Sohail Mulla

Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses

Objective To determine the relation between overweight and obesity in mothers and preterm birth and low birth weight in singleton pregnancies in developed and developing countries. Design Systematic review and meta-analyses. Data sources Medline and Embase from their inceptions, and reference lists of identified articles. Study selection Studies including a reference group of women with normal body mass index that assessed the effect of overweight and obesity on two primary outcomes: preterm birth (before 37 weeks) and low birth weight (<2500 g). Data extraction Two assessors independently reviewed titles, abstracts, and full articles, extracted data using a piloted data collection form, and assessed quality. Data synthesis 84 studies (64 cohort and 20 case-control) were included, totalling 1 095 834 women. Although the overall risk of preterm birth was similar in overweight and obese women and women of normal weight, the risk of induced preterm birth was increased in overweight and obese women (relative risk 1.30, 95% confidence interval 1.23 to 1.37). Although overall the risk of having an infant of low birth weight was decreased in overweight and obese women (0.84, 0.75 to 0.95), the decrease was greater in developing countries than in developed countries (0.58, 0.47 to 0.71 v 0.90, 0.79 to 1.01). After accounting for publication bias, the apparent protective effect of overweight and obesity on low birth weight disappeared with the addition of imputed “missing” studies (0.95, 0.85 to 1.07), whereas the risk of preterm birth appeared significantly higher in overweight and obese women (1.24, 1.13 to 1.37). Conclusions Overweight and obese women have increased risks of preterm birth and induced preterm birth and, after accounting for publication bias, appeared to have increased risks of preterm birth overall. The beneficial effects of maternal overweight and obesity on low birth weight were greater in developing countries and disappeared after accounting for publication bias.

Preterm birth and low birth weight among in vitro fertilization singletons: A systematic review and meta-analyses

Our objective was to determine the risks of preterm birth (PTB) and low birth weight (LBW) in singletons conceived through in vitro fertilization (IVF)+/-intracytoplasmic sperm injection (ICSI) compared to spontaneously conceived singletons after matching or controlling for at least maternal age. The MOOSE guidelines for meta-analysis of observational studies were followed. Medline and Embase were searched using comprehensive search strategies. Bibliographies of identified articles were reviewed. English language studies examining LBW or PTB in singletons conceived by IVF or IVF/intracytoplasmic sperm injection, compared with spontaneously conceived singletons, that matched or controlled for at least maternal age. Two reviewers independently assessed titles, abstracts, full articles and study quality and extracted data. Dichotomous data were meta-analyzed using relative risks (RR) as measures of effect size with a random effects model and for continuous data weighted mean difference was calculated. Seventeen studies were included with 31,032 singletons conceived through IVF (+/-ICSI) and 81,119 spontaneously conceived singletons. After matching or controlling for maternal age and often other factors, compared to spontaneously conceived singletons, IVF singletons had increased risks of our two primary outcomes, PTB (RR 1.84, 95% CI 1.54, 2.21) and LBW (<2500 g, RR 1.60, 95% CI 1.29, 1.98). Singletons conceived through IVF or IVF/ICSI were at increased risk for late PTB (32-36 weeks, RR 1.52, 95% CI 1.01, 2.30), moderate PTB <32-33 weeks (RR 2.27, 95% CI 1.73, 2.97), very LBW (<1500 g, RR 2.65, 95% CI 1.83, 3.84), and intrauterine growth restriction (RR 1.45, 95% CI 1.04, 2.00), lower birth weights (-97 g, 95% CI -161 g, -33 g) and shorter mean gestations (-0.6 weeks, 95% CI -0.9 weeks, -0.4 weeks). In conclusion, IVF singletons have significantly increased risks of PTB, LBW and other adverse perinatal outcomes compared to spontaneously conceived singletons after matching or controlling for maternal age at least.

Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic Review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Development of clinical practice guidelines involves making trade-offs between desirable and undesirable consequences of alternative management strategies. Although the relative value of health states to patients should provide the basis for these trade-offs, few guidelines have systematically summarized the relevant evidence. We conducted a systematic review relating to values and preferences of patients considering antithrombotic therapy. METHODS We included studies examining patient preferences for alternative approaches to antithrombotic prophylaxis and studies that examined, in the context of antithrombotic prophylaxis or treatment, how patients value alternative health states and experiences with treatment. We conducted a systematic search and compiled structured summaries of the results. Steps in the process that involved judgment were conducted in duplicate. RESULTS We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four with stroke or myocardial infarction prophylaxis, six with thrombolysis in acute stroke or myocardial infarction, and 17 with burden of antithrombotic treatment. CONCLUSION Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.

Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review

Objective To assess the reporting, extent, and handling of loss to follow-up and its potential impact on the estimates of the effect of treatment in randomised controlled trials. Design Systematic review. We calculated the percentage of trials for which the relative risk would no longer be significant under a number of assumptions about the outcomes of participants lost to follow-up. Data sources Medline search of five top general medical journals, 2005-07. Eligibility criteria Randomised controlled trials that reported a significant binary primary patient important outcome. Results Of the 235 eligible reports identified, 31 (13%) did not report whether or not loss to follow-up occurred. In reports that did give the relevant information, the median percentage of participants lost to follow-up was 6% (interquartile range 2-14%). The method by which loss to follow-up was handled was unclear in 37 studies (19%); the most commonly used method was survival analysis (66, 35%). When we varied assumptions about loss to follow-up, results of 19% of trials were no longer significant if we assumed no participants lost to follow-up had the event of interest, 17% if we assumed that all participants lost to follow-up had the event, and 58% if we assumed a worst case scenario (all participants lost to follow-up in the treatment group and none of those in the control group had the event). Under more plausible assumptions, in which the incidence of events in those lost to follow-up relative to those followed-up is higher in the intervention than control group, results of 0% to 33% trials were no longer significant. Conclusion Plausible assumptions regarding outcomes of patients lost to follow-up could change the interpretation of results of randomised controlled trials published in top medical journals.

Prevalence, Characteristics, and Publication of Discontinued Randomized Trials

IMPORTANCE The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Low gestational weight gain and the risk of preterm birth and low birthweight: a systematic review and meta‐analyses

Background. Low gestational weight gain is common, with potential adverse perinatal outcomes. Objective. To determine the relation between low gestational weight gain and preterm birth and low birthweight in singletons in developing and developed countries. Data sources. Medline, EMBASE and reference lists were searched, identifying 6 283 titles and abstracts. Methods of study selection. Following the MOOSE consensus statement, two assessors independently reviewed titles, abstracts, full articles, extracted data and assessed quality. Results. Fifty‐five studies, 37 cohort and 18 case‐control, were included, involving 3 467 638 women. In the cohort studies (crude data, generally supported where available by adjusted data and case‐control studies), women with low total gestational weight gain had increases in preterm birth <37 weeks [RR 1.64 (95%CI 1.62–1.65)], 32–36 weeks [RR 1.39 (95%CI 1.38–1.40)] and ≤32 weeks [RR 3.80 (95%CI 3.72–3.88)]. Low total gestational weight gain was associated with increased risks of low birthweight <2 500 g [RR 1.85 (95%CI 1.72–2.00)], in developing and developed countries [RR 1.84 (95%CI 1.71–1.99) and RR 3.02 (95%CI 1.37–6.63), respectively], 1 500–2 500 g [RR 2.02 (95%CI 1.88–2.17)] and <1 500 g (RR 2.00 (95%CI 1.67–2.40)]. Women with low weekly gestational weight gain were at increased risk of preterm birth [RR 1.56 (95%CI 1.26–1.94)], 32–36 weeks [RR 2.43 (95%CI 2.37–2.50)] and ≤32 weeks [RR 2.31 (95%CI 2.20–2.42)] but not low birthweight [RR 1.64 (95%CI 0.89–3.02)]. Conclusions. In this systematic review, we determined that singletons born to women with low total gestational weight gain have higher risks of preterm birth and low birthweight, with the lower the gain, the higher the risks.

