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1.
N Engl J Med ; 381(15): 1434-1443, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597020

RESUMO

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).


Assuntos
Deficiências do Desenvolvimento/prevenção & controle , Nutrição Enteral/métodos , Fórmulas Infantis , Doenças do Prematuro/prevenção & controle , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Leite Humano , Pré-Escolar , Nutrição Enteral/efeitos adversos , Enterocolite Necrosante/prevenção & controle , Seguimentos , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Unidades de Terapia Intensiva Neonatal , Tempo de Internação , Sepse/prevenção & controle
2.
Health Technol Assess ; 23(54): 1-54, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31590702

RESUMO

BACKGROUND: Sepsis is a leading cause of direct and indirect maternal death in both the UK and globally. All forms of operative delivery are associated with an increased risk of sepsis, and the National Institute for Health and Care Excellence's guidance recommends the use of prophylactic antibiotics at all caesarean deliveries, based on substantial randomised controlled trial evidence of clinical effectiveness. A Cochrane review, updated in 2017 (Liabsuetrakul T, Choobun T, Peeyananjarassri K, Islam QM. Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 2017;8:CD004455), identified only one small previous trial of prophylactic antibiotics following operative vaginal birth (forceps or ventouse/vacuum extraction) and, given the small study size and extreme result, suggested that further robust evidence is needed. OBJECTIVES: To investigate whether or not a single dose of prophylactic antibiotic following operative vaginal birth is clinically effective for preventing confirmed or presumed maternal infection, and to investigate the associated impact on health-care costs. DESIGN: A multicentre, randomised, blinded, placebo-controlled trial. SETTING: Twenty-seven maternity units in the UK. PARTICIPANTS: Women who had an operative vaginal birth at ≥ 36 weeks' gestation, who were not known to be allergic to penicillin or constituents of co-amoxiclav and who had no indication for ongoing antibiotics. INTERVENTIONS: A single dose of intravenous co-amoxiclav (1 g of amoxicillin/200 mg of clavulanic acid) or placebo (sterile saline) allocated through sealed, sequentially numbered, indistinguishable packs. MAIN OUTCOME MEASURES: Primary outcome - confirmed or suspected infection within 6 weeks of giving birth. Secondary outcomes - severe sepsis, perineal wound infection, perineal pain, use of pain relief, hospital bed stay, hospital/general practitioner visits, need for additional perineal care, dyspareunia, ability to sit comfortably to feed the baby, maternal general health, breastfeeding, wound breakdown, occurrence of anaphylaxis and health-care costs. RESULTS: Between March 2016 and June 2018, 3427 women were randomised: 1719 to the antibiotic arm and 1708 to the placebo arm. Seven women withdrew, leaving 1715 women in the antibiotic arm and 1705 in the placebo arm for analysis. Primary outcome data were available for 3225 out of 3420 women (94.3%). Women randomised to the antibiotic arm were significantly less likely to have confirmed or suspected infection within 6 weeks of giving birth (180/1619, 11%) than women randomised to the placebo arm (306/1606, 19%) (relative risk 0.58, 95% confidence interval 0.49 to 0.69). Three serious adverse events were reported: one in the placebo arm and two in the antibiotic arm (one was thought to be causally related to the intervention). LIMITATIONS: The follow-up rate achieved for most secondary outcomes was 76%. CONCLUSIONS: This trial has shown clear evidence of benefit of a single intravenous dose of prophylactic co-amoxiclav after operative vaginal birth. These results may lead to reconsideration of official policy/guidance. Further analysis of the mechanism of action of this single dose of antibiotic is needed to investigate whether earlier, pre-delivery or repeated administration could be more effective. Until these analyses are completed, there is no indication for administration of more than a single dose of prophylactic antibiotic, or for pre-delivery administration. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11166984. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 54. See the National Institute for Health Research Journals Library website for further project information.

3.
Lancet ; 394(10204): 1181-1190, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31472930

RESUMO

BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.


Assuntos
Cesárea , Trabalho de Parto Induzido , Pré-Eclâmpsia/terapia , Nascimento Prematuro , Adulto , Pressão Sanguínea , Parto Obstétrico/métodos , Gerenciamento Clínico , Inglaterra , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Tempo de Internação , Morte Materna , Morbidade , Morte Perinatal , Gravidez , País de Gales , Adulto Jovem
4.
Lancet ; 394(10201): 849-860, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31378395

RESUMO

BACKGROUND: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.


