There is life beyond the statistical significance

This article challenges the “tyranny of P-value” and promote more valuable and applicable interpretations of the results of research on health care delivery. We provide here solid arguments to retire statistical significance as the unique way to interpret results, after presenting the current state of the debate inside the scientific community. Instead, we promote reporting the much more informative confidence intervals and eventually adding exact P-values. We also provide some clues to integrate statistical and clinical significance by referring to minimal important differences and integrating the effect size of an intervention and the certainty of evidence ideally using the GRADE approach. We have argued against interpreting or reporting results as statistically significant or statistically non-significant. We recommend showing important clinical benefits with their confidence intervals in cases of point estimates compatible with results benefits and even important harms. It seems fair to report the point estimate and the more likely values along with a very clear statement of the implications of extremes of the intervals. We recommend drawing conclusions, considering the multiple factors besides P-values such as certainty of the evidence for each outcome, net benefit, economic considerations and values and preferences. We use several examples and figures to illustrate different scenarios and further suggest a wording to standardize the reporting. Several statistical measures have a role in the scientific communication of studies, but it is time to understand that there is life beyond the statistical significance. There is a great opportunity for improvement towards a more complete interpretation and to a more standardized reporting.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; ArgentinaFil: Belizan, Jose. 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; ArgentinaFil: Piaggio, Gilda. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Yaya, Sanni. Imperial College London; Reino Unido. University of Ottawa; Canad

Inter-pregnancy interval and risk of recurrent pre-eclampsia: systematic review and meta-analysis

Background: Women with a history of pre-eclampsia have a higher risk of developing pre-eclampsia in subsequentpregnancies. However, the role of the inter-pregnancy interval on this association is unclear.Objective: To explore the effect of inter-pregnancy interval on the risk of recurrent pre-eclampsia or eclampia.Search strategy: MEDLINE, EMBASE and LILACS were searched (inception to July 2015).Selection criteria: Cohort studies assessing the risk of recurrent pre-eclampsia in the immediate subsequentpregnancy according to different birth intervals.Data collection and analysis: Two reviewers independently performed screening, data extraction, methodologicaland quality assessment.Meta-analysis of adjusted odds ratios (aOR) with 95 % confidence intervals (CI) was used to measure the associationbetween various interval lengths and recurrent pre-eclampsia or eclampsia.Main results: We identified 1769 articles and finally included four studies with a total of 77,561 women. The meta-analysisof two studies showed that compared to inter-pregnancy intervals of 2?4 years, the aOR for recurrent pre-eclampsia was 1.01 [95 % CI 0.95 to 1.07, I2 0 %] with intervals of less than 2 years and 1.10 [95 % CI 1.02 to 1.19, I2 0 %] with intervals longerthan 4 years.Conclusion: Compared to inter-pregnancy intervals of 2 to 4 years, shorter intervals are not associated with an increasedrisk of recurrent pre-eclampsia but longer intervals appear to increase the risk. The results of this review should beinterpreted with caution as included studies are observational and thus subject to possible confounding factors.Keywords: Recurrence, Pre-eclampsia, Eclampsia, Inter-pregnancy interval, Birth interval, Meta-analysis, Systematic review,Birth spacing, Hypertensive disorders of pregnancyFil: Cormick, Gabriela. 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; ArgentinaFil: Betran, Ana Pilar. World Health Organization; SuizaFil: 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; ArgentinaFil: Hall, David R.. Stellenbosch University; Sudáfrica. Tygerberg Hospital; SudáfricaFil: Hofmyer, G. Justus. University of the Witwatersrand; Sudáfrica. University of Fort Hare; Sudáfrica. Walter Sisulu University; Sudáfric

