at identifying the optimal threshold of DTF to predict weaning success are warranted. TRIAL REGISTRATION: PROSPERO CRD42020209295, October 15, 2020.

Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK.

BACKGROUND: Some autoimmune diseases are associated with an increased risk of cardiovascular disease. We aimed to determine whether or not this is true, and to what extent, for a broad range of autoimmune conditions. METHODS: In this population-based study, we used linked primary and secondary care records from the Clinical Practice Research Datalink (CPRD), GOLD and Aurum datasets, to assemble a cohort of individuals across the UK who were newly diagnosed with any of 19 autoimmune diseases between Jan 1, 2000, and Dec 31, 2017, younger than 80 years at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. We also assembled a matched cohort with up to five individuals matched on age, sex, socioeconomic status, region, and calendar year, who were free of autoimmune disease and free of cardiovascular diseases up to 12 months after study entry. Both cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular outcomes and used Cox proportional hazards models to examine differences in patients with and without autoimmune diseases. FINDINGS: Of 22 009 375 individuals identified from the CPRD databases, we identified 446 449 eligible individuals with autoimmune diseases and 2 102 830 matched controls. In the autoimmune cohort, mean age at diagnosis was 46·2 years (SD 19·8), and 271 410 (60·8%) were women and 175 039 (39·2%) were men. 68 413 (15·3%) people with and 231 410 (11·0%) without autoimmune diseases developed incident cardiovascular disease during a median of 6·2 years (IQR 2·7-10·8) of follow-up. The incidence rate of cardiovascular disease was 23·3 events per 1000 patient-years among patients with autoimmune disease and 15·0 events per 1000 patient-years among those without an autoimmune disease (hazard ratio [HR] 1·56 [95% CI 1·52-1·59]). An increased risk of cardiovascular disease with autoimmune disease was seen for every individual cardiovascular disease and increased progressively with the number of autoimmune diseases present (one disease: HR 1·41 [95% CI 1·37-1·45]; two diseases: 2·63 [2·49-2·78]); three or more diseases: 3·79 [3·36-4·27]), and in younger age groups (age <45 years: 2·33 [2·16-2·51]; 55-64 years: 1·76 [1·67-1·85]; ≥75 years: 1·30 [1·24-1·36]). Among autoimmune diseases, systemic sclerosis (3·59 [2·81-4·59]), Addison's disease (2·83 [1·96-4·09]), systemic lupus erythematosus (2·82 [2·38-3·33]), and type 1 diabetes (2·36 [2·21-2·52]) had the highest overall cardiovascular risk. INTERPRETATION: These findings warrant targeted cardiovascular prevention measures, in particular in younger patients with autoimmune diseases, and further research into pathophysiological mechanisms underlying these complications. FUNDING: Horizon 2020 Marie Sklodowska-Curie Actions and European Society of Cardiology.

Clinical prediction models for serious infections in children: external validation in ambulatory care.

BACKGROUND: Early distinction between mild and serious infections (SI) is challenging in children in ambulatory care. Clinical prediction models (CPMs), developed to aid physicians in clinical decision-making, require broad external validation before clinical use. We aimed to externally validate four CPMs, developed in emergency departments, in ambulatory care. METHODS: We applied the CPMs in a prospective cohort of acutely ill children presenting to general practices, outpatient paediatric practices or emergency departments in Flanders, Belgium. For two multinomial regression models, Feverkidstool and Craig model, discriminative ability and calibration were assessed, and a model update was performed by re-estimation of coefficients with correction for overfitting. For two risk scores, the SBI score and PAWS, the diagnostic test accuracy was assessed. RESULTS: A total of 8211 children were included, comprising 498 SI and 276 serious bacterial infections (SBI). Feverkidstool had a C-statistic of 0.80 (95% confidence interval 0.77-0.84) with good calibration for pneumonia and 0.74 (0.70-0.79) with poor calibration for other SBI. The Craig model had a C-statistic of 0.80 (0.77-0.83) for pneumonia, 0.75 (0.70-0.80) for complicated urinary tract infections and 0.63 (0.39-0.88) for bacteraemia, with poor calibration. The model update resulted in improved C-statistics for all outcomes and good overall calibration for Feverkidstool and the Craig model. SBI score and PAWS performed extremely weak with sensitivities of 0.12 (0.09-0.15) and 0.32 (0.28-0.37). CONCLUSIONS: Feverkidstool and the Craig model show good discriminative ability for predicting SBI and a potential for early recognition of SBI, confirming good external validity in a low prevalence setting of SBI. The SBI score and PAWS showed poor diagnostic performance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02024282. Registered on 31 December 2013.

