Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis.
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ABSTRACT:
SUBMITTER: Crowther CA
PROVIDER: S-EPMC5627896 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
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Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis.
Crowther Caroline A CA Middleton Philippa F PF Voysey Merryn M Askie Lisa L Duley Lelia L Pryde Peter G PG Marret Stéphane S Doyle Lex W LW
PLoS medicine 20171004 10
<h4>Background</h4>Babies born preterm are at an increased risk of dying in the first weeks of life, and those who survive have a higher rate of cerebral palsy (CP) compared with babies born at term. The aim of this individual participant data (IPD) meta-analysis (MA) was to assess the effects of antenatal magnesium sulphate, compared with no magnesium treatment, given to women at risk of preterm birth on important maternal and fetal outcomes, including survival free of CP, and whether effects d ...[more]
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Project description:BackgroundThere is widespread, increasing use of magnesium sulphate in obstetric practice for pre-eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analysis to assess whether antenatal magnesium sulphate is associated with unintended adverse neonatal outcomes.Methods and findingsCINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science, were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and non-randomised trials, cohort and case-control studies, and case reports assessing antenatal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis, compared with placebo/no treatment or a different magnesium sulphate regimen, were included. The primary outcome was perinatal death. Secondary outcomes included pre-specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened 5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects meta-analysis. Non-randomised data were tabulated and narratively summarised. We included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23 trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotection (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/no treatment, and 22 compared different regimens. For perinatal death, no clear difference in randomised trials was observed between magnesium sulphate and placebo/no treatment (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moderate to high risk of bias) observed an increased risk of perinatal death with >48 versus ≤48 grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal outcomes were observed in randomised trials, and a very limited number of possible adverse outcomes warranting further consideration were identified in non-randomised studies. Where non-randomised studies observed possible harms, often no or few confounders were controlled for (moderate to high risk of bias), samples were small (200 babies or fewer), and/or results were from subgroup analyses. Limitations include missing data for important outcomes across most studies, heterogeneity of included studies, and inclusion of published data only.ConclusionsOur findings do not support clear associations between antenatal magnesium sulphate for beneficial indications and adverse neonatal outcomes. Further large, high-quality studies (prospective cohorts or individual participant data meta-analyses) assessing specific outcomes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes, would further inform safety recommendations. PROSPERO: CRD42013004451.
| S-EPMC6897495 | biostudies-literature
Project description:BackgroundAntenatal magnesium sulphate (MgSO4) therapy given to women at risk of preterm birth reduced the risk of cerebral palsy in early childhood. However, its effect on longer-term neurological outcomes remains uncertain. This study aimed to assess the effects of antenatal MgSO4 therapy on school-age outcomes of preterm infants.MethodsWe conducted a systematic review and meta-analysis. We searched MEDLINE, EMBASE, CENTRAL, and CINAHL for randomized controlled trials (RCTs). Two reviewers independently evaluated the eligibility for inclusion and extracted data.ResultsTen RCTs were included. Only two of them were on school-age outcomes. Antenatal MgSO4 therapy had no impact on cerebral palsy, hearing impairment, neurosensory disability, and death at school-age. Meta-analysis on mental retardation and visual impairment was not able to be performed due to different methods of evaluation. In the analysis of short-term outcomes conducted as secondary outcomes, antenatal MgSO4 therapy increased the risk of maternal adverse events with any symptom (3 RCTs; risk ratio 2.79; 95% confidence interval 1.10 to 7.05, low certainty of evidence) but was not associated with any neonatal symptoms.ConclusionsThe number of cases was insufficient to determine the impact of antenatal MgSO4 therapy on school-age outcomes. Further accumulation of long-term data is required.
| S-EPMC10453514 | biostudies-literature
Project description:AimTo review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE).MethodThis was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability).ResultsTwenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision.InterpretationGiven the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries.
