Number Needed To Treat To Harm Research Articles

Assessing effectiveness of endoscope-assisted medial orbital wall fracture repair vs. no surgery using benefit-risk metrics and literature review

PurposesTo evaluate clinical usefulness of endoscope-assisted medial orbital wall fracture repair via the retrocaruncular approach (rc-EAMOWFR) vs. no surgery (NS), and to perform a narrative review of relevant literature. MethodsThis was a retrospective cohort study enrolling isolated medial orbital wall fracture (IMOWF) eyes presented to two German level 1 trauma centers during a 7-year interval. The predictor variable was treatment type (rc-EAMOWFR vs. NS), and the main outcomes were late enophthalmos (LE) and retrobulbar hemorrhage (RH) assessed at 9–15 posttraumatic months. Descriptive and bivariate statistics were computed at α = 95%. Binary adjustments enabled calculation of number needed to treat (NNT), to harm (NNH), and likelihood to be helped or harmed (LHH) for demonstrating benefit-risk tradeoffs. Moreover, a narrative review was also performed. ResultsThe sample comprised 502 patients (28.3% females; mean age, 46.5±19.2 years) with 541 IMOWF eyes (5.9% NS; 7.2% LE; 1.3% RH). Operated eyes had significantly lower LE events than NS eyes (symptomatic IMOWF: P < .0001; 95% confidence interval [CI], .03 to .16; NNT = 2 [95% CI, 1.1 to 6.1]; asymptomatic IMOWF: P < .0001; 95% CI, .01 to .07; NNT = 2 [95% CI, 1.1 to 1.8]). There were 7 (1.5%) RH events following rc-EAMOWFR (P = .99; 95% CI, .06 to 17.4; NNH = 68 [95% CI, 38.3 to 254.2]). LHH calculations posited that rc-EAMOWFR was 34 times more likely to prevent LE than to cause RH, regardless of fracture symptoms. Our results conformed to those of other 15 studies. ConclusionsThe results of this study suggest that all IMOWFs be treated. rc-EAMOWFR performed in every 68 IMOWFs would be at risk of one RH event, but prevent 34 eyes from LE due to untreated fractures. Nearly 72% of untreated IMOWFs develop LE after 9 months.

Benefit-risk appraisal of lip-split mandibular “swing” vs. transoral approaches to posterior oral/oropharyngeal carcinomas using number needed to treat, to harm, and likelihood to be helped or harmed

Purposes: To evaluate benefit-risk profiles of lip-split mandibular “swing” vs. transoral approaches (LS-MSA; TOA) to the American Joint Committee on Cancer (AJCC) stage I-III posterior oral/oropharyngeal carcinomas (PO/OPC). MethodsUsing a retrospective double-cohort study design, we enrolled stage I-III PO/OPC patients treated in two German medical centers during a 4-year interval. The predictor variable was surgical technique (LS-MSA/TOA), and main outcomes were complete resection with R0 margins (CR-R0), 5-year overall survival and recurrence (OS5; R5), and adverse events (AEs). Descriptive and bivariate statistics were computed with α = 95%. Benefit-risk profiles were investigated using number needed to treat (NNT), to harm (NNH), and likelihood to be helped or harmed (LLH). ResultsAt 5-year follow-ups of 202 subjects, LS-MSA caused significantly better CR-R0 (P = 0.001; NNT: 4) and fewer R5 (P = 0.003; NNT: 5), but more risks of wound dehiscence ([WD]; P = 0.01; NNH = 8), and orocutaneous fistula ([OCF]; P = 0.01; NNH: 10). LLH calculations demonstrated that LS-MSA was 2 and 1.6 times more likely to result in CR-R0 and fewer R5 than an incident of WD. There was no significant difference in OS5, postoperative infections (within 30 postoperative days) and AE domains according to the University of Washington Quality of Life questionnaire version 4 (UW-QoLv4) between the surgical approach groups. ConclusionsCompared to TOA, LS-MSA is an efficacious and tolerable intervention for inspecting and eradicating stage I-III PO/OPCs, and reducing recurrences at 5-year follow-ups. Post-LS-MSA WD and OCF require meticulous concerns and more investigations.

Blood pressure targets in adults with hypertension.