How to Use a Noninferiority Trial: Users' Guides to the Medical Literature

Clinical investigators are increasingly testing treatments that have the primary benefit of decreased burden or harms relative to an existing standard. The goal of the resulting randomized trials--called noninferiority trials--is to establish that the novel treatments effectiveness is not substantially less than the existing standard. Conclusions from these trials are, however, based on noninferiority thresholds specified by authors whose judgments may not coincide with those of patients and clinicians. This article highlights issues related to validity, interpretation, and applicability of results specific to noninferiority trials. Suboptimal administration of standard treatment or exclusive reliance on the analyze-as-randomized approach that is standard for conventional superiority trials may produce misleading results in noninferiority trials. Clinicians should judge whether the novel treatments impact on effectiveness outcomes--the prime reason for wanting to prescribe it--is sufficiently close to that of standard treatment that they are comfortable substituting it for the existing standard. Trading off desirable and undesirable consequences is an individual decision: given the benefits of a novel treatment, some patients may perceive the uncertainty regarding a reduction in treatment effectiveness as acceptable while others may not.

Maternal Height and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analyses

OBJECTIVE Preterm birth (PTB) and low birth weight (LBW) are the leading causes of neonatal morbidity and mortality, but the effect of maternal height on these outcomes continues to be debated. Our objective was to determine the relationships between maternal height and PTB and LBW. DATA SOURCES Medline and EMBASE were searched from their inceptions. STUDY SELECTION Studies with a reference group that assessed the effect of maternal height on PTB (< 37 weeks) and LBW (< 2500 grams) in singletons were included. DATA EXTRACTION Data were extracted independently by two reviewers. DATA SYNTHESIS Fifty-six studies were included involving 333 505 women. In the cohort studies, the unadjusted risk of PTB in short-statured women was increased (relative risk [RR] 1.23; 95% CI 1.11 to 1.37), as was the unadjusted risk of LBW (RR 1.81; 95% CI 1.47 to 2.23), although not all of the studies with adjusted data found the same association. Maternal tall stature was not associated with PTB (unadjusted RR 0.97; 95% CI 0.82 to 1.14), although LBW was decreased (unadjusted RR 0.56; 95% CI 0.46 to 0.69), but not in the adjusted data. CONCLUSION From our complete systematic review and meta-analyses, to our knowledge the first in this area, we conclude that short-statured women have higher unadjusted risks of PTB and LBW and tall women have approximately one half the unadjusted risk of LBW of women of reference height.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

Objective To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. Design Cohort of protocols of randomised controlled trial and subsequent full journal publications. Setting Six research ethics committees in Switzerland, Germany, and Canada. Data sources 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. Results Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. Conclusions Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

High Gestational Weight Gain and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis

OBJECTIVE Many women have high gestational weight gain (GWG), but potential neonatal consequences are not yet well quantified. We sought to determine the relationship between high GWG and preterm birth (PTB) and low birth weight (LBW) in singleton births. DATA SOURCES We searched Medline and Embase and reference lists. STUDY SELECTION Two assessors independently performed all steps. We selected studies assessing high total or weekly GWG on PTB (< 37 weeks) and LBW (< 2500 grams). DATA EXTRACTION AND SYNTHESIS Thirty-eight studies, 24 cohort and 14 case-control, were included involving 2 124 907 women. Most contained unadjusted data. Women with high total GWG had a decreased risk overall of PTB < 37 weeks (relative risk [RR] 0.75; 95% CI 0.60 to 0.96), PTB 32 to 36 weeks (RR 0.70; 95% CI 0.70 to 0.71), and < 32 weeks (RR 0.87; 95% CI 0.85 to 0.90). High GWG was associated with lower risk of LBW (RR 0.64; 95% CI 0.53 to 0.78). Women with the highest GWG had lower risks of LBW (RR 0.55; 95% CI 0.32 to 0.94) than women with moderately high GWG (RR 0.73; 95% CI 0.60 to 0.89). Women with the highest weekly GWG had greater risks of PTB (RR 1.51; 95% CI 1.47 to 1.55) than women with moderately high weekly GWG (RR 1.09; 95% CI 1.05 to 1.13). Women with high weekly GWG were at increased risk of PTB 32 to 36 weeks (RR 1.14; 95% CI 1.10 to 1.17 and < 32 weeks (RR 1.81; 95% CI 1.73 to 1.90). CONCLUSION Although women with high total GWG have lower unadjusted risks of PTB and LBW, high weekly GWG is associated with increased PTB, and more adjusted studies are needed, as are more studies in obese women. Potential benefits of high GWG for the infant must be balanced against maternal risks and other known infant risks such as high birth weight.