Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research (IMSR), WHO Collaborating Centre for Global Women's Health Research, University of Birmingham, Birmingham, UK.
Cochrane Database Syst Rev. 2022 Aug 10;8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2.
Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.
To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.
We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.
We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.
At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.
This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).
AUTHORS' CONCLUSIONS: Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.
早产是新生儿和儿童死亡的主要原因。保胎药物旨在通过抑制子宫收缩来延迟早产，以便有时间给予皮质激素促进胎儿肺成熟、硫酸镁进行神经保护，并将孕妇转运至具有适当新生儿护理设施的地方。然而，这些药物的有效性和安全性仍存在不确定性。
评估不同类别的保胎药物在延迟早产方面的相对有效性和安全性，并提供现有药物的排名。
我们检索了 Cochrane 妊娠和分娩组的试验注册库、ClinicalTrials.gov（2021 年 4 月 21 日）和纳入研究的参考文献列表。
我们纳入了所有评估保胎药物有效性或不良影响的随机对照试验。我们排除了准随机和非随机试验。我们根据预先设定的标准评估所有研究，以判断其可信度。
至少两名综述作者独立评估试验是否纳入以及是否存在偏倚，并提取数据。我们进行了两两比较和网络荟萃分析，以确定所有可用保胎药物的相对效果和排名。我们使用 GRADE 评估网络荟萃分析中每种保胎药物与安慰剂或无治疗相比的效应估计的确定性。
这项网络荟萃分析包括 122 项试验（13697 名妇女），涉及六种保胎药物类别、保胎药物联合治疗以及安慰剂或无治疗。大多数试验纳入了有早产威胁、单胎妊娠、妊娠 24 至 34 周的妇女。我们判断 25 项（20%）研究的偏倚风险较低。总体而言，证据的确定性存在差异。网络荟萃分析的相对效果表明，与安慰剂或无保胎药物治疗相比，所有保胎药物都可能有效延迟早产。β激动剂可能在 48 小时（风险比[RR]1.12，95%置信区间[CI]1.05 至 1.20；低确定性证据）和 7 天（RR 1.14，95%CI 1.03 至 1.25；低确定性证据）内有效延迟早产。COX 抑制剂可能在 48 小时（RR 1.11，95%CI 1.01 至 1.23；低确定性证据）内有效延迟早产。钙通道阻滞剂可能在 48 小时（RR 1.16，95%CI 1.07 至 1.24；低确定性证据）和 7 天（RR 1.15，95%CI 1.04 至 1.27；中确定性证据）内有效延迟早产，并可能延长 5 天的妊娠时间（0.1 更多至 9.2 更多；高确定性证据）。硫酸镁可能在 48 小时（RR 1.12，95%CI 1.02 至 1.23；中确定性证据）内有效延迟早产。催产素受体拮抗剂可能在 48 小时（RR 1.13，95%CI 1.05 至 1.22；中确定性证据）和 7 天（RR 1.18，95%CI 1.07 至 1.30；高确定性证据）内有效延迟早产，并可能延长 10 天的妊娠时间（95%CI 2.3 更多至 16.7 更多）。一氧化氮供体可能在 48 小时（RR 1.17，95%CI 1.05 至 1.31；中确定性证据）和 7 天（RR 1.18，95%CI 1.02 至 1.37；中确定性证据）内有效延迟早产。保胎药物联合治疗可能在 48 小时（RR 1.17，95%CI 1.07 至 1.27；中确定性证据）和 7 天（RR 1.19，95%CI 1.05 至 1.34；中确定性证据）内有效延迟早产。一氧化氮供体在 48 小时和 7 天的延迟分娩（连续结局）以及早产方面的排名最高，其次是钙通道阻滞剂、催产素受体拮抗剂和保胎药物联合治疗。β激动剂（RR 14.4，95%CI 6.11 至 34.1；中确定性证据）、钙通道阻滞剂（RR 2.96，95%CI 1.23 至 7.11；中确定性证据）、硫酸镁（RR 3.90，95%CI 1.09 至 13.93；中确定性证据）和保胎药物联合治疗（RR 6.87，95%CI 2.08 至 22.7；低确定性证据）更可能导致治疗终止。钙通道阻滞剂可能降低神经发育障碍发病率的风险（RR 0.51，95%CI 0.30 至 0.85；低确定性证据）和呼吸障碍发病率的风险（RR 0.68，95%CI 0.53 至 0.88；低确定性证据），并导致新生儿出生体重小于 2000 克的风险降低（RR 0.49，95%CI 0.28 至 0.87；低确定性证据）。一氧化氮供体可能导致新生儿出生体重更高（平均差异[MD]425.53 克更多，95%CI 224.32 克更多至 626.74 克更多；低确定性证据）、出生体重小于 2500 克的新生儿更少（RR 0.40，95%CI 0.24 至 0.69；低确定性证据）和胎龄更长（MD 1.35 周更多，95%CI 0.37 周更多至 2.32 周更多；低确定性证据）。保胎药物联合治疗可能导致出生体重小于 2500 克的新生儿更少（RR 0.74，95%CI 0.59 至 0.93；低确定性证据）。在母亲不良影响方面，β激动剂可能导致呼吸困难（RR 12.09，95%CI 4.66 至 31.39；中确定性证据）、心悸（RR 7.39，95%CI 3.83 至 14.24；中确定性证据）、呕吐（RR 1.91，95%CI 1.25 至 2.91；中确定性证据）、可能头痛（RR 1.91，95%CI 1.07 至 3.42；低确定性证据）和心动过速（RR 3.01，95%CI 1.17 至 7.71；低确定性证据），与安慰剂或无治疗相比。COX 抑制剂可能导致呕吐（RR 2.54，95%CI 1.18 至 5.48；低确定性证据）。钙通道阻滞剂（RR 2.59，95%CI 1.39 至 4.83；低确定性证据）和一氧化氮供体可能导致头痛（RR 4.20，95%CI 2.13 至 8.25；中确定性证据）。
与安慰剂或无保胎药物治疗相比，我们评估的所有保胎药物类别（β激动剂、钙通道阻滞剂、硫酸镁、催产素受体拮抗剂、一氧化氮供体）及其联合治疗在 48 小时和 7 天内都可能有效延迟早产。保胎药物与一系列不良反应相关（从轻微到潜在严重），与安慰剂或无保胎药物治疗相比，β激动剂和保胎药物联合治疗更可能导致治疗终止。保胎药物对新生儿和围产期死亡率等新生儿结局以及母婴感染等安全性结局的影响不确定。