This is the first update of this review first published in 2009. When treating elevated blood pressure, doctors usually try to achieve a blood pressure target. That target is the blood pressure value below which the optimal clinical benefit is supposedly obtained. "The lower the better" approach that guided the treatment of elevated blood pressure for many years was challenged during the last decade due to lack of evidence from randomised trials supporting that strategy. For that reason, the standard blood pressure target in clinical practice during the last years has been less than 140/90 mm Hg for the general population of patients with elevated blood pressure. However, new trials published in recent years have reintroduced the idea of trying to achieve lower blood pressure targets. Therefore, it is important to know whether the benefits outweigh harms when attempting to achieve targets lower than the standard target. The primary objective was to determine if lower blood pressure targets (any target less than or equal to 135/85 mm Hg) are associated with reduction in mortality and morbidity as compared with standard blood pressure targets (less than or equal to 140/ 90 mm Hg) for the treatment of patients with chronic arterial hypertension. The secondary objectives were: to determine if there is a change in mean achieved systolic blood pressure (SBP) and diastolic blood pressure (DBP associated with "lower targets" as compared with "standard targets" in patients with chronic arterial hypertension; and to determine if there is a change in withdrawals due to adverse events with "lower targets" as compared with "standard targets", in patients with elevated blood pressure. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up toMay 2019: the Cochrane Hypertension Specialised Register, CENTRAL (2019, Issue 4), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. Randomised controlled trials (RCTs) comparing patients allocated to lower or to standard blood pressure targets (see above). Two review authors (JAA, VL) independently assessed the included trials and extracted data. Primary outcomes were total mortality; total serious adverse events; myocardial infarction, stroke, congestive heart failure, end stage renal disease, and other serious adverse events. Secondary outcomes were achieved mean SBP and DBP, withdrawals due to adverse effects, and mean number of antihypertensive drugs used. We assessed the risk of bias of each trial using the Cochrane risk of bias tool and the certainty of the evidence using the GRADE approach. MAIN RESULTS: This update includes 11 RCTs involving 38,688 participants with a mean follow-up of 3.7 years. This represents 7new RCTs compared with the original version. At baseline the mean weighted age was 63.1 years and the mean weighted blood pressure was 155/91 mm Hg. Lower targets do not reduce total mortality (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.05; 11 trials, 38,688 participants; high-certainty evidence) and do not reduce total serious adverse events (RR 1.04, 95% CI 0.99 to 1.08; 6 trials, 18,165 participants; moderate-certainty evidence). This means that the benefits of lower targets do not outweigh the harms as compared to standard blood pressure targets. Lower targets may reduce myocardial infarction (RR 0.84, 95% CI 0.73 to 0.96; 6 trials, 18,938 participants,absolute risk reduction (ARR) 0.4%, number needed to treat to benefit (NNTB) 250 over 3.7 years) and congestive heart failure (RR 0.75, 95% CI 0.60 to 0.92; 5 trials, 15,859 participants,ARR 0.6%, NNTB167 over 3.7 years) (low-certainty for both outcomes). Reduction in myocardial infarction and congestive heart failure was not reflected in total serious adverse events. This may be due to an increase in other serious adverse events (RR 1.44, 95% CI 1.32 to 1.59; 6 trials. 18,938 participants,absolute risk increase (ARI) 3%, number needed to treat to harm (NNTH) 33 over four years) (low-certainty evidence). Participants assigned to a "lower" target received one additional antihypertensive medication and achieved a significantly lower mean SBP (122.8 mm Hg versus 135.0 mm Hg,and a lower mean DBP (82.0 mm Hg versus 85.2 mm Hg,than those assigned to "standard target". For the general population of persons with elevated blood pressure, the benefits of trying to achieve a lower blood pressure target rather than a standard target (≤ 140/90 mm Hg) do not outweigh the harms associated with that intervention. Further research is needed to see if some groups of patients would benefit or be harmed by lower targets. The results of this review are primarily applicable to older people with moderate to high cardiovascular risk. They may not be applicable to other populations.

Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants. The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2ViewTM as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp). Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age). The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I2) test. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I2 = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I2 = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.