| S-EPMC11579813 | biostudies-literature
Project description:AimTo evaluate the effectiveness of intravenous magnesium sulphate in the treatment of acute asthmatic attacks in children by meta-analysis.MethodsA systematic and comprehensive search of the literature was performed to identify controlled clinical trials of magnesium sulphate in paediatric acute asthma which evaluated outcomes of hospitalisation or short term pulmonary function tests or symptom scores. Unpublished data were searched by personal contacts with authors and specialists. Two reviewers independently assessed trial qualities and synthesised data. Heterogeneity among studies was evaluated by the Cochrane Q test. Outcome data were pooled by random or fixed effect models depending on presence or absence of heterogeneity.ResultsFive randomised placebo controlled trials involving a total of 182 patients were identified. They compared intravenous magnesium sulphate to placebo in treating paediatric patients with moderate to severe asthmatic attacks in the emergency department, with co-therapies of inhaled beta2 agonists and systemic steroids. The studies were of high quality with results judged to be valid. Four studies showed that magnesium sulphate was effective, while one study found it ineffective. There was no significant heterogeneity in the primary outcome of hospitalisation. In the fixed effect model, magnesium sulphate is effective in preventing hospitalisation (OR 0.290, 95% CI 0.143 to 0.589). The number needed to treat is 4 (95% CI 3 to 8). Secondary outcomes of short term pulmonary function tests and clinical symptom scores also showed significant improvement.ConclusionIntravenous magnesium sulphate probably provides additional benefit in moderate to severe acute asthma in children treated with bronchodilators and steroids.
| S-EPMC1720072 | biostudies-literature
Project description: Not available
| S-EPMC5690438 | biostudies-literature
Project description:BackgroundAntenatal magnesium sulphate, widely used in obstetrics to improve maternal and infant outcomes, may be associated with adverse effects for the mother sufficient for treatment cessation. This systematic review aimed to quantify maternal adverse effects attributed to treatment, assess how adverse effects vary according to different regimens, and explore women's experiences with this treatment.MethodsBibliographic databases were searched from their inceptions to July 2012 for studies of any design that reported on maternal adverse effects associated with antenatal magnesium sulphate given to improve maternal or infant outcomes. Primary outcomes were life-threatening adverse effects of treatment (death, cardiac arrest, respiratory arrest). For randomised controlled trials, data were meta-analysed, and risk ratios (RR) pooled using fixed-effects or random-effects models. For non-randomised studies, data were tabulated by design, and presented as RR, odds ratios or percentages, and summarised narratively.ResultsA total of 143 publications were included (21 randomised trials, 15 non-randomised comparative studies, 32 case series and 75 reports of individual cases), of mixed methodological quality. Compared with placebo or no treatment, magnesium sulphate was not associated with an increased risk of maternal death, cardiac arrest or respiratory arrest. Magnesium sulphate significantly increased the risk of 'any adverse effects' overall (RR 4.62, 95% CI 2.42-8.83; 4 trials, 13,322 women), and treatment cessation due to adverse effects (RR 2.77; 95% CI 2.32-3.30; 5 trials, 13,666 women). Few subgroup differences were observed (between indications for use and treatment regimens). In one trial, a lower dose regimen (2 g/3 hours) compared with a higher dose regimen (5 g/4 hours) significantly reduced treatment cessation (RR 0.05; 95% CI 0.01-0.39, 126 women). Adverse effect estimates from studies of other designs largely supported data from randomised trials. Case reports supported an association between iatrogenic overdose of magnesium sulphate and life-threatening consequences.ConclusionsAppropriate administration of antenatal magnesium sulphate was not shown to be associated with serious maternal adverse effects, though an increase in 'minor' adverse effects and treatment cessation was shown. Larger trials are needed to determine optimal regimens, achieving maximal effectiveness with minimal adverse effects, for each antenatal indication for use. Vigilance in the use of magnesium sulphate is essential for women's safety.