Assuntos
Colagogos e Coleréticos/administração & dosagem , Colestase Intra-Hepática/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Adulto , Alanina Transaminase/sangue , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colestase Intra-Hepática/sangue , Método Duplo-Cego , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Nascimento Vivo/epidemiologia , Morte Perinatal/prevenção & controle , Gravidez , Complicações na Gravidez/sangue , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/prevenção & controle , Prurido/prevenção & controle , Natimorto/epidemiologia
5.
Reprod Health ; 16(1): 81, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196113

RESUMO

BACKGROUND: Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman's ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time - especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25-30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. METHODS: E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective. DISCUSSION: E-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61225414 . Date assigned 29/12/2015.


Assuntos
Criopreservação/economia , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Congelamento , Infertilidade Feminina/terapia , Nascimento Vivo/epidemiologia , Adolescente , Adulto , Análise Custo-Benefício , Criopreservação/métodos , Implantação do Embrião , Embrião de Mamíferos , Feminino , Fertilização In Vitro/legislação & jurisprudência , Humanos , Síndrome de Hiperestimulação Ovariana/epidemiologia , Síndrome de Hiperestimulação Ovariana/prevenção & controle , Indução da Ovulação , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Taxa de Gravidez , Adulto Jovem
6.
Lancet ; 393(10189): 2395-2403, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31097213

RESUMO

BACKGROUND: Risk factors for maternal infection are clearly recognised, including caesarean section and operative vaginal birth. Antibiotic prophylaxis at caesarean section is widely recommended because there is clear systematic review evidence that it reduces incidence of maternal infection. Current WHO guidelines do not recommend routine antibiotic prophylaxis for women undergoing operative vaginal birth because of insufficient evidence of effectiveness. We aimed to investigate whether antibiotic prophylaxis prevented maternal infection after operative vaginal birth. METHODS: In a blinded, randomised controlled trial done at 27 UK obstetric units, women (aged ≥16 years) were allocated to receive a single dose of intravenous amoxicillin and clavulanic acid or placebo (saline) following operative vaginal birth at 36 weeks gestation or later. The primary outcome was confirmed or suspected maternal infection within 6 weeks of delivery defined by a new prescription of antibiotics for specific indications, confirmed systemic infection on culture, or endometritis. We did an intention-to-treat analysis. This trial is registered with ISRCTN, number 11166984, and is closed to accrual. FINDINGS: Between March 13, 2016, and June 13, 2018, 3427 women were randomly assigned to treatment: 1719 to amoxicillin and clavulanic acid, and 1708 to placebo. Seven women withdrew, leaving 1715 in the amoxicillin and clavulanic acid group and 1705 in the placebo groups. Primary outcome data were missing for 195 (6%) women. Significantly fewer women allocated to amoxicillin and clavulanic acid had a confirmed or suspected infection (180 [11%] of 1619) than women allocated to placebo (306 [19%] of 1606; risk ratio 0·58, 95% CI 0·49-0·69; p<0·0001). One woman in the placebo group reported a skin rash and two women in the amoxicillin and clavulanic acid reported other allergic reactions, one of which was reported as a serious adverse event. Two other serious adverse events were reported, neither was considered causally related to the treatment. INTERPRETATION: This trial shows benefit of a single dose of prophylactic antibiotic after operative vaginal birth and guidance from WHO and other national organisations should be changed to reflect this. FUNDING: NIHR Health Technology Assessment programme.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Parto Obstétrico/efeitos adversos , Infecção Puerperal/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Feminino , Humanos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
7.
Neonatology ; : 1-7, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31137030

