How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis

Purpose: To compare the effectiveness of starting the ovarian stimulation on the early follicular phase (“Conventional”) with the newer range of non-conventional approaches starting in the luteal phase (“Luteal”), random-start, and studies implementing them in DuoStim (“Conventional”+“Luteal”). Methods: Systematic review. We searched CENTRAL, PubMed, and Embase, on March 2020. We included randomized and non-randomized controlled trials that compared “Luteal,” random-start ovarian stimulation or DuoStim with “Conventional”; we analyzed them by subgroups: oocyte freezing and patients undergoing ART treatments, both, in the general infertile population and among poor responders. Results: The following results come from a sensitivity analysis that included only the low/moderate risk of bias studies. When comparing “Luteal” to “Conventional,” clinically relevant differences in MII oocytes were ruled out in all subgroups. We found that “Luteal” probably increases the COH length both, in the general infertile population (OR 2.00 days, 95% CI 0.81 to 3.19, moderate-quality evidence) and in oocyte freezing cycles (MD 0.85 days, 95% CI 0.53 to 1.18, moderate-quality evidence). When analyzing DuoStim among poor responders, we found that it appears to generate a higher number of MII oocytes in comparison with a single “Conventional” (MD 3.35, 95%CI 2.54–4.15, moderate-quality evidence). Conclusion: Overall, this systematic review of the available data demonstrates that in poor responders, general infertile population and oocyte freezing for cancer stimulation in the late follicular and luteal phases can be utilized in non-conventional approaches such as random-start and DuoStim cycles, offering similar outcomes to the conventional cycles but potentially with increased flexibility, within a reduced time frame. However, more well-designed trials are required to establish certainty.Fil: Glujovsky, Demian. Centro de Estudios en Ginecología y Reproducción; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Pesce, Romina. Hospital Italiano; ArgentinaFil: Miguens, Mariana. Centro de Estudios en Ginecología y Reproducción; ArgentinaFil: Sueldo, Carlos E.. Centro de Estudios en Ginecología y Reproducción; Argentina. University Of California, San Francisco; Estados UnidosFil: Lattes, Karinna. No especifíca;Fil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentin

Quality of evidence matters: is it well reported and interpreted in infertility journals?

Purpose: To evaluate if the authors of published systematic reviews (SRs) reported the level of quality of evidence (QoE) in the top 5 impact factor infertility journals and to analyze if they used an appropriate wording to describe it. Methods: This is a cross-sectional study. We searched in PubMed for SRs published in 2017 in the five infertility journals with the highest impact factor. We analyzed the proportion of SRs published in the top 5 impact factor infertility journals that reported the SRs’ QoE, and the proportion of those SRs in which authors used consistent wording to describe QoE and magnitude of effect. Results: The QoE was reported in only 21.4% of the 42 included SRs and in less than 10% of the abstracts. Although we did not find important differences in the report of QoE of those that showed statistically significant differences or not, p value was associated with the wording chosen by the authors. We found inconsistent reporting of the size the effect estimate in 54.8% (23/42) and in the level of QoE in 92.9% (39/42). Whereas the effect size was more consistently expressed in studies with statistically significant findings, QoE was better expressed in those cases in which the p value was over 0.05. Conclusion: We found that in 2017, less than 25% of the authors reported the overall QoE when publishing SRs. Authors focused more on statistical significance as a binary concept than on methodological limitations like study design, imprecision, indirectness, inconsistency, and publication bias. Authors should make efforts to report the QoE and interpret results accordingly.Fil: Glujovsky, Demian. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Sueldo, Carlos E.. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bardach, Ariel Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: del Pilar Valanzasca, María. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Comandé, Daniel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Instituto de Efectividad Clínica y Sanitaria; Argentin

Advanced sperm selection techniques for assisted reproduction (Review)