Prescribed hypocaloric nutrition support for critically-ill adults

Background There are controversies about the amount of calories and the type of nutritional support that should be given to critically‐ill people. Several authors advocate the potential benefits of hypocaloric nutrition support, but the evidence is inconclusive. Objectives To assess the effects of prescribed hypocaloric nutrition support in comparison with standard nutrition support for critically‐ill adults Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, Embase and LILACS (from inception to 20 June 2017) with a specific strategy for each database. We also assessed three websites, conference proceedings and reference lists, and contacted leaders in the field and the pharmaceutical industry for undetected/unpublished studies. There was no restriction by date, language or publication status. Selection criteria We included randomized and quasi‐randomized controlled trials comparing hypocaloric nutrition support to normo‐ or hypercaloric nutrition support or no nutrition support (e.g. fasting) in adults hospitalized in intensive care units (ICUs). Data collection and analysis We used standard methodological procedures expected by Cochrane. We meta‐analysed data for comparisons in which clinical heterogeneity was low. We conducted prespecified subgroup and sensitivity analyses, and post hoc analyses, including meta‐regression. Our primary outcomes were: mortality (death occurred during the ICU and hospital stay, or 28‐ to 30‐day all‐cause mortality); length of stay (days stayed in the ICU and in the hospital); and Infectious complications. Secondary outcomes included: length of mechanical ventilation. We assessed the quality of evidence with GRADE. Main results We identified 15 trials, with a total of 3129 ICU participants from university‐associated hospitals in the USA, Colombia, Saudi Arabia, Canada, Greece, Germany and Iran. There are two ongoing studies. Participants suffered from medical and surgical conditions, with a variety of inclusion criteria. Four studies used parenteral nutrition and nine studies used only enteral nutrition; it was unclear whether the remaining two used parenteral nutrition. Most of them could not achieve the proposed caloric targets, resulting in small differences in the administered calories between intervention and control groups. Most studies were funded by the US government or non‐governmental associations, but three studies received funding from industry. Five studies did not specify their funding sources. The included studies suffered from important clinical and statistical heterogeneity. This heterogeneity did not allow us to report pooled estimates of the primary and secondary outcomes, so we have described them narratively. When comparing hypocaloric nutrition support with a control nutrition support, for hospital mortality (9 studies, 1775 participants), the risk ratios ranged from 0.23 to 5.54; for ICU mortality (4 studies, 1291 participants) the risk ratios ranged from 0.81 to 5.54, and for mortality at 30 days (7 studies, 2611 participants) the risk ratios ranged from 0.79 to 3.00. Most of these estimates included the null value. The quality of the evidence was very low due to unclear or high risk of bias, inconsistency and imprecision. Participants who received hypocaloric nutrition support compared to control nutrition support had a range of mean hospital lengths of stay of 15.70 days lower to 10.70 days higher (10 studies, 1677 participants), a range of mean ICU lengths of stay 11.00 days lower to 5.40 days higher (11 studies, 2942 participants) and a range of mean lengths of mechanical ventilation of 13.20 days lower to 8.36 days higher (12 studies, 3000 participants). The quality of the evidence for this outcome was very low due to unclear or high risk of bias in most studies, inconsistency and imprecision. The risk ratios for infectious complications (10 studies, 2804 participants) of each individual study ranged from 0.54 to 2.54. The quality of the evidence for this outcome was very low due to unclear or high risk of bias, inconsistency and imprecision We were not able to explain the causes of the observed heterogeneity using subgroup and sensitivity analyses or meta‐regression. Authors' conclusions The included studies had substantial clinical heterogeneity. We found very low‐quality evidence about the effects of prescribed hypocaloric nutrition support on mortality in hospital, in the ICU and at 30 days, as well as in length of hospital and ICU stay, infectious complications and the length of mechanical ventilation. For these outcomes there is uncertainty about the effects of prescribed hypocaloric nutrition, since the range of estimates includes both appreciable benefits and harms. Given these limitations, results must be interpreted with caution in the clinical field, considering the unclear balance of the risks and harms of this intervention. Future research addressing the clinical heterogeneity of participants and interventions, study limitations and sample size could clarify the effects of this intervention.Fil: Perman, Mario I. Hospital Italiano; ArgentinaFil: Ciapponi, Agustín. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Franco, Juan V.A.. Hospital Italiano; ArgentinaFil: Loudet, Cecilia. Universidad Nacional de La Plata; ArgentinaFil: Crivelli, Adriana. Hospital HIGA San Martín; ArgentinaFil: Garrote, Virginia. Hospital Italiano; ArgentinaFil: Perman, Gastón. Hospital Italiano; Argentin