RESUMO

BACKGROUND: Randomised controlled trials provide the best evidence for the effects of interventions and are a key tool in the effort to improve the care and outcomes for newborn infants. METHODS: We discuss the role of randomisation for minimising selection bias in clinical trials and describe examples of seminal trials that have shaped the development of modern perinatal care. We consider the challenges inherent in designing and delivering large, simple, and pragmatic trials, and the need for the development and adoption of core outcome sets to ensure that trials provide high-quality evidence of sufficient validity and applicability to guide policy and practice. RESULTS: Since the earliest days of modern neonatology, the randomised controlled trial has been recognised as the best method for assessing treatments and practices. While many strategies that reduce mortality and morbidity have been introduced following randomised trials, there are, however, important examples of ineffective or potentially harmful practices that have been adopted in the absence of trial-based evidence. Typically, randomised controlled trials in perinatal care need to recruit several thousand participants to be able to detect modest but potentially important effects of new interventions on the most important but rare outcomes. Given the concerns about the financial burden and regulatory complexity of standard trial designs, innovative "efficient" trial designs are being evaluated to streamline processes while safeguarding participants. CONCLUSIONS: Well-conducted randomised controlled trials provide the most robust evaluation of interventions aimed at improving outcomes for newborn infants and their families. Increasingly, these trials will need to be large and multicentre (often international) and use a simple and pragmatic protocol, incorporating meticulous follow-up procedures and assessment of long-term outcomes.

8.
JMIR Form Res ; 3(2): e9910, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30958277

RESUMO

BACKGROUND: Most food in the United Kingdom is purchased in supermarkets, and many of these purchases are routinely tracked through supermarket loyalty card data. Using such data may be an effective way to develop remote public health interventions and to measure objectively their effectiveness at changing food purchasing behavior. OBJECTIVE: The Front-of-pack food Labels: Impact on Consumer Choice (FLICC) study is a pilot randomized controlled trial of a digital behavior change intervention. This pilot trial aimed to collect data on recruitment and retention rates and to provide estimates of effect sizes for the primary outcome (healthiness of ready meals and pizzas purchased) to inform a larger trial. METHODS: The intervention consisted of a website where participants could access tailored feedback on previous purchases of ready meals and pizzas, set goals for behavior change, and model and practice the recommended healthy shopping behavior using traffic light labels. The control consisted of Web-based information on traffic light labeling. Participants were recruited via email from a list of loyalty card holders held by the participating supermarket. All food and drink purchases for the participants for the 6 months before recruitment, during the 6-week intervention period, and during a 12-week washout period were transferred to the research team by the participating supermarket. Healthiness of ready meals and pizzas was measured using a predeveloped scale based solely on the traffic light colors on the foods. Questionnaires were completed at recruitment, end of the intervention, and end of washout to estimate the effect of the intervention on variables that mediate behavior change (eg, belief and intention formation). RESULTS: We recruited 496 participants from an initial email to 50,000 people. Only 3 people withdrew from the study, and purchase data were received for all other participants. A total of 208 participants completed all 3 questionnaires. There was no difference in the healthiness of purchased ready meals and pizzas between the intervention and control arms either during the intervention period (P=.32) or at washout (P=.59). CONCLUSIONS: Although the FLICC study did not find evidence of an impact of the intervention on food purchasing behavior, the unique methods used in this pilot trial are informative for future studies that plan to use supermarket loyalty card data in collaboration with supermarket partners. The experience of the trial showcases the possibilities and challenges associated with the use of loyalty card data in public health research. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19316955; http://www.isrctn.com/ISRCTN19316955 (Archived by WebCite at http://www.webcitation.org/76IVZ9WjK). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s40814-015-0015-1.

9.
JAMA ; 321(16): 1610-1620, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31012939

RESUMO

Importance: The quality of reporting of randomized clinical trials is suboptimal. In an era in which the need for greater research transparency is paramount, inadequate reporting hinders assessment of the reliability and validity of trial findings. The Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement was developed to improve the reporting of randomized clinical trials, but the primary focus was on parallel-group trials with 2 groups. Multi-arm trials that use a parallel-group design (comparing treatments by concurrently randomizing participants to one of the treatment groups, usually with equal probability) but have 3 or more groups are relatively common. The quality of reporting of multi-arm trials varies substantially, making judgments and interpretation difficult. While the majority of the elements of the CONSORT 2010 Statement apply equally to multi-arm trials, some elements need adaptation, and, in some cases, additional issues need to be clarified. Objective: To present an extension to the CONSORT 2010 Statement for reporting multi-arm trials to facilitate the reporting of such trials. Design: A guideline writing group, which included all authors, formed following the CONSORT group meeting in 2014. The authors met in person and by teleconference bimonthly between 2014 and 2018 to develop and revise the checklist and the accompanying text, with additional discussions by email. A draft manuscript was circulated to the wider CONSORT group of 36 individuals, plus 5 other selected individuals known for their specialist knowledge in clinical trials, for review. Extensive feedback was received from 14 individuals and, after detailed consideration of their comments, a final revised version of the extension was prepared. Findings: This CONSORT extension for multi-arm trials expands on 10 items of the CONSORT 2010 checklist and provides examples of good reporting and a rationale for the importance of each extension item. Key recommendations are that multi-arm trials should be identified as such and require clear objectives and hypotheses referring to all of the treatment groups. Primary treatment comparisons should be identified and authors should report the planned and unplanned comparisons resulting from multiple groups completely and transparently. If statistical adjustments for multiplicity are applied, the rationale and method used should be described. Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides specific guidance for the reporting of multi-arm parallel-group randomized clinical trials and should help provide greater transparency and accuracy in the reporting of such trials.