Abstract 11: Assessing the True ImpACT-24B: Magnitude of Benefit of Sphenopalatine Ganglion Stimulation for Acute Ischemic Stroke with Confirmed Cortical Involvement

Background: Sphenopalatine ganglion (SPG) stimulation enhances collateral flow, stabilizes blood-brain barrier, and showed evidence of benefit in patients with confirmed cortical involvement (CCI) when started 8-24h after onset in the ImpACT-24B randomized trial. To characterize SPG stimulation benefit magnitude, we derived number needed to treat (NNT) values based on shifts over all levels of 3 month global disability. Methods: From the distribution of the 7-level modified Rankin Scale (mRS) at 3m in SPG- and sham-stimulation CCI patients, NNT to benefit (NNTB) and NNT to harm (NNTH) values were derived by automated (algorithmic min-max) and expert generation of joint outcome distribution tables. For dichotomized mRS outcomes, net NNT values were derived directly from absolute risk differences. Results: Among 520 patients with confirmed cortical infarction ineligible for thrombolysis, 244 were treated with SPG and 276 with sham stimulation. NNT values for dichotomized and shift mRS outcomes are shown in the Table. Of the 6 possible binary cutpoints on the mRS, 4 showed more favorable outcome with SPG stimulation. The dichotomized endpoint with the greatest group difference was ambulatory and capable of bodily self-care (mRS 0-3), 62.3% vs 51.1%, NNTB 8.9. Across all 6 individual possible dichotomizations of the mRS, the NNTB ranged from 8.9 to -166.7. For shifts by 1 or more levels across all 6 transitions of the mRS, the biologically most plausible NNTB was 5.7 (IQR 5.6-6.5), NNTH 34.5 (IQR 30.3-40.0), and net NNTB 6.8 (IQR 6.5-7.7), These values correlated closely with the automatically derived net NNTB of 5.9. Conclusions: The findings of this pivotal trial indicate that, out of every 1000 CCI patients treated with SPG stimulation, 146 patients will have a less disabled 3-month outcome, including 76 more who will be functionally independent. SPG stimulation can substantially improve the outcome of thrombolysis-ineligible acute ischemic stroke patients.

Trastuzumab combined with doublet or single-agent chemotherapy as a first-line treatment for HER2-positive metastatic breast cancer.

e12511 Background: To investigate the efficacy and safety of doublet vs. single-agent chemotherapy (CT) plus trastuzumab as first-line treatments for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC). Methods: We searched for randomized clinical trials (RCTs) that investigated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcome measures for this analysis included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Meta-analyses and trial sequential analyses (TSA) were conducted. The study quality was evaluated using the GRADE framework. The PROSPERO registry number is CRD42016043766. Results: The results from four RCTs that included 1,044 participants were pooled. Moderate-quality evidence indicated that doublet CT+H better correlated with prolonged PFS (hazard ratio [HR] = 0.69, 95% confidence interval (CI) 0.63 to 0.75, P &lt; 0.0001) and OS (HR = 0.90, 95% CI 0.88 to 0.92, P &lt; 0.0001) than did single-agent CT+H; however, moderate-quality evidence indicated there was no significant difference between the two drug regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98 to 1.17, P = 0.157), as confirmed by TSA, which indicated that the cumulative Z-curve entered the futility area. There was moderate-quality evidence that the treatment-related grade 3 to 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000; number needed to treat to harm (NNTH) = 20), nausea/vomiting (RR = 4.26, P = 0.002; NNTH = 25), diarrhea (RR = 2.81, P = 0.002; NNTH = 25), and stomatitis (RR = 5.02, P= 0.003; NNTH = 25) were more frequent with doublet CT+H than single-agent CT+H. Conclusions: Doublet CT+H is associated with longer PFS and OS than single-agent CT+H when used as a first-line therapy for HER2-positive MBC.

Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis.