Prospective Performance Evaluation of the miDiagnostics COVID-19 PCR Test for Rapid SARS-CoV-2 Detection on Nasopharyngeal Swabs.

Rapid diagnosis or exclusion of SARS-CoV-2 infection is essential for correct medical management decisions regarding COVID-19. High-throughput laboratory-based reverse transcriptase (RT)-PCR testing is accurate with longer turnaround times, while rapid antigen tests show moderate sensitivity. In search of a fast and reliable COVID-19 test, we aimed to validate the rapid miDiagnostics COVID-19 PCR test. We recruited symptomatic and asymptomatic participants in a mobile COVID-19 test center in Belgium. We collected three nasopharyngeal samples from each participant. The index sample was tested on the miDiagnostics COVID-19 PCR reader, the reference sample was tested on the reference TaqPath COVID-19 PCR test in the Belgian Reference Center for Respiratory Pathogens of University Hospitals Leuven, and a third sample was collected for discordance testing with the PerkinElmer SARS-CoV-2 PCR kit. A total of 770 participants yielded 763 sets of included nasopharyngeal samples. Overall positive percent agreement and negative percent agreement of the miDiagnostics COVID-19 PCR test were 95.5% (92.6% to 97.4%) and 94.9% (92.3 to 96.8%), rising to 98.6% (96.5% to 99.6%) and 96.5% (92.6% to 98.7%) in symptomatic patients. Discordance testing reclassified 15 of 21 false-positive cases as true positive. A retest of the miDiagnostics PCR test was performed in 61 tests (7.4%) due to a technical error. The miDiagnostics COVID-19 PCR test showed excellent clinical accuracy. The fast and reliable results allow for rapid correct diagnosis and tailored medical management decisions regarding COVID-19.

Cost-effectiveness of point-of-care interventions to tackle inappropriate prescribing of antibiotics in high- and middle-income countries: a systematic review.

BACKGROUND: Antimicrobial resistance (AMR) is propagated by widespread inappropriate use of antibiotics. In response, point-of-care interventions (POCIs) have been developed in primary care to preserve antibiotic effectiveness. Many of these POCIs are adopted based on their clinical value. However, assessment of their cost-effectiveness is crucial as well. OBJECTIVES: To summarize the evidence on cost-effectiveness of POCIs aimed at tackling inappropriate antibiotic prescriptions in primary care in middle- and high-income countries. We also evaluate the quality of the evidence with particular attention to how these economic evaluations faced the challenge of capturing the impact of these POCIs on AMR. METHODS: Six scientific databases (MEDLINE, Embase, Web of Science, NHS EED, NHS HTA, the Cochrane Library) were searched for eligible articles published from 1999 to 2022. Their quality was appraised by means of the Drummond and CHEERS checklist. RESULTS: Twenty-nine articles met the selection criteria. Using their own (implicit) definitions of cost-effectiveness, evidence reported that point-of-care testing, scoring tools, electronic interventions, communication training, and multidimensional and educational interventions are more cost-effective than standard care. In contrast, studies found dipstick testing and audit-and-feedback interventions to be not cost-effective. Data synthesis took a narrative approach as eligible studies were not similar and/or reliable enough to pool their results through meta-analysis. CONCLUSIONS: More high-quality evidence is needed to attain a thorough understanding of the cost-effectiveness of POCIs. Heterogeneity in terms of interventions and efficiency measures complicates comparing and generalizing results. Methodological recommendations are urgently needed to economically evaluate POCIs, focusing on how AMR should be accounted for.