Assuntos
Editoração/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Lista de Checagem , Humanos , Publicações Periódicas como Assunto/normas
10.
Trials ; 20(1): 85, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691508

RESUMO

BACKGROUND: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks' gestation, without increasing problems related to infant immaturity or complications, remains unclear. METHODS/DESIGN: The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks' gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). DISCUSSION: Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. TRIAL REGISTRATION: ISRCTN01879376 . Registered on 25 November 2013.


Assuntos
Parto Obstétrico/métodos , Pré-Eclâmpsia/terapia , Nascimento Prematuro , Fatores Etários , Desenvolvimento Infantil , Pré-Escolar , Parto Obstétrico/efeitos adversos , Inglaterra , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Estudos Multicêntricos como Assunto , Morte Perinatal/prevenção & controle , Ensaios Clínicos Pragmáticos como Assunto , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Tempo , Resultado do Tratamento , País de Gales
11.
J Pediatr ; 204: 301-304.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30314661

RESUMO

Infants in the Australian and UK Benefits of Oxygen Saturation Targeting-II trials treated using revised oximeters spent more time within their planned pulse oximeter saturation target ranges than infants treated using the original oximeters (P < .001). This may explain the larger mortality difference seen with revised oximeters. If so, average treatment effects from the Neonatal Oxygen Prospective Meta-analysis trials may be underestimates.


Assuntos
Mortalidade Infantil , Oximetria/métodos , Oxigênio/sangue , Austrália , Calibragem , Humanos , Lactente , Recém-Nascido , Oximetria/instrumentação , Reino Unido
12.
Health Technol Assess ; 22(74): 1-60, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30574860

RESUMO

BACKGROUND: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. OBJECTIVE: To determine whether or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) reduces the risk of late-onset infection (acquired > 72 hours after birth) and other morbidity and mortality in very preterm infants. DESIGN: Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks of gestation, sex and single versus multiple births. SETTING: UK neonatal units between May 2014 and September 2017. PARTICIPANTS: Infants born at < 32 weeks' gestation and aged < 72 hours at trial enrolment. INTERVENTIONS: Eligible infants were allocated individually (1 : 1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. Parents, caregivers and outcome assessors were unaware of group assignment. OUTCOMES: Primary outcome - microbiologically confirmed or clinically suspected late-onset infection. Secondary outcomes - microbiologically confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD and mortality; days of receipt of antimicrobials until 34 weeks' postmenstrual age; length of stay in hospital; and length of stay in intensive care, high-dependency and special-care settings. RESULTS: Of 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay in intensive care, high-dependency or special-care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group. CONCLUSIONS: Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants. FUTURE WORK: Increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88261002. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation.


Assuntos
Nutrição Enteral , Lactente Extremamente Prematuro , Doenças do Prematuro/prevenção & controle , Lactoferrina/administração & dosagem , Animais , Bovinos , Enterocolite Necrosante/prevenção & controle , Feminino , Idade Gestacional , Humanos , Masculino
13.
Lancet ; 392(10164): 2595-2605, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30509743

RESUMO

BACKGROUND: Infant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain. METHODS: In this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 µg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34-42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile-Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25). FINDINGS: Between Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI -2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40-1·56) with morphine and 0·75 (0·33-1·22) with placebo (median difference 0·25, 95% CI -0·16 to 0·80; p=0·25). INTERPRETATION: Administration of oral morphine (100 µg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants. FUNDING: Wellcome Trust and National Institute for Health Research.


