Hannah Fraser

Adverse events in women and children who have received intrapartum antibiotic prophylaxis treatment : a systematic review.

BackgroundAdverse events from intrapartum antibiotic prophylaxis (IAP) are poorly documented yet essential to inform clinical practice for neonatal group B Streptococcus (GBS) disease prevention. In this systematic review, we appraised and synthesised the evidence on the adverse events of IAP in the mother and/or her child.MethodsWe searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane, and Science Citation Index from date of inception until October 16th 2016. Reference lists of included studies and relevant systematic reviews were hand-searched. We included primary studies in English that reported any adverse events from intrapartum antibiotics for any prophylactic purpose compared to controls. The search was not restricted to prophylaxis for GBS but excluded women with symptoms of infection or undergoing caesarean section. Two reviewers assessed the methodological quality of studies, using the Cochrane Risk of Bias tool, and the Risk of Bias Assessment Tool for Nonrandomised Studies. Results were synthesised narratively and displayed in text and tables.ResultsFrom 2364 unique records, 30 studies were included. Despite a wide range of adverse events reported in 17 observational studies and 13 randomised controlled trials (RCTs), the evidence was inconsistent and at high risk of bias. Only one RCT investigated the long-term effects of IAP reporting potentially serious outcomes such as cerebral palsy; however, it had limited applicability and unclear biological plausibility. Seven observational studies showed that IAP for maternal GBS colonisation alters the infant microbiome. However, study populations were not followed through to clinical outcomes, therefore clinical significance is unknown. There was also observational evidence for increased antimicrobial resistance, however studies were at high or unclear risk of bias.ConclusionsThe evidence base to determine the frequency of adverse events from intrapartum antibiotic prophylaxis for neonatal GBS disease prevention is limited. As RCTs may not be possible, large, better quality, and longitudinal observational studies across countries with widespread IAP could fill this gap.Trial registrationCRD42016037195.

Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy

BackgroundTyrosinemia type 1 is an autosomal recessive disorder of amino acid metabolism. Without treatment, death in childhood is common. Treatment with nitisinone and dietary restrictions are associated with improved outcomes; some studies suggest better outcomes when treatment begins at an asymptomatic stage. Newborn screening allows for earlier identification, but there is uncertainty regarding the test accuracy of the current method: succinylacetone measurement in dried blood spots using tandem mass spectrometry.MethodsWe conducted a systematic review of literature published up to January 2016. Two reviewers independently assessed titles, abstracts, full texts, and conducted quality appraisals. A single reviewer extracted data, which was checked by a second reviewer.ResultsTen studies provided test accuracy data: five studies reporting screening experiences and five case–control studies. Sensitivity (29 cases in total) and specificity (34,403 controls in total) were 100% in the case–control studies, but could not be calculated in the studies reporting screening experiences due to a lack of follow-up of screen-negative babies. Positive predictive values in the screening experience studies ranged from 66.7% (2 true positive cases, 1 false positive case from ~500,000 people screened) to 100% (8 true positive cases from 856,671 people screened); negative predictive values could not be calculated. Positive and negative predictive values cannot be calculated from case–control studies.ConclusionsScreening for Tyrosinemia type 1 using tandem mass spectrometry measurement of succinylacetone from dried blood spots appears to be promising. Confirmation of test accuracy data should be obtained from studies that include a two-year follow-up of individuals who screen negative.

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis : systematic review and economic evaluation

BACKGROUND At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-β) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost-effectiveness. OBJECTIVES To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-β and GA in relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. REVIEW METHODS Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost-effectiveness analysis used published literature, findings from the Department of Healths risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. RESULTS In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was £31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of £33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was £34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of £12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-β-1 (125 µg) was the most cost-effective option of the individual DMTs compared with BSC (ICER £7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER £16,500 per QALY gained). LIMITATIONS Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. CONCLUSIONS DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow-up and systematic review and meta-synthesis of qualitative studies. STUDY REGISTRATION This study is registered as PROSPERO CRD42016043278. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Bacterial load and molecular markers associated with early-onset Group B Streptococcus

Background: The natural history of neonatal group B Streptococcus (GBS) is poorly understood. Little is known about the bacterial factors influencing the transmission of GBS from mother to neonate, or the development of invasive early-onset GBS disease (EOGBS) in colonized neonates. We reviewed whether bacterial load and molecular markers are associated with GBS vertical transmission and progression to EOGBS. Methods: We searched Medline, Embase, Cochrane and Web of Science from inception to October 10, 2016, for observational studies in English. We also hand-searched reference lists of relevant publications and experts cross-checked included studies. Two reviewers independently screened studies, extracted data and appraised the quality of included studies using the Quality in Prognosis Studies tool. We conducted random-effects meta-analyses where possible and narratively synthesized the evidence in text and tables. Results: Seventeen studies were included from 1107 records retrieved from electronic databases and publication references. Meta-analyses of 3 studies showed that neonates colonized by serotype III had a higher risk of developing EOGBS than serotype Ia (pooled risk ratio: 1.51, 95% confidence interval: 1.12–2.03) and serotype II (risk ratio: 1.95, 95% confidence interval: 1.10–3.45). Eleven studies showed that in heavily colonized mothers, 2–3 times more neonates were colonized, and in heavily colonized neonates, up to 15 times more neonates had EOGBS, compared with light colonization. Most evidence was published before 2000 and was at risk of bias. Conclusions: Acknowledging the difficulty of natural history studies, well-controlled studies are needed to assess the predictive value of pathogen subtype and heavy load; they may be useful for better-targeted prevention.