Clinical effectiveness of rehabilitation in ambulatory care for patients with persisting symptoms after COVID-19: a systematic review.

BACKGROUND: Lingering symptoms after acute COVID-19 present a major challenge to ambulatory care services. Since there are reservations regarding their optimal management, we aimed to collate all available evidence on the effects of rehabilitation treatments applicable in ambulatory care for these patients. METHODS: On 9 May 2022, we systematically searched articles in COVID-19 collections, Embase, MEDLINE, Cochrane Library, Web of Science, CINAHL, PsycArticles, PEDro, and EuropePMC. References were eligible if they reported on the clinical effectiveness of a rehabilitation therapy applicable in ambulatory care for adult patients with persisting symptoms continuing 4 weeks after the onset of COVID-19. The quality of the studies was evaluated using the CASP cohort study checklist and the Cochrane Risk of Bias Assessment Tool. Summary of Findings tables were constructed and the certainty of evidence was assessed using the GRADE framework. RESULTS: We included 38 studies comprising 2,790 participants. Physical training and breathing exercises may reduce fatigue, dyspnoea, and chest pain and may improve physical capacity and quality of life, but the evidence is very weak (based on 6 RCTs and 12 cohort studies). The evidence underpinning the effect of nutritional supplements on fatigue, dyspnoea, muscle pain, sensory function, psychological well-being, quality of life, and functional capacity is very poor (based on 4 RCTs). Also, the evidence-base is very weak about the effect of olfactory training on sensory function and quality of life (based on 4 RCTs and 3 cohort studies). Multidisciplinary treatment may have beneficial effects on fatigue, dyspnoea, physical capacity, pulmonary function, quality of life, return to daily life activities, and functional capacity, but the evidence is very weak (based on 5 cohort studies). The certainty of evidence is very low due to study limitations, inconsistency, indirectness, and imprecision. CONCLUSIONS: Physical training, breathing exercises, olfactory training and multidisciplinary treatment can be effective rehabilitation therapies for patients with persisting symptoms after COVID-19, still with high uncertainty regarding these effects. These findings can guide ambulatory care practitioners to treat these patients and should be incorporated in clinical practice guidelines. High-quality studies are needed to confirm our hypotheses and should report on adverse events.

Laser versus sham for genitourinary syndrome of menopause: A randomised controlled trial.

OBJECTIVE: To assess whether CO2 laser treatment is more effective than sham application in relieving the most bothersome symptom (MBS) in women with genitourinary syndrome of menopause (GSM). DESIGN: Single-centre, sham-controlled, double-blind, randomised trial. SETTING: A tertiary centre in Belgium. POPULATION: Sixty women with moderate to severe GSM symptoms. METHODS: All participants eventually received three consecutive laser and three consecutive sham applications, either first laser followed by sham, or conversely. MAIN OUTCOME MEASURES: The primary outcome was the participant-reported change in severity of the MBS at 12 weeks. Secondary outcomes included subjective (patient satisfaction, sexual function, urinary function) and objective (pH, Vaginal Health Index Score, in vivo microscopy) measurements assessing the short-term effect and the longevity of treatment effects at 18 months after start of the therapy. Adverse events were reported at every visit. RESULTS: The MBS severity score decreased from 2.86 ± 0.35 to 2.17 ± 0.93 (-23.60%; 95% CI -36.10% to -11.10%) in women treated with laser compared with 2.90 ± 0.31 to 2.52 ± 0.78 (-13.20%; 95% CI -22.70% to -3.73%) in those receiving sham applications (p = 0.13). There were no serious adverse events reported up to 18 months. CONCLUSIONS: In women with GSM, the treatment response 12 weeks after laser application was comparable to that of sham applications. There were no obvious differences for secondary outcomes and no serious adverse events were reported.