Background: Assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) bring together gametes outside of the body to enhance the probability of fertilisation and pregnancy. Advanced sperm selection techniques are increasingly being employed in ART, most commonly in cycles utilising ICSI. Advanced sperm selection techniques are thought to improve the chance that structurally intact and mature sperm with high DNA integrity are selected for fertilisation. Advanced sperm selection strategies include selection according to surface charge; sperm apoptosis; sperm birefringence; ability to bind to hyaluronic acid; and sperm morphology under ultra-high magnification. These techniques theoretically improve ART outcomes. Objectives: To evaluate the impact of advanced sperm selection techniques on ART outcomes. Search methods: Systematic search of electronic databases (Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American and Caribbean Health Science Information Database (LILACS)), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform), conference abstracts (Web of Knowledge) and grey literature (OpenGrey) for relevant randomised controlled trials. We handsearched the reference lists of included studies and similar reviews. The search was conducted in May 2014. Selection criteria: We included randomised controlled trials (RCTs) comparing an advanced sperm selection technique versus standard IVF or ICSI or versus another advanced sperm selection technique. We excluded studies of sperm selection using ultra-high magnification (intracytoplasmic morphologically selected sperm injection, or IMSI), as they are the subject of a separate Cochrane review. Quasi-randomised and pseudo-randomised trials were excluded. Our primary outcome measure was live birth rate per woman randomly assigned. Secondary outcome measures included clinical pregnancy per woman randomly assigned, miscarriage per clinical pregnancy and fetal abnormality per clinical pregnancy. Data collection and analysis: Two review authors independently assessed eligibility of studies and risk of bias, and performed data extraction. Disagreements were resolved by consultation with a third review author. Study investigators were consulted to resolve other queries that arose. Risk ratios (RRs) were calculated with 95% confidence intervals (CIs). We planned to combine studies using a fixed-effect model, if sufficient data were available. The quality of the evidence was evaluated using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. Main results: Two RCTs were included in the review. Both evaluated sperm selection by hyaluronanic acid binding for ICSI, but only one reported live births. No studies were identified that were related to surface charge selection, sperm apoptosis or sperm birefringence. One RCT compared hyaluronanic acid binding versus conventional ICSI. Live birth was not reported. Evidence was insufficient to show whether there was a difference between groups in clinical pregnancy rates (RR 1.01, 95% CI 0.84 to 1.22, one RCT, 482 women). This evidence was deemed to be of low quality, mainly as the result of poor reporting of methods and findings. Miscarriage data were unclear, and fetal abnormality rates were not reported. The other RCT compared two different hyaluronanic acid binding techniques, SpermSlow and physiological intracytoplasmic sperm injection (PISCI). Evidence was insufficient to indicate whether there was a difference between groups in rates of live birth (RR 1.16, 95% CI 0.65 to 2.05, one RCT, 99 women), clinical pregnancy (RR 1.07, 95% CI 0.67 to 1.71, one RCT, 99 women) or miscarriage (RR 0.76, 95% CI 0.24 to 2.44, one RCT, 41 women). The evidence for these comparisons was deemed to be of low quality, as it was limited by imprecision and poor reporting of study methods. Fetal abnormality rates were not reported. Authors' conclusions: Evidence was insufficient to allow review authors to determine whether sperm selected by hyaluronanic acid binding improve live birth or pregnancy outcomes in ART, and no clear data on adverse effects were available. Evidence was also insufficient to show whether there is a difference in efficacy between the hyaluronic acid binding methods SpermSlow and PICSI. No randomised evidence evaluating sperm selection by sperm apoptosis, sperm birefringence or surface charge was found. Further studies of suitable quality are required to evaluate whether any of these advanced sperm selection techniques can be recommended for use in clinical practice

A methodological survey of the analysis, reporting and interpretation of Absolute Risk Reduction in systematic reviews (ARROW) : a study protocol

Q2Q1Protocolo1-8Background: Clinicians, providers and guideline panels use absolute effects to weigh the advantages and downsides of treatment alternatives. Relative measures have the potential to mislead readers. However, little is known about the reporting of absolute measures in systematic reviews. The objectives of our study are to determine the proportion of systematic reviews that report absolute measures of effect for the most important outcomes, and ascertain how they are analyzed, reported and interpreted. Methods/design: We will conduct a methodological survey of systematic reviews published in 2010. We will conduct a 1:1 stratified random sampling of Cochrane vs. non-Cochrane systematic reviews. We will calculate the proportion of systematic reviews reporting at least one absolute estimate of effect for the most patient-important outcome for the comparison of interest. We will conduct multivariable logistic regression analyses with the reporting of an absolute estimate of effect as the dependent variable and pre-specified study characteristics as the independent variables. For systematic reviews reporting an absolute estimate of effect, we will document the methods used for the analysis, reporting and interpretation of the absolute estimate. Discussion: Our methodological survey will inform current practices regarding reporting of absolute estimates in systematic reviews. Our findings may influence recommendations on reporting, conduct and interpretation of absolute estimates. Our results are likely to be of interest to systematic review authors, funding agencies, clinicians, guideline developers and journal editors