The quality of clinical practice guidelines for preoperative care using the AGREE II instrument: A systematic review

Background: Our aim was to summarize and compare relevant recommendations from evidence-based CPGs (EB-CPGs). Methods: Systematic review of clinical practice guidelines. Data sources: PubMed, EMBase, Cochrane Library, LILACS, Tripdatabase, and additional sources. In July 2017, we searched CPGs that were published in the last 10 years, without language restrictions, in electronic databases, and also searched specific CPG sources, reference lists, and consulted experts. Pairs of independent reviewers selected EB-CPGs and rated their methodological quality using the AGREE-II instrument. We summarized recommendations, its supporting evidence, and strength of recommendations according to the GRADE methodology. Results: We included 16 EB-CPGs out of 2262 references identified. Only nine of them had searches within the last 5 years and seven used GRADE. The median (percentile 25-75) AGREE-II scores for rigor of development was 49% (35-76%) and the domain "applicability"obtained the worst score 16% (9-31%). We summarized 31 risk stratification recommendations, 21.6% of which were supported by high/moderate quality of evidence (41% of them were strong recommendations), and 16 therapeutic/preventive recommendations, 59% of which were supported by high/moderate quality of evidence (75.7% strong). We found inconsistency in ratings of evidence level. "Guidelines' applicability"and "monitoring"were the most deficient domains. Only half of the EB-CPGs were updated in the past 5 years. Conclusions: We present many strong recommendations that are ready to be considered for implementation as well as others to be interrupted, and we reveal opportunities to improve guidelines' quality.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; ArgentinaFil: Tapia López, Elena. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Virgilio, Sacha. 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; Argentin