Predictors for sexual dysfunction in the first year postpartum: A systematic review and meta-analysis.

BACKGROUND: Pregnancy and childbirth increase the risk for pelvic floor dysfunction, including sexual dysfunction. So far, the mechanisms and the extent to which certain risk factors play a role remain unclear. OBJECTIVES: In this systematic review of the literature we aimed to determine risk factors for sexual dysfunction in the first year after childbirth. SEARCH STRATEGY: We searched MEDLINE, Embase and CENTRAL using the search strategy: sexual dysfunction AND obstetric events. SELECTION CRITERIA: We included original, comparative studies, reported in English, that used validated questionnaires and the ICS/IUGA terminology for sexual dysfunction, dyspareunia and vaginal dryness. DATA COLLECTION AND ANALYSIS: We assessed the quality and the risk of bias of the included studies with the Newcastle-Ottawa scale. We extracted the reported data and we performed random-effects meta-analysis to obtain the summary odds ratios (ORs) with 95% confidence intervals (95% CIs). Heterogeneity across studies was assessed using the I2 statistic. MAIN RESULTS: Anal sphincter injury was associated with increased odds for both sexual dysfunction (OR 3.00, 95%CI 1.28-7.03) and dyspareunia (OR 1.92, 95% CI 1.47-2.52). Episiotomy was associated with dyspareunia (OR 1.64, 95% CI 1.25-2.14), but not with sexual dysfunction (OR 1.90, 95% CI 0.94-3.84). Compared with spontaneous birth, caesarean section reduced the odds for dyspareunia (OR 0.68, 95% CI 0.54-0.86) but not for sexual dysfunction (OR 1.14, 95% CI 0.89-1.46). Instrumental vaginal birth increased the odds for sexual dysfunction (OR 1.70, 95% CI 1.05-2.76), yet no difference was found for dyspareunia (OR 1.82, 95% CI 0.88-3.75). One study of low quality reported on vaginal dryness and found no association with obstetric events. CONCLUSIONS: Perineal trauma, rather than mode of birth, increases the odds for sexual dysfunction in the first year after childbirth. TWEETABLE ABSTRACT: Perineal trauma, rather than mode of birth, correlates with sexual dysfunction and dyspareunia postpartum. #dyspareunia #OASI #episiotomy.

Biomarkers of acute kidney injury after pediatric cardiac surgery: a meta-analysis of diagnostic test accuracy.

Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLINE, Embase, Scopus, and reference lists were searched for relevant studies published by March 2021. Diagnostic accuracy parameters were extracted and analyzed using hierarchical summary receiver operating characteristic (HSROC) method. Pooled estimates of the area under the curve (AUC) were calculated using conventional random-effects meta-analysis. Fifty-six articles investigating 49 biomarkers in 8617 participants fulfilled our eligibility criteria. Data from 37 studies were available for meta-analysis. Of the 10 biomarkers suitable for HSROC analysis, urinary neutrophil gelatinase-associated lipocalin (uNGAL) to creatinine (Cr) ratio yielded the highest diagnostic odds ratio (91.0, 95% CI 90.1-91.9), with a sensitivity of 91.3% (95% CI 91.2-91.3%) and a specificity of 89.7% (95% CI 89.6-89.7%). These results were confirmed in pooled AUC analysis, as uNGAL-to-Cr ratio and uNGAL were the only elaborately studied biomarkers (> 5 observations) with pooled AUCs ≥ 0.800. Liver fatty acid-binding protein (L-FABP), serum cystatin C (sCysC), serum NGAL (sNGAL), and interleukin-18 (IL-18) all had AUCs ≥ 0.700. CONCLUSION: A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management. WHAT IS KNOWN: • Acute kidney injury (AKI) occurs in about 30-60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes. However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury. • Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy. WHAT IS NEW: • Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers. • A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.

Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection.