Assuntos
Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Dor Processual/tratamento farmacológico , Administração Oral , Analgésicos Opioides/efeitos adversos , Bradicardia/induzido quimicamente , Feminino , Idade Gestacional , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/terapia , Masculino , Morfina/efeitos adversos , Consumo de Oxigênio/efeitos dos fármacos , Medição da Dor , Método Simples-Cego , Taquicardia/induzido quimicamente , Falha de Tratamento
14.
Res Integr Peer Rev ; 3: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30397513

RESUMO

Background: Randomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data. Methods: The development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial "long list" of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the "long list" and generate a "short list" of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline. Discussion: Development of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data.

15.
Trials ; 19(1): 657, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482254

RESUMO

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. METHODS: The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks' gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks' gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks' gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. DISCUSSION: Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Colestase Intra-Hepática/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Colagogos e Coleréticos/efeitos adversos , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/mortalidade , Inglaterra , Feminino , Morte Fetal/prevenção & controle , Idade Gestacional , Humanos , Recém-Nascido , Estudos Multicêntricos como Assunto , Morte Perinatal/prevenção & controle , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/mortalidade , Nascimento Prematuro/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Natimorto , Fatores de Tempo , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos , País de Gales
16.
BMJ Open ; 8(8): e025266, 2018 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-30082372

RESUMO

INTRODUCTION: Randomised controlled trials (RCTs) conducted using cohorts and routinely collected health data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. The development of an extension of the CONsolidated Standards of Reporting Trials (CONSORT) statement for RCTs using cohorts and routinely collected health data is being undertaken with the goal of improving reporting quality by setting standards early in the process of uptake of these designs. To develop this extension to the CONSORT statement, a scoping review will be conducted to identify potential modifications or clarifications of existing reporting guideline items, as well as additional items needed for reporting RCTs using cohorts and routinely collected health data. METHODS AND ANALYSIS: In separate searches, we will seek publications on methods or reporting or that describe protocols or results from RCTs using cohorts, registries, electronic health records and administrative databases. Data sources will include Medline and the Cochrane Methodology Register. For each of the four main types of RCTs using cohorts and routinely collected health data, separately, two investigators will independently review included publications to extract potential checklist items. A potential item will either modify an existing CONSORT 2010, Strengthening the Reporting of Observational Studies in Epidemiology or REporting of studies Conducted using Observational Routinely collected health Data item or will be proposed as a new item. Additionally, we will identify examples of good reporting in RCTs using cohorts and routinely collected health data. ETHICS AND DISSEMINATION: The proposed scoping review will help guide the development of the CONSORT extension statement for RCTs conducted using cohorts and routinely collected health data.


Assuntos
Estudos de Coortes , Guias como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Demandas Administrativas em Assistência à Saúde , Registros Eletrônicos de Saúde , Humanos , Sistema de Registros , Literatura de Revisão como Assunto
17.
JAMA ; 319(21): 2190-2201, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29872859

RESUMO

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective: To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation. Exposures: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. Results: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.


Assuntos
Deficiências do Desenvolvimento/epidemiologia , Enterocolite Necrosante/epidemiologia , Lactente Extremamente Prematuro , Doenças do Prematuro/epidemiologia , Oxigênio/sangue , Cegueira/epidemiologia , Paralisia Cerebral/epidemiologia , Surdez/epidemiologia , Feminino , Humanos , Incidência , Lactente , Mortalidade Infantil , Recém-Nascido , Doenças do Prematuro/mortalidade , Estimativa de Kaplan-Meier , Masculino , Oximetria , Oxigênio/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Semin Fetal Neonatal Med ; 23(4): 267-272, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29602579

RESUMO

Despite several decades of research into treatments for patent ductus arteriosus (PDA), there is continued uncertainty regarding whether, when, and how best to treat PDA and the long-term consequences. There are almost 5000 babies enrolled into clinical trials, but the questions remain largely unanswered. Many of the trials performed over the period were well designed and addressed important clinical questions, but the results are not necessarily directly applicable to the clinical management dilemmas of today since perinatal care has improved over time per se, the patient population is typically more premature, and there have been technological advances in diagnosis. This article examines some of the approaches taken, how trial designs evolved over time, especially in terms of the patient population and outcomes evaluated, and it offers points to consider when planning future research.