Developing a core outcome set for future infertility research : An international consensus development study

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form

Type-Specific HPV Prevalence in Cervical Cancer and High-Grade Lesions in Latin America and the Caribbean: Systematic Review and Meta-Analysis

Fil: Ciapponi, Agustin. Institute for Clinical Effectiveness and Health Policy (IECS); Argentina.Fil: Bardach, Ariel. Institute for Clinical Effectiveness and Health Policy (IECS); Argentina.Fil: Glujovsky, Demian. Institute for Clinical Effectiveness and Health Policy (IECS); Argentina.Fil: Gibbons, Luz. Institute for Clinical Effectiveness and Health Policy (IECS); Argentina.Fil: Picconi, María Alejandra. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Virología. Servicio Virus Oncogénicos; Argentina.Background: Cervical cancer is a major public health problem in Latin America and the Caribbean (LA&C), showing some of the highest incidence and mortality rates worldwide. Information on HPV type distribution in high-grade cervical lesions (HSIL) and invasive cervical cancer (ICC) is crucial to predict the future impact of HPV16/18 vaccines and screening programmes, and to establish an appropriate post-vaccinal virologic surveillance. The aim was to assess the prevalence of HPV types in HSIL and ICC in studies in LA&C. Methods and Findings: We performed a systematic review, following the MOOSE guidelines for systematic reviews of observational studies, and the PRISMA statement for reporting systematic reviews and meta-analyses. Inclusion criteria were at least ten cases of HSIL/ICC, and HPV-type elicitation. The search, without language restrictions, was performed in MEDLINE, Cochrane Library, EMBASE, LILACS from inception date to December 2009, proceedings, reference lists and consulting experts. A meta-analysis was performed using arc-sine transformations to stabilize the variance of simple proportions. Seventy-nine studies from 18 countries were identified, including 2446 cases of HSIL and 5540 of ICC. Overall, 46.5% of HSIL cases harbored HPV 16 and 8.9% HPV18; in ICC, 53.2% of cases harbored HPV 16 and 13.2% HPV 18. The next five most common types, in decreasing frequency, were HPV 31, 58, 33, 45, and 52. Study's limitations comprise the cross-sectional design of most included studies and their inherent risk of bias, the lack of representativeness, and variations in the HPV type-specific sensitivity of different PCR protocols. Conclusions: This study is the broadest summary of HPV type distribution in HSIL and ICC in LA&C to date. These data are essential for local decision makers regarding HPV screening and vaccination policies. Continued HPV surveillance would be useful, to assess the potential for changing type-specific HPV prevalence in the post-vaccination era in Latin America

Misleading reporting and interpretation of results in major infertility journals

Objective To evaluate the proportion of randomized controlled trials (RCTs) published in top infertility journals indexed on PubMed that reported their results with proper effect estimates and their precision estimation, while correctly interpreting both measures. Design Cross-sectional study evaluating all the RCTs published in top infertility journals during 2014. Setting Not applicable. Patient(s) Not applicable. Intervention(s) Not applicable. Main Outcome Measure(s) Proportion of RCTs that reported both relative and absolute effect size measures and its precision. Result(s) Among the 32 RCTs published in 2014 in the top infertility journals reviewed, 37.5% (95% confidence interval [CI], 21.1-56.3) did not mention in their abstracts whether the difference among the study arms was statistically or clinically significant, and only 6.3% (95% CI, 0.8-20.8) used a CI of the absolute difference. Similarly, in the results section, these elements were observed in 28.2% (95% CI, 13.7-46.7) and 15.6% (95% CI, 5.3-32.8), respectively. Only one study clearly expressed the minimal clinically important difference in their methods section, but we found related proxies in 53% (95% CI, 34.7-70.9). None of the studies used CIs to draw conclusions about the clinical or statistical significance. We found 13 studies where the interpretation of the findings could be misleading. Conclusion(s) Recommended reporting items are underused in top infertility journals, which could lead to misleading interpretations. Authors, reviewers, and editorial boards should emphasize their use to improve reporting quality.Fil: Glujovsky, Demian. Instituto de Efectividad Clínica y Sanitaria; Argentina. Centro de Reproducción y Genética Humana.; ArgentinaFil: Sueldo, Carlos. Centro de Reproducción y Genética Humana.; Argentina. University of California st San Francisco; Estados UnidosFil: Borghi, Carolina. Centro de Reproducción y Genética Humana.; ArgentinaFil: Nicotra, Pamela. Centro de Reproducción y Genética Humana.; ArgentinaFil: Andreucci, Sara. Centro de Reproducción y Genética Humana.; ArgentinaFil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; Argentin