BACKGROUND: Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020. OBJECTIVES: To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design. SEARCH METHODS: We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions. SELECTION CRITERIA: We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample. DATA COLLECTION AND ANALYSIS: We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. MAIN RESULTS: We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. AUTHORS' CONCLUSIONS: Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening.

Antibody tests for identification of current and past infection with SARS-CoV-2.

BACKGROUND: The diagnostic challenges associated with the COVID-19 pandemic resulted in rapid development of diagnostic test methods for detecting SARS-CoV-2 infection. Serology tests to detect the presence of antibodies to SARS-CoV-2 enable detection of past infection and may detect cases of SARS-CoV-2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARS-CoV-2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARS-CoV-2 epidemiology. OBJECTIVES: To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARS-CoV-2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARS-CoV-2. Sources of heterogeneity investigated included: timing of test, test method, SARS-CoV-2 antigen used, test brand, and reference standard for non-SARS-CoV-2 cases. SEARCH METHODS: The COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) 'COVID-19: Living map of the evidence' and the Norwegian Institute of Public Health 'NIPH systematic and living map on COVID-19 evidence'. We did not apply language restrictions. SELECTION CRITERIA: We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RT-PCR test. Small studies with fewer than 25 SARS-CoV-2 infection cases were excluded. We included any reference standard to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR), clinical diagnostic criteria, and pre-pandemic samples). DATA COLLECTION AND ANALYSIS: We use standard screening procedures with three reviewers. Quality assessment (using the QUADAS-2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for meta-analysis, we fitted univariate random-effects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria. MAIN RESULTS: We included 178 separate studies (described in 177 study reports, with 45 as pre-prints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARS-CoV-2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARS-CoV-2 infection were most commonly hospital inpatients (78/178, 44%), and pre-pandemic samples were used by 45% (81/178) to estimate specificity. Over two-thirds of studies recruited participants based on known SARS-CoV-2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARS-CoV-2 vaccines and present data for naturally acquired antibody responses. Seventy-nine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzyme-linked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%). Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies. Average sensitivities for current SARS-CoV-2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot. Average specificities were consistently high and precise, particularly for pre-pandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies). Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescent-phase infection) and specific (pre-pandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spike-protein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescent-phase infection. Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity. In a low-prevalence (2%) setting, where antibody testing is used to diagnose COVID-19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARS-CoV-2 infection. In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days post-symptom onset or post-positive PCR) of SARS-CoV-2 infection. AUTHORS' CONCLUSIONS: Some antibody tests could be a useful diagnostic tool for those in whom molecular- or antigen-based tests have failed to detect the SARS-CoV-2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with post-acute sequelae of COVID-19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for sero-epidemiological purposes. The applicability of results for detection of vaccination-induced antibodies is uncertain.

Point-of-care tests for pediatric urinary tract infections in general practice: a diagnostic accuracy study.

BACKGROUND: Early diagnosis of pediatrics urinary tract infections in the outpatient settings is challenging but essential to prevent hospitalization and kidney damage. OBJECTIVE: We aimed to evaluate the diagnostic test accuracy of a selection of point-of-care tests for pediatric urinary tract infections in general practice. METHODS: A prospective cross-sectional study in 26 general practices in Flanders, Belgium (clinicaltrials.gov, NCT03835104). Urine was sampled systematically from children between 3 months to 18 years presenting with an acute illness of maximum 10 days. Samples were analyzed at the central laboratory with a routine dipstick test, the Utriplex test, the Uriscreen test and the Rapidbac as index tests, and with urine culture showing more than 105 colony-forming units per milliliter of one pathogen as reference standard. For each test, we calculated sensitivity, specificity, positive and negative likelihood ratios, and predictive values with 95% confidence intervals. RESULTS: Three-hundred urine samples were available for analysis of which 30 samples were culture positive (10%). Sensitivities and specificities were 32% (95% CI 16%-52%) and 86% (95% CI 82%-90%) for the dipstick test, 21% (95% CI 8%-40%) and 94% (95% CI 91%-97%) for the Utriplex test, 40% (95% CI 16%-68%) and 83% (95% CI 75%-88%) for the Rapidbac test, and 67% (95% CI 38%-88%) with 69% (95% CI 60%-76%) for the Uriscreen test. CONCLUSION: All 4 point-of-care tests were suboptimal for use in the broad range of children presenting with acute illnesses to general practice. General practitioners need novel methods for obtaining reliable urine samples during the time of the consultation, especially for children not yet toilet-trained.