| S-EPMC4015216 | biostudies-literature
Project description:When combining results across related studies, a multivariate meta-analysis allows the joint synthesis of correlated effect estimates from multiple outcomes. Joint synthesis can improve efficiency over separate univariate syntheses, may reduce selective outcome reporting biases, and enables joint inferences across the outcomes. A common issue is that within-study correlations needed to fit the multivariate model are unknown from published reports. However, provision of individual participant data (IPD) allows them to be calculated directly. Here, we illustrate how to use IPD to estimate within-study correlations, using a joint linear regression for multiple continuous outcomes and bootstrapping methods for binary, survival and mixed outcomes. In a meta-analysis of 10 hypertension trials, we then show how these methods enable multivariate meta-analysis to address novel clinical questions about continuous, survival and binary outcomes; treatment-covariate interactions; adjusted risk/prognostic factor effects; longitudinal data; prognostic and multiparameter models; and multiple treatment comparisons. Both frequentist and Bayesian approaches are applied, with example software code provided to derive within-study correlations and to fit the models.
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Project description:BackgroundMagnesium sulphate given to women prior to very preterm birth protects the perinatal brain, so fewer babies die or develop cerebral palsy. How magnesium sulphate exerts these beneficial effects remains uncertain. The MagNUM Study aimed to assess the effect of exposure to antenatal magnesium sulphate on MRI measures of brain white matter microstructure at term equivalent age.MethodsNested cohort study within the Magnesium sulphate at 30 to <34 weeks' Gestational age Neuroprotection Trial (MAGENTA). Australian New Zealand Clinical Trials Registry ACTRN12611000491965. Mothers at risk of preterm birth at 30 to <34 weeks' gestation were randomised to receive either 4 g of magnesium sulphate heptahydrate [8 mmol magnesium ions], or saline placebo, when preterm birth was planned or expected within 24 h. Participating babies underwent diffusion tensor MRI at term equivalent age. The main outcomes were fractional anisotropy across the white matter tract skeleton compared using Tract-based Spatial Statistics (TBSS), with adjustment for postmenstrual age at birth and at MRI, and MRI site. Researchers and families were blind to treatment group allocation during data collection and analyses.FindingsOf the 109 babies the demographics of the 49 babies exposed to magnesium sulphate were similar to the 60 babies exposed to placebo. In babies whose mothers were allocated to magnesium sulphate, fractional anisotropy was lower within the corticospinal tracts and corona radiata, the superior and inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi compared to babies whose mothers were allocated placebo (P < 0·05).InterpretationIn babies born preterm after 30 weeks' gestation, antenatal magnesium sulphate exposure did not promote development of white matter microstructure in pathways affecting motor or cognitive function. This suggests that if the neuroprotective effect of magnesium sulphate treatment prior to preterm birth is confirmed at this gestation, the mechanisms are not related to accelerated white matter maturation inferred from fractional anisotropy.FundingThis study was funded by a project grant from the Health Research Council of New Zealand (HRC 14/153).
| S-EPMC9043972 | biostudies-literature
Project description:Individual participant data (IPD) meta-analyses of randomised trials are considered a reliable way to assess participant-level treatment effect modifiers but may not make the best use of the available data. Traditionally, effect modifiers are explored one covariate at a time, which gives rise to the possibility that evidence of treatment-covariate interaction may be due to confounding from a different, related covariate. We aimed to evaluate current practice when estimating treatment-covariate interactions in IPD meta-analysis, specifically focusing on involvement of additional covariates in the models. We reviewed 100 IPD meta-analyses of randomised trials, published between 2015 and 2020, that assessed at least one treatment-covariate interaction. We identified four approaches to handling additional covariates: (1) Single interaction model (unadjusted): No additional covariates included (57/100 IPD meta-analyses); (2) Single interaction model (adjusted): Adjustment for the main effect of at least one additional covariate (35/100); (3) Multiple interactions model: Adjustment for at least one two-way interaction between treatment and an additional covariate (3/100); and (4) Three-way interaction model: Three-way interaction formed between treatment, the additional covariate and the potential effect modifier (5/100). IPD is not being utilised to its fullest extent. In an exemplar dataset, we demonstrate how these approaches lead to different conclusions. Researchers should adjust for additional covariates when estimating interactions in IPD meta-analysis providing they adjust their main effects, which is already widely recommended. Further, they should consider whether more complex approaches could provide better information on who might benefit most from treatments, improving patient choice and treatment policy and practice.
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Project description:Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
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