Burden of influenza in Latin America and the Caribbean: a systematic review and meta-analysis

Fil: Savy, Vilma. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Ciapponi, Agustín. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Bardach, Ariel. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Glujovsky, Demián. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Aruj, Patricia. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Mazzoni, Agustina. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Gibbons, Luz. Instituto de Efectividad Clínica y Política de salud; Argentina.Fil: Ortega-Barria, Eduardo. GlaxoSmithKline Biologicals; Brasil.Fil: Colindres, Romulo. GlaxoSmithKline Biologicals; Brasil.Objective: Influenza causes severe morbidity and mortality. This systematic review aimed to assess the incidence, etiology, and resource usage for influenza in Latin America and the Caribbean. Design: Meta-analytic systematic review. Arcsine transformations and DerSimonian Laird random effects model were used for meta-analyses. Setting: A literature search from 1980 to 2008 in MEDLINE, Cochrane Library, EMBASE, LILACS, Ministries of Health, PAHO, proceedings, reference lists, and consulting experts. Sample: We identified 1092 references, of which 31 were finally included, in addition to influenza surveillance reports. We also used information from the 10 reports from the collaborative group for epidemiological surveillance of influenza and other respiratory virus (GROG), and information retrieved from the WHO global flu database FLUNET. Main outcome measures: Incidence, percentage of influenza specimens out of the total received by influenza centers and resource-use outcomes. Results: A total of 483 130 specimens of patients with influenza were analyzed. Meta-analysis showed an annual rate of 36 080 (95%CI 28 550 43 610) influenza-like illness per 100 000 persons-years. The percentage of influenza out of total specimens received by influenza centers ranged between 4.66% and 15.42%, with type A the most prevalent, and A subtype H3 predominating. The mean length of stay at hospital due to influenza ranged between 5.8 12.9 days, total workdays lost due to influenza-like illnesses were 17 150 days, and the mean direct cost of hospitalization was US$575 per laboratory-confirmed influenza case. Conclusions: Our data show that seasonal influenza imposes a high morbidity and economic burden to the region. However, the vaccine-uptake rate has been low in this region. Population-based cohort studies are required to improve the knowledge about incidence and resource utilization, which would inform healthcare authorities for decision making

Characteristics of Randomized Trials Published in Latin America and the Caribbean According to Funding Source

Few studies have assessed the nature and quality of randomized controlled trials (RCTs) in Latin America and the Caribbean (LAC). The aims of this systematic review are to evaluate the characteristics (including the risk of bias assessment) of RCT conducted in LAC according to funding source. A review of RCTs published in 2010 in which the author's affiliation was from LAC was performed in PubMed and LILACS. Two reviewers independently extracted data and assessed the risk of bias. The primary outcomes were risk of bias assessment and funding source. A total of 1,695 references were found in PubMed and LILACS databases, of which 526 were RCTs (N = 73.513 participants). English was the dominant publication language (93%) and most of the RCTs were published in non-LAC journals (84.2%). Only five of the 19 identified countries accounted for nearly 95% of all RCTs conducted in the region (Brazil 70.9%, Mexico 10.1%, Argentina 5.9%, Colombia 3.8%, and Chile 3.4%). Few RCTs covered priority areas related with Millennium Development Goals like maternal health (6.7%) or high priority infectious diseases (3.8%). Regarding children, 3.6% and 0.4% RCT evaluated nutrition and diarrhea interventions respectively but none pneumonia. As a comparison, aesthetic and sport related interventions account for 4.6% of all trials. A random sample of RCTs (n = 358) was assessed for funding source: exclusively public (33.8%); private (e.g. pharmaceutical company) (15.3%); other (e.g. mixed, NGO) (15.1%); no funding (35.8%). Overall assessments for risk of bias showed no statistically significant differences between RCTs and type of funding source. Statistically significant differences favoring private and others type of funding was found when assessing trial registration and conflict of interest reporting. Findings of this study could be used to provide more direction for future research to facilitate innovation, improve health outcomes or address priority health problems