This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks, and benefit-risk ratios of disease-modifying treatments (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS). In May 2016, we conducted a systematic review using the PubMed and Cochrane Central Register of Controlled Trials databases to identify phase III, randomized controlled trials with a duration of ≥2 years that assessed first-line (dimethyl fumarate [DMF], glatiramer acetate [GA], β-interferons [IFN], and teriflunomide) or second-line (alemtuzumab, fingolimod, and natalizumab) DMTs in patients with RRMS. Meta-analyses were performed to estimate relative risks (RRs) on annualized relapse rate (ARR), proportion of relapse-free patients (PPR-F), disability progression (PP-F-CDPS3M), and safety outcomes. NNTB and NNTH values were calculated applying RRs to control event rates. LHH was calculated as NNTH/NNTB ratio. The lowest NNTBs on ARR, PPR-F, and PP-F-CDPS3M were found with IFN-β-1a-SC (NNTB 3, 95% CI 2-4; NNTB 7, 95% CI 4-18; NNTB 4, 95% CI 3-7, respectively) and natalizumab (NNTB 2, 95% CI 2-3; NNTB 4, 95% CI 3-6; NNTB 9, 95% CI 6-19, respectively). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14, 95% 2-426) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22, 95% 17-41). LHHs >1 were more frequent with IFN-β-1a-SC and natalizumab. These metrics may be valuable for benefit-risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B (versus a common comparator in trial A and trial B, respectively) does not necessarily mean that the number of patients needed to be treated for one patient to encounter one aditional outcome of interest over a defined period of time is lower with drug A than with drug B. Overall, IFN-β-1a-SC and natalizumab seem to have the most favorable benefit-risk ratios among first- and second-line DMTs, respectively.

Antibiotics for otitis media with effusion in children.

Otitis media with effusion (OME) is characterised by an accumulation of fluid in the middle ear behind an intact tympanic membrane, without the symptoms or signs of acute infection. Since most cases of OME will resolve spontaneously, only children with persistent middle ear effusion and associated hearing loss potentially require treatment. Previous Cochrane reviews have focused on the effectiveness of ventilation tube insertion, adenoidectomy, nasal autoinflation, antihistamines, decongestants and corticosteroids in OME. This review, focusing on the effectiveness of antibiotics in children with OME, is an update of a Cochrane review published in 2012. To assess the benefits and harms of oral antibiotics in children up to 18 years with OME. The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 3); PubMed; Ovid EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 April 2016. Randomised controlled trials comparing oral antibiotics with placebo, no treatment or therapy of unproven effectiveness in children with OME. We used the standard methodological procedures expected by Cochrane. Twenty-five trials (3663 children) were eligible for inclusion. Two trials did not report on any of the outcomes of interest, leaving 23 trials (3258 children) covering a range of antibiotics, participants, outcome measures and time points for evaluation. Overall, we assessed most studies as being at low to moderate risk of bias.We found moderate quality evidence (six trials including 484 children) that children treated with oral antibiotics are more likely to have complete resolution at two to three months post-randomisation (primary outcome) than those allocated to the control treatment (risk ratio (RR) 2.00, 95% confidence interval (CI) 1.58 to 2.53; number needed to treat to benefit (NNTB) 5). However, there is evidence (albeit of low quality; five trials, 742 children) indicating that children treated with oral antibiotics are more likely to experience diarrhoea, vomiting or skin rash (primary outcome) than those allocated to control treatment (RR 2.15, 95% CI 1.29 to 3.60; number needed to treat to harm (NNTH) 20).In respect of the secondary outcome of complete resolution at any time point, we found low to moderate quality evidence from five meta-analyses, including between two and 14 trials, of a beneficial effect of antibiotics, with a NNTB ranging from 3 to 7. Time periods ranged from 10 to 14 days to six months.In terms of other secondary outcomes, only two trials (849 children) reported on hearing levels at two to four weeks and found conflicting results. None of the trials reported data on speech, language and cognitive development or quality of life. Low quality evidence did not show that oral antibiotics were associated with a decrease in the rate of ventilation tube insertion (two trials, 121 children) or in tympanic membrane sequelae (one trial, 103 children), while low quality evidence indicated that children treated with antibiotics were less likely to have acute otitis media episodes within four to eight weeks (five trials, 1086 children; NNTB 18) and within six months post-randomisation (two trials, 199 children; NNTB 5). It should, however, be noted that the beneficial effect of oral antibiotics on acute otitis media episodes within four to eight weeks was no longer significant when we excluded studies with high risk of bias. This review presents evidence of both benefits and harms associated with the use of oral antibiotics to treat children up to 16 years with OME. Although evidence indicates that oral antibiotics are associated with an increased chance of complete resolution of OME at various time points, we also found evidence that these children are more likely to experience diarrhoea, vomiting or skin rash. The impact of antibiotics on short-term hearing is uncertain and low quality evidence did not show that oral antibiotics were associated with fewer ventilation tube insertions. Furthermore, we found no data on the impact of antibiotics on other important outcomes such as speech, language and cognitive development or quality of life.Even in situations where clear and relevant benefits of oral antibiotics have been demonstrated, these must always be carefully balanced against adverse effects and the emergence of bacterial resistance. This has specifically been linked to the widespread use of antibiotics for common conditions such as otitis media.

Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome.

A wide variety of surfactant preparations have been developed and tested including synthetic surfactants and surfactants derived from animal sources. Although clinical trials have demonstrated that both synthetic surfactant and animal derived surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of animal derived surfactant products, perhaps due to the protein content of animal derived surfactant. To compare the effect of animal derived surfactant to protein free synthetic surfactant preparations in preterm infants at risk for or having respiratory distress syndrome (RDS). Searches were updated of the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014), PubMed, CINAHL and EMBASE (1975 through November 2014). All languages were included. Randomized controlled trials comparing administration of protein free synthetic surfactants to administration of animal derived surfactant extracts in preterm infants at risk for or having respiratory distress syndrome were considered for this review. Data collection and analysis were conducted according to the standards of the Cochrane Neonatal Review Group. Fifteen trials met the inclusion criteria. The meta-analysis showed that the use of animal derived surfactant rather than protein free synthetic surfactant resulted in a significant reduction in the risk of pneumothorax [typical relative risk (RR) 0.65, 95% CI 0.55 to 0.77; typical risk difference (RD) -0.04, 95% CI -0.06 to -0.02; number needed to treat to benefit (NNTB) 25; 11 studies, 5356 infants] and a marginal reduction in the risk of mortality (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD -0.02, 95% CI -0.04 to -0.00; NNTB 50; 13 studies, 5413 infants).Animal derived surfactant was associated with an increase in the risk of necrotizing enterocolitis [typical RR 1.38, 95% CI 1.08 to 1.76; typical RD 0.02, 95% CI 0.01 to 0.04; number needed to treat to harm (NNTH) 50; 8 studies, 3462 infants] and a marginal increase in the risk of any intraventricular hemorrhage (typical RR 1.07, 95% CI 0.99 to 1.15; typical RD 0.02, 95% CI 0.00 to 0.05; 10 studies, 5045 infants) but no increase in Grade 3 to 4 intraventricular hemorrhage (typical RR 1.08, 95% CI 0.91 to 1.27; typical RD 0.01, 95% CI -0.01 to 0.03; 9 studies, 4241 infants).The meta-analyses supported a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of animal derived surfactant preparations (typical RR 0.95, 95% CI 0.91 to 1.00; typical RD -0.03, 95% CI -0.06 to 0.00; 6 studies, 3811 infants). No other relevant differences in outcomes were noted. Both animal derived surfactant extracts and protein free synthetic surfactant extracts are effective in the treatment and prevention of respiratory distress syndrome. Comparative trials demonstrate greater early improvement in the requirement for ventilator support, fewer pneumothoraces, and fewer deaths associated with animal derived surfactant extract treatment. Animal derived surfactant may be associated with an increase in necrotizing enterocolitis and intraventricular hemorrhage, though the more serious hemorrhages (Grade 3 and 4) are not increased. Despite these concerns, animal derived surfactant extracts would seem to be the more desirable choice when compared to currently available protein free synthetic surfactants.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