Calcium supplementation for prevention of primary hypertension

Background: Hypertension is a major public health problem that increases the risk of cardiovascular and kidney diseases. Several studies have shown an inverse association between calcium intake and blood pressure, as small reductions in blood pressure have been shown to produce rapid reductions in vascular disease risk even in individuals with normal blood pressure ranges. This is the first update of the review to evaluate the effect of calcium supplementation in normotensive individuals as a preventive health measure. Objectives: To assess the efficacy and safety of calcium supplementation versus placebo or control for reducing blood pressure in normotensive people and for the prevention of primary hypertension. Search methods: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to September 2020: the Cochrane Hypertension Specialised Register, CENTRAL (2020, Issue 9), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and the US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. Selection criteria: We selected trials that randomised normotensive people to dietary calcium interventions such as supplementation or food fortification versus placebo or control. We excluded quasi-random designs. The primary outcomes were hypertension (defined as blood pressure ≥ 140/90 mmHg) and blood pressure measures. Data collection and analysis: Two review authors independently selected trials for inclusion, abstracted the data and assessed the risks of bias. We used the GRADE approach to assess the certainty of evidence. Main results: The 2020 updated search identified four new trials. We included a total of 20 trials with 3512 participants, however we only included 18 for the meta-analysis with 3140 participants. None of the studies reported hypertension as a dichotomous outcome. The effect on systolic and diastolic blood pressure was: mean difference (MD) -1.37 mmHg, 95% confidence interval (CI) -2.08, -0.66; 3140 participants; 18 studies; I2 = 0%, high-certainty evidence; and MD -1.45, 95% CI -2.23, -0.67; 3039 participants; 17 studies; I2 = 45%, high-certainty evidence, respectively. The effect on systolic and diastolic blood pressure for those younger than 35 years was: MD -1.86, 95% CI -3.45, -0.27; 452 participants; eight studies; I2 = 19%, moderate-certainty evidence; MD -2.50, 95% CI -4.22, -0.79; 351 participants; seven studies; I2 = 54%, moderate-certainty evidence, respectively. The effect on systolic and diastolic blood pressure for those 35 years or older was: MD -0.97, 95% CI -1.83, -0.10; 2688 participants; 10 studies; I2 = 0%, high-certainty evidence; MD -0.59, 95% CI -1.13, -0.06; 2688 participants; 10 studies; I2 = 0%, high-certainty evidence, respectively. The effect on systolic and diastolic blood pressure for women was: MD -1.25, 95% CI -2.53, 0.03; 1915 participants; eight studies; I2 = 0%, high-certainty evidence; MD -1.04, 95% CI -1.86, -0.22; 1915 participants; eight studies; I2 = 4%, high-certainty evidence, respectively. The effect on systolic and diastolic blood pressure for men was MD -2.14, 95% CI -3.71, -0.59; 507 participants; five studies; I2 = 8%, moderate-certainty evidence; MD -1.99, 95% CI -3.25, -0.74; 507 participants; five studies; I2 = 41%, moderate-certainty evidence, respectively. The effect was consistent in both genders regardless of baseline calcium intake. The effect on systolic blood pressure was: MD -0.02, 95% CI -2.23, 2.20; 302 participants; 3 studies; I2 = 0%, moderate-certainty evidence with doses less than 1000 mg; MD -1.05, 95% CI -1.91, -0.19; 2488 participants; 9 studies; I2 = 0%, high-certainty evidence with doses 1000 to 1500 mg; and MD -2.79, 95% CI -4.71, 0.86; 350 participants; 7 studies = 8; I2 = 0%, moderate-certainty evidence with doses more than 1500 mg. The effect on diastolic blood pressure was: MD -0.41, 95% CI -2.07, 1.25; 201 participants; 2 studies; I2 = 0, moderate-certainty evidence; MD -2.03, 95% CI -3.44, -0.62; 1017 participants; 8 studies; and MD -1.35, 95% CI -2.75, -0.05; 1821 participants; 8 studies; I2 = 51%, high-certainty evidence, respectively. None of the studies reported adverse events. Authors' conclusions: An increase in calcium intake slightly reduces both systolic and diastolic blood pressure in normotensive people, particularly in young people, suggesting a role in the prevention of hypertension. The effect across multiple prespecified subgroups and a possible dose response effect reinforce this conclusion. Even small reductions in blood pressure could have important health implications for reducing vascular disease. A 2 mmHg lower systolic blood pressure is predicted to produce about 10% lower stroke mortality and about 7% lower mortality from ischaemic heart disease. There is a great need for adequately-powered clinical trials randomising young people. Subgroup analysis should involve basal calcium intake, age, sex, basal blood pressure, and body mass index. We also require assessment of side effects, optimal doses and the best strategy to improve calcium intake.Fil: Cormick, Gabriela. 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; 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; ArgentinaFil: Cafferata, María Luisa. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Cormick, María Sol. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Belizan, Jose. 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

Posture and fluids for preventing post-dural puncture headache

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of posture (bed rest and different positions after a lumbar puncture) and administration of supplementary fluids on preventing post‐dural puncture headache (PDPH) in patients who underwent dural puncture for diagnostic or therapeutic causes

Overview of evidence-based clinical practice guidelines for difficult airway management in adults: a systematic review

Background : The aim of the clinical practice guidelines (CPGs) in the management of difficult airway is to provide optimal responses to a potentially life-threatening clinical problem.Objective : to summarize and compare relevant recommendations and algorithms from evidence-based CPGs (EB-CPGs).Methods : We conducted a systematic review (overview) of CPGs, following Cochrane methods. We summarized recommendations, its supporting evidence and strength of recommendations according to the GRADE methodology. In July 2018, we searched CPGs that were published in the last 10 years, without language restrictions, in electronic databases, and searched specific CPG sources, reference lists and consulted experts. We searched PubMed, EMBASE, Cochrane Library, LILACS, Tripdatabase and additional sources. Pairs of independent reviewers selected EB-CPGs and rated their methodological quality using the AGREE-II instrument. We included those EB-CPGs reporting standard methods for identification, data collection, study risk of bias assessment and recommendations’ level of evidence. Discrepancies were solved by consensus.Results: We included 11 EB-CPGs out of 2505 references identified in literature searches within the last ten years. Only three of them used the GRADE system. The domains with better performance in the AGREE-II assessment, were ‘adequate description of scoping’ and ‘objectives’ while those with worst performance were ‘‘Guidelines’ applicability’ and ‘monitoring’. As a result, only three EB-CPGs were classified as ‘Highly recommended, two as ‘Recommended’ and six as ‘Not recommended. We summarized 22 diagnostic recommendations, 22% of which were supported by high/moderate quality of evidence (41% of them were considered by developers as strong recommendations), and 16 therapeutic/preventive recommendations, 59% of which were supported by high/moderate quality of evidence (76% strong). Only half of the EB-CPGs were updated in the past five years.Conclusions : The main EB-CPGs in the management of difficult airway in anesthesia presented significant heterogeneity in terms of their quality and system of grading the evidence and strength of recommendation used, and most used their own systems. We present many strong recommendations that are ready to be considered for implementation, and we reveal opportunities to improve guidelines’ quality.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; ArgentinaFil: Perelli, Lucas. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Cohen Arazi, Hernán. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Solioz, Germán. 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; Argentin