Prospective SARS-CoV-2 cohort study among primary health care providers during the second COVID-19 wave in Flanders, Belgium.

BACKGROUND: Primary health care providers (PHCPs) are assumed to be at high risk of a COVID-19 infection, as they are exposed to patients with usually less personal protective equipment (PPE) than other frontline health care workers (HCWs). Nevertheless, current research efforts focussed on the assessment of COVID-19 seroprevalence rates in the general population or hospital HCWs. OBJECTIVE: We aimed to determine the seroprevalence in PHCPs during the second SARS-CoV-2 wave in Flanders (Belgium) and compared it to the seroprevalence in the general population. We also assessed risk factors, availability of PPE and attitudes towards the government guidelines over time. METHODS: A prospective cohort of PHCPs (n = 698), mainly general practitioners, was asked to complete a questionnaire and self-sample capillary blood by finger-pricking at five distinct points in time (June-December 2020). We analysed the dried blood spots for IgG antibodies using a Luminex multiplex immunoassay. RESULTS: The seroprevalence of PHCPs remained stable between June and September (4.6-5.0%), increased significantly from October to December (8.1-13.4%) and was significantly higher than the seroprevalence of the general population. The majority of PHCPs were concerned about becoming infected, had adequate PPE and showed increasing confidence in government guidelines. CONCLUSIONS: The marked increase in seroprevalence during the second COVID-19 wave shows that PHCPs were more at risk during the second wave compared to the first wave in Flanders. This increase was only slightly higher in PHCPs than in the general population suggesting that the occupational health measures implemented provided sufficient protection when managing patients.

Using Belgian pharmacy dispensing data to assess antibiotic use for children in ambulatory care.

BACKGROUND: The desired effect of antibiotics is compromised by the rapid escalation of antimicrobial resistance. Children are particularly at high-risk for unnecessary antibiotic prescribing, which is owing to clinicians' diagnostic uncertainty combined with parents' concerns and expectations. Recent Belgian data on ambulatory antibiotic prescribing practices for children are currently lacking. Therefore, we aim to analyse different aspects of antibiotic prescriptions for children in ambulatory care. METHODS: Pharmacy dispensing data on antibiotics for systematic use referring from 2010 to 2019 were retrieved from Farmanet, a database of pharmaceutical dispensations in community pharmacies. Population data were obtained from the Belgian statistical office (Statbel). Descriptive statistics were performed in Microsoft Excel. The Mann-Kendall test for trend analysis and the seasplot function for seasonality testing were conducted in R. RESULTS: The past decade, paediatric antibiotic use and expenditures have relatively decreased in Belgian ambulatory care with 35.5% and 44.3%, respectively. The highest volumes of antibiotics for children are prescribed by GPs working in Walloon region and rural areas, to younger children, and during winter. The most prescribed class of antibiotics for children are the penicillins and the biggest relative reduction in number of packages is seen for the sulfonamides and trimethoprim and quinolone antibacterials. CONCLUSIONS: Paediatric antibiotic use has decreased in Belgian ambulatory care. Further initiatives are needed to promote prudent antibiotic prescribing in ambulatory care.

Point-of-care C-reactive protein test results in acute infections in children in primary care: an observational study.