Atrial fibrillation is the most frequent sustained arrhythmia. Atrial fibrillation frequently recurs after restoration of normal sinus rhythm. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear. This is an update of a review previously published in 2008 and 2012. To determine in patients who have recovered sinus rhythm after having atrial fibrillation, the effects of long-term treatment with antiarrhythmic drugs on death, stroke, embolism, drug adverse effects and recurrence of atrial fibrillation. We updated the searches of CENTRAL in The Cochrane Library (2013, Issue 12 of 12), MEDLINE (to January 2014) and EMBASE (to January 2014). The reference lists of retrieved articles, recent reviews and meta-analyses were checked. Two independent authors selected randomised controlled trials comparing any antiarrhythmic drug with a control (no treatment, placebo, drugs for rate control) or with another antiarrhythmic drug in adults who had atrial fibrillation and in whom sinus rhythm was restored. Post-operative atrial fibrillation was excluded. Two authors independently assessed quality and extracted data. Studies were pooled, if appropriate, using Peto odds ratio (OR). All results were calculated at one year of follow-up. In this update three new studies, with 534 patients, were included making a total of 59 included studies comprising 21,305 patients. All included studies were randomised controlled trials. Allocation concealment was adequate in 17 trials, it was unclear in the remaining 42 trials. Risk of bias was assessed in all domains only in the trials included in this update.Compared with controls, class IA drugs quinidine and disopyramide (OR 2.39, 95% confidence interval (95% CI) 1.03 to 5.59, number needed to treat to harm (NNTH) 109, 95% CI 34 to 4985) and sotalol (OR 2.23, 95% CI 1.1 to 4.50, NNTH 169, 95% CI 60 to 2068) were associated with increased all-cause mortality. Other antiarrhythmics did not seem to modify mortality, but our data could be underpowered to detect mild increases in mortality for several of the drugs studied.Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of atrial fibrillation (OR 0.19 to 0.70, number needed to treat to beneft (NNTB) 3 to 16). Beta-blockers (metoprolol) also significantly reduced atrial fibrillation recurrences (OR 0.62, 95% CI 0.44 to 0.88, NNTB 9).All analysed drugs increased withdrawals due to adverse affects and all but amiodarone, dronedarone and propafenone increased pro-arrhythmia. Only 11 trials reported data on stroke. None of them found any significant difference with the exception of a single trial than found less strokes in the group treated with dronedarone compared to placebo. This finding was not confirmed in others studies on dronedarone.We could not analyse heart failure and use of anticoagulation because few original studies reported on these measures. Several class IA, IC and III drugs, as well as class II drugs (beta-blockers), are moderately effective in maintaining sinus rhythm after conversion of atrial fibrillation. However, they increase adverse events, including pro-arrhythmia, and some of them (disopyramide, quinidine and sotalol) may increase mortality. Possible benefits on clinically relevant outcomes (stroke, embolism, heart failure) remain to be established.

Glutamine supplementation for critically ill adults.

Glutamine supplementation for critically ill adults.

Colchicine for acute gout.

Colchicine for acute gout.

Calcium channel blockers for inhibiting preterm labour and birth.

Calcium channel blockers for inhibiting preterm labour and birth.

Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of early initiation of EPO or darepoetin (initiated before eight days after birth) in reducing red blood cell (RBC) transfusions in preterm and/orlow birth weight infants. The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of identified trials and reviews, Pediatric Academic Societies Annual meetings 2000 to 2013 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp) were searched in July 2013. Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weightinfants. The methods of the Neonatal Cochrane Review Group were used. The updated review includes 27 studies enrolling 2209 infants. One study enrolling infants at a mean age of > eight days and one duplicate publication were excluded. One new study using darepoetin was identified.Early EPO reduced the risk of the 'use of one or more RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.73 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I(2) = 54% for both; number needed to treat to benefit (NNTB) 7, 95% CI 6 to 10; 16 studies, 1661 infants).The total volume of RBCs transfused per infant was reduced (typical mean difference (MD) 7 mL/kg, 95% CI -12 to - 2; I(2) = 63%; 7 studies, 581 infants). The number of RBC transfusions per infant was minimally reduced (typical MD -0.27, 95% CI -0.42 to -0.12; I(2) = 64%; 13 studies, 951 infants). The number of donors to whom the infants were exposed was significantly reduced (MD-0.54, 95% CI -0.89 to -0.20; I(2) = 0%; 3 studies, 254 infants).There was a non-significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.37, 95% CI 0.87 to 2.17; I(2) = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I(2) = 29%; 7 studies, 801 infants). A post hoc analysis including all studies that reported on ROP stage ≥ 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I(2) = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I(2) = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity). In an Italian study in which the authors compared the use of early intravenous EPO with subcutaneous EPO the overall incidence of stage ≥ 3 was 15%, similar to the incidence of 17% in the study by Romagnoli and co-workers.The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months varied. Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure after study entry. The small reductions are likely to be of limited clinical importance. Donor exposure is probably not avoided since all but one study included infants who had received RBC transfusions prior to trial entry. In this update there was no significant increase in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age. In a post hoc analysis including all studies that reported on ROP stage ≥ 3 regardless of age at initiation of treatment there was an increased risk of ROP. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months vary in the studies published to date. Ongoing research should deal with the issue of ROP and evaluate current clinical practice that will limit donor exposure. Due to the limited benefits and the possibly increased risk of ROP, administration of EPO is not recommended. Darbepoetin requires further study. The possible neuroprotective role of EPO in neonates will be reviewed in separate Cochrane reviews.