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

Short-term exposure to particulate matter (PM10 and PM2.5), nitrogen dioxide (NO2), and ozone (O3) and all-cause and cause-specific mortality: Systematic review and meta-analysis

Background: Air pollution is a leading cause of mortality and morbidity worldwide. Short-term exposure (from one hour to days) to selected air pollutants has been associated with human mortality. This systematic review was conducted to analyse the evidence on the effects of short-term exposure to particulate matter with aerodynamic diameters less or equal than 10 and 2.5 µm (PM10, PM2.5), nitrogen dioxide (NO2), and ozone (O3), on all-cause mortality, and PM10 and PM2.5 on cardiovascular, respiratory, and cerebrovascular mortality. Methods: We included studies on human populations exposed to outdoor air pollution from any source, excluding occupational exposures. Relative risks (RRs) per 10 µg/m3 increase in air pollutants concentrations were used as the effect estimates. Heterogeneity between studies was assessed using 80% prediction intervals. Risk of bias (RoB) in individual studies was analysed using a new domain-based assessment tool, developed by a working group convened by the World Health Organization and designed specifically to evaluate RoB within eligible air pollution studies included in systematic reviews. We conducted subgroup and sensitivity analyses by age, sex, continent, study design, single or multicity studies, time lag, and RoB. The certainty of evidence was assessed for each exposure-outcome combination. The protocol for this review was registered with PROSPERO (CRD42018087749). Results: We included 196 articles in quantitative analysis. All combinations of pollutants and all-cause and cause-specific mortality were positively associated in the main analysis, and in a wide range of sensitivity analyses. The only exception was NO2, but when considering a 1-hour maximum exposure. We found positive associations between pollutants and all-cause mortality for PM10 (RR: 1.0041; 95% CI: 1.0034–1.0049), PM2.5 (RR: 1.0065; 95% CI: 1.0044–1.0086), NO2 (24-hour average) (RR: 1.0072; 95% CI: 1.0059–1.0085), and O3 (RR: 1.0043; 95% CI: 1.0034–1.0052). PM10 and PM2.5 were also positively associated with cardiovascular, respiratory, and cerebrovascular mortality. We found some degree of heterogeneity between studies in three exposure-outcome combinations, and this heterogeneity could not be explained after subgroup analysis. RoB was low or moderate in the majority of articles. The certainty of evidence was judged as high in 10 out of 11 combinations, and moderate in one combination. Conclusions: This study found evidence of a positive association between short-term exposure to PM10, PM2.5, NO2, and O3 and all-cause mortality, and between PM10 and PM2.5 and cardiovascular, respiratory and cerebrovascular mortality. These results were robust through several sensitivity analyses. In general, the level of evidence was high, meaning that we can be confident in the associations found in this study.Fil: Orellano, Pablo Wenceslao. Universidad Tecnológica Nacional. Facultad Regional San Nicolás; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Reynoso, Julieta Itati. Hospital General “San Felipe"; ArgentinaFil: Quaranta, Nancy Esther. Universidad Tecnológica Nacional. Facultad Regional San Nicolás; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; 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; 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; Argentin

Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology

Background: Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer. The rationale for blastocyst-stage transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates. Objectives: To determine whether blastocyst-stage (day 5 to 6) embryo transfer improves the live birth rate (LBR) per fresh transfer, and other associated outcomes, compared with cleavage-stage (day 2 to 3) embryo transfer. Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL, from inception to October 2021. We also searched registers of ongoing trials and the reference lists of studies retrieved. Selection criteria: We included randomised controlled trials (RCTs) which compared the effectiveness of IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer. Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were LBR per fresh transfer and cumulative clinical pregnancy rates (cCPR). Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy, high-order multiple pregnancy, miscarriage (all following first embryo transfer), failure to transfer embryos, and whether supernumerary embryos were frozen for transfer at a later date (frozen-thawed embryo transfer). We assessed the overall quality of the evidence for the main comparisons using GRADE methods. Main results: We included 32 RCTs (5821 couples or women). The live birth rate following fresh transfer was higher in the blastocyst-stage transfer group (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 to 1.51; I2 = 53%; 15 studies, 2219 women; low-quality evidence). This suggests that if 31% of women achieve live birth after fresh cleavage-stage transfer, between 32% and 41% would do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR. A post hoc analysis showed that vitrification could increase the cCPR. This is an interesting finding that warrants further investigation when more studies using vitrification are published. The CPR was also higher in the blastocyst-stage transfer group, following fresh transfer (OR 1.25, 95% CI 1.12 to 1.39; I2 = 51%; 32 studies, 5821 women; moderate-quality evidence). This suggests that if 39% of women achieve a clinical pregnancy after fresh cleavage-stage transfer, between 42% and 47% will probably do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer increases multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; I2 = 30%; 19 studies, 3019 women; low-quality evidence) or miscarriage rates (OR 1.12, 95% CI 0.90 to 1.38; I2 = 24%; 22 studies, 4208 women; low-quality evidence). This suggests that if 9% of women have a multiple pregnancy after fresh cleavage-stage transfer, between 8% and 12% would do so after fresh blastocyst-stage transfer. However, a sensitivity analysis restricted only to studies with low or 'some concerns' for risk of bias, in the subgroup of equal number of embryos transferred, showed that blastocyst transfer probably increases the multiple pregnancy rate. Embryo freezing rates (when there are frozen supernumerary embryos for transfer at a later date) were lower in the blastocyst-stage transfer group (OR 0.48, 95% CI 0.40 to 0.57; I2 = 84%; 14 studies, 2292 women; low-quality evidence). This suggests that if 60% of women have embryos frozen after cleavage-stage transfer, between 37% and 46% would do so after blastocyst-stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; I2 = 36%; 17 studies, 2577 women; moderate-quality evidence). This suggests that if 1% of women have no embryos transferred in planned fresh cleavage-stage transfer, between 2% and 4% probably have no embryos transferred in planned fresh blastocyst-stage transfer. The evidence was of low quality for most outcomes. The main limitations were serious imprecision and serious risk of bias, associated with failure to describe acceptable methods of randomisation. Authors' conclusions: There is low-quality evidence for live birth and moderate-quality evidence for clinical pregnancy that fresh blastocyst-stage transfer is associated with higher rates of both than fresh cleavage-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR derived from fresh and frozen-thawed cycles following a single oocyte retrieval. Although there is a benefit favouring blastocyst-stage transfer in fresh cycles, more evidence is needed to know whether the stage of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage. They should also evaluate women with a poor prognosis to enable those undergoing assisted reproductive technology (ART) and service providers to make well-informed decisions on the best treatment option available.Fil: Glujovsky, Demián. Centro de Estudios en Ginecología y Reproducción; ArgentinaFil: Quinteiro Retamar, Andrea Marta. Centro de Estudios en Ginecología y Reproducción; ArgentinaFil: Alvarez Sedo, Cristian Roberto. Centro de Estudios en Ginecología y Reproducción; 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; ArgentinaFil: Cornelisse, Simone. No especifíca;Fil: Blake, Deborah. No especifíca