Assuntos
Permeabilidade do Canal Arterial/tratamento farmacológico , Indometacina/uso terapêutico , Incerteza , Ensaios Clínicos como Assunto , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Assistência Perinatal
19.
Health Technol Assess ; 22(9): 1-186, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29437032

RESUMO

BACKGROUND: Continuous electronic fetal monitoring (EFM) in labour is widely used and computerised interpretation has the potential to increase its utility. OBJECTIVES: This trial aimed to find out whether or not the addition of decision support software to assist in the interpretation of the cardiotocograph (CTG) reduced the number of poor neonatal outcomes, and whether or not it was cost-effective. DESIGN: Two-arm individually randomised controlled trial. The allocations were computer generated using stratified block randomisation employing variable block sizes. The trial was not masked. SETTING: Labour wards in England, Scotland and the Republic of Ireland. PARTICIPANTS: Women in labour having EFM, with a singleton or twin pregnancy, at ≥ 35 weeks' gestation. INTERVENTIONS: Decision support or no decision support. MAIN OUTCOME MEASURES: The primary outcomes were (1) a composite of poor neonatal outcome {intrapartum stillbirth or early neonatal death (excluding lethal congenital anomalies), or neonatal morbidity [defined as neonatal encephalopathy (NNE)], or admission to a neonatal unit within 48 hours for ≥ 48 hours (with evidence of feeding difficulties, respiratory illness or NNE when there was evidence of compromise at birth)}; and (2) developmental assessment at the age of 2 years in a subset of surviving children. RESULTS: Between 6 January 2010 and 31 August 2013, 47,062 women were randomised and 46,042 were included in the primary analysis (22,987 in the decision support group and 23,055 in the no decision support group). The short-term primary outcome event rate was higher than anticipated. There was no evidence of a difference in the incidence of poor neonatal outcome between the groups: 0.7% (n = 172) of babies in the decision support group compared with 0.7% (n = 171) of babies in the no decision support group [adjusted risk ratio 1.01, 95% confidence interval (CI) 0.82 to 1.25]. There was no evidence of a difference in the long-term primary outcome of the Parent Report of Children's Abilities-Revised with a mean score of 98.0 points [standard deviation (SD) 33.8 points] in the decision support group and 97.2 points (SD 33.4 points) in the no decision support group (mean difference 0.63 points, 95% CI -0.98 to 2.25 points). No evidence of a difference was found for health resource use and total costs. There was evidence that decision support did change practice (with increased fetal blood sampling and a lower rate of repeated alerts). LIMITATIONS: Staff in the control group may learn from exposure to the decision support arm of the trial, resulting in improved outcomes in the control arm. This was identified in the planning stage and felt to be unlikely to have a significant effect on the results. As this was a pragmatic trial, the response to CTG alerts was left to the attending clinicians. CONCLUSIONS: This trial does not support the hypothesis that the use of computerised interpretation of the CTG in women who have EFM in labour improves the clinical outcomes for mothers or babies. FUTURE WORK: There continues to be an urgent need to improve knowledge and training about the appropriate response to CTG abnormalities, including timely intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98680152. FUNDING: This project was funded by the National Institute for Health Research (NIHR) HTA programme and will be published in full in Health Technology Assessment; Vol. 22, No. 9. See the NIHR Journals Library website for further project information. Sara Kenyon was part funded by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands.


Assuntos
Cardiotocografia/métodos , Sistemas de Apoio a Decisões Clínicas/organização & administração , Frequência Cardíaca Fetal/fisiologia , Trabalho de Parto , Pré-Escolar , Análise Custo-Benefício , Sistemas de Apoio a Decisões Clínicas/economia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Morte Perinatal , Gravidez , Medicina Estatal , Natimorto/epidemiologia , Avaliação da Tecnologia Biomédica , Reino Unido
20.
JAMA ; 318(23): 2337-2343, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29260229

RESUMO

Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration-registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.


Assuntos
Ensaios Clínicos como Assunto/normas , Interpretação Estatística de Dados , Estatística como Assunto/normas , Técnica Delfos
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