Background

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 differed by participant or treatment characteristics such as the reason the woman was at risk of preterm birth, why treatment was given, the gestational age at which magnesium sulphate treatment was received, or the dose and timing of the administration of magnesium sulphate.

Methods and findings

Trials in which women considered at risk of preterm birth (<37 weeks’ gestation) were randomised to magnesium sulphate or control treatment and where neurologic outcomes for the baby were reported were eligible for inclusion. The primary outcomes were infant death or CP and severe maternal outcome potentially related to treatment. Studies were identified based on the Cochrane Pregnancy and Childbirth search strategy using the terms [antenatal or prenatal] and [magnesium] and [preterm or premature or neuroprotection or 'cerebral palsy']. The date of the last search was 28 February 2017. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. For each prespecified outcome, IPD were analysed using a 1-stage approach. All 5 trials identified were included, with 5,493 women and 6,131 babies. Overall, there was no clear effect of magnesium sulphate treatment compared with no treatment on the primary infant composite outcome of death or CP (relative risk [RR] 0.94, 95% confidence interval (CI) 0.85 to 1.05, 6,131 babies, 5 trials, p = 0.07 for heterogeneity of treatment effect across trials). In the prespecified sensitivity analysis restricted to data from the 4 trials in which the intent of treatment was fetal neuroprotection, there was a significant reduction in the risk of death or CP with magnesium sulphate treatment compared with no treatment (RR 0.86, 95% CI 0.75 to 0.99, 4,448 babies, 4 trials), with no significant heterogeneity (p = 0.28). The number needed to treat (NNT) to benefit was 41 women/babies to prevent 1 baby from either dying or having CP. For the primary outcome of severe maternal outcome potentially related to magnesium sulphate treatment, no events were recorded from the 2 trials providing data. When the individual components of the composite infant outcome were assessed, no effect was seen for death overall (RR 1.03, 95% CI 0.91 to 1.17, 6,131 babies, 5 trials) or in the analysis of death using only data from trials with the intent of fetal neuroprotection (RR 0.95, 95% CI 0.80 to 1.13, 4,448 babies, 4 trials). For cerebral palsy in survivors, magnesium sulphate treatment had a strong protective effect in both the overall analysis (RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5 trials, NNT to benefit 46) and the neuroprotective intent analysis (RR 0.68, 95% CI 0.53 to 0.87, 3,988 babies, 4 trials, NNT to benefit 42). No statistically significant differences were seen for any of the other secondary outcomes. The treatment effect varied little by the reason the woman was at risk of preterm birth, the gestational age at which magnesium sulphate treatment was given, the total dose received, or whether maintenance therapy was used. A limitation of the study was that not all trials could provide the data required for the planned analyses so that combined with low event rates for some important clinical events, the power to find a difference was limited.

Conclusions

Antenatal magnesium sulphate given prior to preterm birth for fetal neuroprotection prevents CP and reduces the combined risk of fetal/infant death or CP. Benefit is seen regardless of the reason for preterm birth, with similar effects across a range of preterm gestational ages and different treatment regimens. Widespread adoption worldwide of this relatively inexpensive, easy-to-administer treatment would lead to important global health benefits for infants born preterm.

中文翻译：

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评估产前硫酸镁对婴儿的神经保护作用：个体参与者数据荟萃分析

背景

早产婴儿在出生后头几周死亡的风险增加，与足月出生的婴儿相比，存活下来的婴儿患脑瘫 (CP) 的几率更高。这项个体参与者数据 (IPD) 荟萃分析 (MA) 的目的是评估产前硫酸镁与未给予镁治疗相比，对有早产风险的妇女对重要母体和胎儿结局的影响，包括无生存期CP 的影响，以及影响是否因参与者或治疗特征而不同，例如女性有早产风险的原因、给予治疗的原因、接受硫酸镁治疗的胎龄或给药的剂量和时间硫酸镁。

方法和发现

被认为有早产风险（<37 孕周）的妇女被随机分配到硫酸镁或对照治疗，并且报告了婴儿的神经系统结果的试验符合纳入标准。主要结局是婴儿死亡或 CP 以及可能与治疗相关的严重产妇结局。研究是根据 Cochrane 妊娠和分娩搜索策略确定的，使用术语 [产前或产前] 和 [镁] 和 [早产或早产或神经保护或“脑瘫”]。最后一次检索的日期是 2017 年 2 月 28 日。IPD 是从具有合格试验的研究人员那里寻找的。使用 Cochrane Collaboration 的标准评估偏倚风险。对于每个预先指定的结果，IPD 使用 1 阶段方法进行分析。确定的所有 5 项试验都包括在内，其中 5 项，493 名妇女和 6,131 名婴儿。总体而言，与未治疗相比，硫酸镁治疗对死亡或 CP 的主要婴儿复合结局没有明显影响（相对风险 [RR] 0.94，95% 置信区间 (CI) 0.85 至 1.05，6,131 名婴儿，5 项试验，试验间治疗效果的异质性p = 0.07）。在仅限于 4 项治疗目的是胎儿神经保护的试验数据的预先指定的敏感性分析中，与未治疗相比，硫酸镁治疗显着降低了死亡或 CP 的风险（RR 0.86, 95% CI 0.75到 0.99，4,448 名婴儿，4 次试验），没有显着的异质性（p= 0.28)。需要治疗 (NNT) 的人数是 41 名妇女/婴儿，以防止 1 名婴儿死亡或患有 CP。对于可能与硫酸镁治疗相关的严重孕产妇结局的主要结局，提供数据的 2 项试验没有记录任何事件。当评估复合婴儿结局的各个组成部分时，总体死亡（RR 1.03, 95% CI 0.91 至 1.17, 6,131 名婴儿，5 项试验）或仅使用来自有意向的试验的数据进行的死亡分析没有观察到影响胎儿神经保护（RR 0.95，95% CI 0.80 至 1.13，4,448 名婴儿，4 项试验）。对于幸存者的脑瘫，硫酸镁治疗在总体分析（RR 0.68，95% CI 0.54 至 0.87，4,601 名婴儿，5 项试验，NNT 使 46 人受益）和神经保护意图分析（RR 0.68，95% CI 0.53 至 0.87，3,988 名婴儿，4 项试验，NNT 受益 42）。任何其他次要结局均未见统计学显着差异。治疗效果因女性有早产风险的原因、给予硫酸镁治疗的胎龄、接受的总剂量或是否使用维持治疗而变化不大。该研究的一个限制是，并非所有试验都可以提供计划分析所需的数据，因此再加上一些重要临床事件的低事件率，发现差异的能力是有限的。给予硫酸镁治疗的胎龄、接受的总剂量或是否使用维持治疗。该研究的一个限制是，并非所有试验都可以提供计划分析所需的数据，因此再加上一些重要临床事件的低事件率，发现差异的能力是有限的。给予硫酸镁治疗的胎龄、接受的总剂量或是否使用维持治疗。该研究的一个限制是，并非所有试验都可以提供计划分析所需的数据，因此再加上一些重要临床事件的低事件率，发现差异的能力是有限的。

结论

早产前给予产前硫酸镁以保护胎儿神经可预防 CP 并降低胎儿/婴儿死亡或 CP 的综合风险。无论早产的原因是什么，都可以看到益处，在一系列早产胎龄和不同的治疗方案中具有相似的效果。这种相对便宜、易于管理的治疗方法在全球范围内的广泛采用将为早产儿带来重要的全球健康益处。