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2013. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2013 (Abstracts2View™) and clinical trials registries (www.clinicaltrials.gov; www.controlled-trials.com; and who.int/ictrp/en). For this update we moved one study from the early EPO review to this late EPO review. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We include 30 studies (31 comparisons) randomising 1591 preterm infants. Literature searches in 2013 did not identify any new study for inclusion. For this update we moved one study enrolling 230 infants from the early EPO review to this late EPO review.Most included trials were of small sample size. The meta-analysis showed a significant effect of the use of one or more RBC transfusions (20 studies (n = 1142); typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 68%; RD I² = 60%). We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants]. There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was minimal heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). There were no significant differences in other clinical outcomes. There was no reduction in necrotizing enterocolitis in spite of a reduction in the use of RBC transfusions. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (ml/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Neuraminidase inhibitors for preventing and treating influenza in adults and children.

© 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Background: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. Objectives: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. Main results: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). Authors' conclusions: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials...

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically world wide. OBJECTIVE: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. METHODS Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospital stations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).

Vaccines for preventing herpes zoster in older adults.

BACKGROUND: Herpes zoster or, as it is commonly called, 'shingles' is a neurocutaneous disease characterised by the reactivation of varicella zoster virus (VZV), the virus that causes chickenpox, which is latent in the dorsal spinal ganglia when immunity to VZV declines. It is an extremely painful condition which can often last for many weeks or months, impairing the patient's quality of life. The natural aging process is associated with a reduction of cellular immunity which predisposes to herpes zoster. Vaccination with an attenuated form of VZV activates specific T cell production, therefore avoiding viral reactivation. A herpes zoster vaccine with an active virus has been approved for clinical use among older adults by the Food and Drug Administration and has been tested in large populations. OBJECTIVE: To evaluate the effectiveness and safety of vaccination for preventing herpes zoster in older adults. METHODS Search methods: We searched the following sources for relevant studies: CENTRAL 2012, Issue 7, MEDLINE (1948 to July week 1, 2012), EMBASE (2010 to July 2012), LILACS (1982 to July 2012) and CINAHL (1981 to July 2012). We also reviewed reference lists of identified trials and reviews for additional studies. Selection criteria: Randomised controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine with placebo or no vaccine, to prevent herpes zoster in older adults (mean age > 60 years). Data collection and analysis: Two review authors independently collected and analysed data using a data extraction form. They also carried out an assessment of risk of bias. MAIN RESULTS: We identified eight RCTs with a total of 52,269 participants. Three studies were classified at low risk of bias. The main outcomes on effectiveness and safety were extracted from one clinical trial with a low risk of bias. Four studies compared zoster vaccine versus placebo; one study compared high-potency zoster vaccine versus low-potency zoster vaccine; one study compared refrigerated zoster vaccine versus frozen zoster vaccine; one study compared live zoster vaccine versus inactivated zoster vaccine and one study compared zoster vaccine versus pneumococcal polysaccharide vaccine (pneumo 23). Confirmed cases of herpes zoster were less frequent in patients who received the vaccine than in those who received a placebo: risk ratio (RR) 0.49 (95% confidence interval (CI) 0.43 to 0.56), with a risk difference (RD) of 2%, and number needed to treat to benefit (NNTB) of 50. Analyses according to age groups indicated a greater benefit in participants aged 60 to 69 years, RR 0.36 (95% CI 0.30 to 0.45) and in participants aged 70 years and over, RR 0.63 (95% CI 0.53 to 0.75). Vaccine-related systemic adverse effects were more frequent in the vaccinated group (RR 1.29, 95% CI 1.05 to 1.57, number needed to treat to harm (NNTH) = 100). The pooled data risk ratio for adverse effects for participants with one or more inoculation site adverse effect was RR 4.51 (95% CI 2.35 to 8.68), and the NNTH was 2.8 (95% CI 2.3 to 3.4). Side effects were more frequent in younger (60 to 69 years) than in older (70 years and over) participants. AUTHORS' CONCLUSIONS: Herpes zoster vaccine is effective in preventing herpes zoster disease. Although vaccine benefits are larger in the younger age group (60 to 69 years), this is also the age group with more adverse events. In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity.