BACKGROUND: Acute infections are a common reason for children to consult primary care. Serious infections are rare but differentiating them from self-limiting illnesses remains challenging. This can lead to inappropriate antibiotic prescribing. Point-of-care C-reactive protein testing is used to guide antibiotic prescribing in adults. However, in children its use remains unclear. The purpose of this study was to assess point-of-care CRP test levels with respect to patients' characteristics, care setting, preliminary diagnosis, and management. METHODS: A prospective observational study was performed in children with an acute infection presenting to ambulatory care in Belgium. RESULTS: In this study 8280 cases were analysed, of which 6552 had a point-of-care CRP value available. A total of 276 physicians participated. The median patient age was 1.98 years (IQR 0.97 to 4.17), 37% of children presented to a general practitioner, 33% to a paediatric out-patient clinic, and 30% to the emergency department. A total of 131 different preliminary diagnoses were found, with acute upper airway infection as the most frequent. In 6% (n = 513) patients were diagnosed with a serious infection. The most common serious infection was pneumonia. Antibiotics were prescribed in 28% (n = 2030) of all episodes. The median CRP over all infectious episodes was 10 mg/L (IQR < 5-29). Children below 5 years of age and those presenting to a paediatrician had a higher median CRP. Median CRP in patients with serious infections was 21 mg/L (IQR 6 to 63.5). Pneumonia had a median CRP of 48 mg/L (IQR 13-113). In the episodes with antibiotics prescription, median CRP level was 29 mg/L (IQR 10-58) compared to 7 mg/L (IQR < 5-19) when they were not prescribed. CONCLUSION: A low POC CRP as a standalone tool did not seem to be sufficient to rule out serious infections, but its potential in assessing serious infections could increase when integrated in a clinical decision rule. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282 (registered on 31/12/2013).

The Risk of Endometrial Malignancy and Other Endometrial Pathology in Women with Abnormal Uterine Bleeding: An Ultrasound-Based Model Development Study by the IETA Group.

OBJECTIVES: The aim of this study was to develop a model that can discriminate between different etiologies of abnormal uterine bleeding. DESIGN: The International Endometrial Tumor Analysis 1 study is a multicenter observational diagnostic study in 18 bleeding clinics in 9 countries. Consecutive women with abnormal vaginal bleeding presenting for ultrasound examination (n = 2,417) were recruited. The histology was obtained from endometrial sampling, D&C, hysteroscopic resection, hysterectomy, or ultrasound follow-up for >1 year. METHODS: A model was developed using multinomial regression based on age, body mass index, and ultrasound predictors to distinguish between: (1) endometrial atrophy, (2) endometrial polyp or intracavitary myoma, (3) endometrial malignancy or atypical hyperplasia, (4) proliferative/secretory changes, endometritis, or hyperplasia without atypia and validated using leave-center-out cross-validation and bootstrapping. The main outcomes are the model's ability to discriminate between the four outcomes and the calibration of risk estimates. RESULTS: The median age in 2,417 women was 50 (interquartile range 43-57). 414 (17%) women had endometrial atrophy; 996 (41%) had a polyp or myoma; 155 (6%) had an endometrial malignancy or atypical hyperplasia; and 852 (35%) had proliferative/secretory changes, endometritis, or hyperplasia without atypia. The model distinguished well between malignant and benign histology (c-statistic 0.88 95% CI: 0.85-0.91) and between all benign histologies. The probabilities for each of the four outcomes were over- or underestimated depending on the centers. LIMITATIONS: Not all patients had a diagnosis based on histology. The model over- or underestimated the risk for certain outcomes in some centers, indicating local recalibration is advisable. CONCLUSIONS: The proposed model reliably distinguishes between four histological outcomes. This is the first model to discriminate between several outcomes and is the only model applicable when menopausal status is uncertain. The model could be useful for patient management and counseling, and aid in the interpretation of ultrasound findings. Future research is needed to externally validate and locally recalibrate the model.

Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis.

STUDY QUESTION: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer? SUMMARY ANSWER: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer. WHAT IS KNOWN ALREADY: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious. STUDY DESIGN, SIZE, DURATION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group. LIMITATIONS, REASONS FOR CAUTION: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: CRD42019153404.