Evaluation of pre-symptomatic nitisinone treatment on long-term outcomes in Tyrosinemia type 1 patients: a systematic review

BackgroundTyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection.MethodsWe searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second.ResultsWe included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10–24 patients; later treatment: 25–60% of 4–15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health-related outcomes were not possible because of sample size or reporting.ConclusionsThere is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late-treated groups included patients born prior to the availability of nitisinone.

OP33 Symptomatic vs pre-symptomatic treatment of tyrosinemia type 1 with nitisinone: a systematic review

Background Tyrosinemia type 1 is a rare autosomal recessive disorder of amino acid metabolism, affecting approximately 1 in 1 00 000 people. Without treatment, death is common in childhood. Treatment with nitisinone is associated with reductions in mortality and morbidity; some studies suggest better outcomes when treatment is initiated before the symptoms of the disorder present. An apparent benefit of earlier versus later treatment has been used to support the implementation of newborn screening for Tyrosinemia type 1, but these studies have not been synthesised or quality appraised. We conducted a systematic review to examine if individuals treated following screen detection of the disorder had better outcomes than those treated following symptomatic detection. Methods Standard systematic review methods were used. Embase, Medline, Pre-Medline, and Web of Science were searched. Participants were individuals with Tyrosinemia type 1. We compared people who received nitisinone following screen detection of the disorder (early treatment) with those who received nitisinone after symptomatic presentation (late treatment). Any reported outcomes were considered. Two reviewers independently screened and assessed records, and conducted quality appraisal (using the Quality Assessment Tool for Quantitative Studies). Data extraction was carried out by one reviewer, and checked by another. A narrative synthesis of results was carried out. Post-hoc comparisons were conducted to address confounding factors and applicability concerns. Results The titles/abstracts of 470 unique records were examined, and 50 full texts assessed. Seven articles were included in the review. Study sample sizes ranged from 17 to 148. Methodological quality of the studies was moderate to weak. There was evidence of associations between early treatment with nitisinone and lower rates of death, liver disease and transplantations, and renal dysfunction. However, posthoc analyses suggested an association between earlier treatment and lower rates of liver transplantation but not mortality (analysis 1) or no differences in outcomes for those treated earlier versus later (analyses 2 and 3). Discussion Evidence from observational studies suggests that treatment with nitisinone initiated during the pre-symptomatic period may be beneficial to people with Tyrosinemia type 1. However, this is subject to bias and applicability concern; the apparent benefits of early treatment may not be present when these issues are addressed. There are several challenges inherent in rare diseases research, including small and heterogeneous populations, lack of appropriate comparator treatments, and limited knowledge about the disease. Our review suggests that alternative research methods or tolerance of lower levels of evidence may be required.

P92 Lifestyle interventions for the treatment of overweight/obese adolescents–cochrane review

Background The prevalence of overweight and obese adolescents has increased worldwide, presenting a global public health crisis. This review assessed the efficacy of diet, exercise and behavioural interventions for the treatment of overweight/obesity in adolescents (12–17 years). Methods A systematic literature search (up to July 2016) with no language restrictions was performed in CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. Search terms included obesity, diet, exercise and adolescent. References of identified studies and systematic reviews were checked. Authors of included studies were contacted for missed studies. Two reviewers evaluated studies independently at all stages. Eligibility: RCTs that observed participants for ≥six months, overweight/obese (investigator-assessed) adolescents (mean age 12–17 years), interventions with a primary aim to treat overweight/obesity with any form of dietary, exercise and/or behavioural therapy delivered as a single or multi component intervention, any setting and any delivery method. Comparators were no treatment/wait list control, usual care or an alternative concomitant therapy providing it is delivered in the intervention arm. Primary outcomes were changes in BMI/weight measured at baseline and at ≥6 months. Data that could be meta-analysed were expressed as mean differences (MD) with 95% CI otherwise data were reported narratively. Heterogeneity, risk of bias and quality of evidence were assessed. Results The searches generated 16 106 records (duplicates removed). Title and abstract screen excluded 15 422 records. 736 records were assessed for eligibility. 105 trials were included: 50 ongoing; 11 awaiting classification, 44 qualitative synthesis and 39 quantitative synthesis. This review included 4682 participants. BMI change at the longest follow-up was MD −1.18 (95% CI −1.67 to −0.69); p<0.00001; 2774 participants; 28 trials; low quality evidence. Most studies were multi-disciplinary interventions (BMI MD −1.18, 95% CI −1.75 to −0.61, p<0.0001; 2293 participants; 22 studies), some studies were diet alone (BMI MD −0.62, 95% CI −1.29 to 0.06; p=0.07; 277 participants; 3 studies) or exercise alone interventions (BMI MD −1.73, 95% CI −3.12 to −0.34, p=0.01; 229 participants; 4 studies). Studies undertaken in schools showed a lower effect compered to community and health care settings. Conclusion Interventions that involve a combination of diet, exercise and behavioural components appear to be an effective treatment option for overweight/obese adolescents. Effects of lifestyle interventions were maintained at 18–24 months follow-up. Results should be interpreted with caution as the evidence was rated as low quality for inconsistency and publication bias.