Prophylactic antibiotics for inhibiting preterm labour with intact membranes

The aetiology of preterm birth is complex and there is evidence that subclinical genital tract infection influences preterm labour in some women but the role of prophylactic antibiotic treatment in the management of preterm labour is controversial. Since rupture of the membranes is an important factor in the progression of preterm labour, it is important to see if the routine administration of antibiotics confers any benefit or causes harm, prior to membrane rupture. To assess the effects of prophylactic antibiotics administered to women in preterm labour with intact membranes, on maternal and neonatal outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013). Randomised trials that compared antibiotic treatment with placebo or no treatment for women in preterm labour (between 20 and 36 weeks' gestation) with intact membranes. Two review authors independently assessed trial eligibility, and undertook quality assessment and data extraction. We contacted study authors for additional information. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with their respective 95% confidence intervals (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) was calculated where appropriate. In this update (2013), with the addition of three trials (305 women), the large ORACLE II 2001 trial continues to dominate the results of this review. This review now includes a total of 14 studies randomising 7837 women. No significant difference was shown in perinatal or infant mortality for infants of women allocated to any prophylactic antibiotics compared with no antibiotics. However, an increase in neonatal deaths was shown for infants of women receiving any prophylactic antibiotics when compared with placebo (RR 1.57, 95% CI 1.03 to 2.40; NNTH 149, 95% CI 2500 to 61). No reduction in preterm birth or other clinically important short-term outcomes for the infant were shown.Long-term child outcomes to seven years of age were available for infants in the UK enrolled in the ORACLE II trial. Comparing any antibiotics with placebo, a marginally non-statistically significant increase was shown in any functional impairment (RR 1.10, 95% CI 0.99 to 1.23) and cerebral palsy (CP) (RR 1.82, 95% CI 0.99 to 3.34). In subgroup analysis, CP was statistically significantly increased for infants of women allocated to macrolide and beta-lactam antibiotics combined compared with placebo (RR 2.83, 95% CI 1.02 to 7.88; NNTH 35, 95% CI 333 to 9).Further, exposure to any macrolide antibiotics (including erythromycin alone or erythromycin plus co-amoxiclav) versus no macrolide antibiotics (including placebo and co-amoxiclav alone) was shown to increase neonatal death (RR 1.52, 95% CI 1.05 to 2.19; NNTH 139, 95% CI 1429 to 61), any functional impairment (RR 1.11, 95% CI 1.01 to 1.20; NNTH 24, 95% CI 263 to 13) and CP (RR 1.90, 95% CI 1.20 to 3.01; NNTH 64, 95% CI 286 to 29). Exposure to any beta-lactam (beta-lactam alone or in combination with macrolide antibiotics) versus no beta-lactam antibiotics resulted in more neonatal deaths (RR 1.51, 95% CI 1.06 to 2.15; NNTH 143, 95% CI 1250 to 63) and CP (RR 1.67, 95% CI 1.06 to 2.61; NNTH 79, 95% CI 909 to 33), however no difference was shown in functional impairment.Maternal infection was reduced with the use of any prophylactic antibiotics compared with placebo (RR 0.74, 95% CI 0.63 to 0.86; NNTB 34, 95% CI 24 to 63) and any beta-lactam compared with no beta-lactam antibiotics (RR 0.80, 95% CI 0.69 to 0.92; NNTB 47, 95% CI 31 to 119). However, caution should be exercised with this finding due to the possibility of bias shown by funnel plot asymmetry. Any beta-lactam compared with no beta-lactam antibiotics was associated with an increase in maternal adverse drug reaction (RR 1.61, 95% CI 1.02 to 2.54; NNTH 17, 95% CI 526 to 7). This review did not demonstrate any benefit in important neonatal outcomes with the use of prophylactic antibiotics for women in preterm labour with intact membranes, although maternal infection may be reduced. Of concern, is the finding of short- and longer-term harm for children of mothers exposed to antibiotics. The evidence supports not giving antibiotics routinely to women in preterm labour with intact membranes in the absence of overt signs of infection.Further research is required to develop sensitive markers of subclinical infection for women in preterm labour with intact membranes, as this is a group that might benefit from future novel interventions, including new modalities of antibiotic therapy. The results of this review demonstrate the need for future trials in the area of preterm birth to include assessment of long-term neurodevelopmental outcome.