Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, University of Liverpool, Liverpool, UK.
Sydney, Australia.
Cochrane Database Syst Rev. 2022 Aug 9;8(8):CD006764. doi: 10.1002/14651858.CD006764.pub4.
BACKGROUND: Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome (RDS) in preterm infants, there is currently no consensus as to the type of corticosteroid to use, dose, frequency, timing of use or the route of administration. OBJECTIVES: To assess the effects on fetal and neonatal morbidity and mortality, on maternal morbidity and mortality, and on the child and adult in later life, of administering different types of corticosteroids (dexamethasone or betamethasone), or different corticosteroid dose regimens, including timing, frequency and mode of administration. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (9 May 2022) and reference lists of retrieved studies. SELECTION CRITERIA: We included all identified published and unpublished randomised controlled trials or quasi-randomised controlled trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth. We planned to exclude cross-over trials and cluster-randomised trials. We planned to include studies published as abstracts only along with studies published as full-text manuscripts. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 11 trials (2494 women and 2762 infants) in this update, all of which recruited women who were at increased risk of preterm birth or had a medical indication for preterm birth. All trials were conducted in high-income countries. Dexamethasone versus betamethasone Nine trials (2096 women and 2319 infants) compared dexamethasone versus betamethasone. All trials administered both drugs intramuscularly, and the total dose in the course was consistent (22.8 mg or 24 mg), but the regimen varied. We assessed one new study to have no serious risk of bias concerns for most outcomes, but other studies were at moderate (six trials) or high (two trials) risk of bias due to selection, detection and attrition bias. Our GRADE assessments ranged between high- and low-certainty, with downgrades due to risk of bias and imprecision. Maternal outcomes The only maternal primary outcome reported was chorioamnionitis (death and puerperal sepsis were not reported). Although the rate of chorioamnionitis was lower with dexamethasone, we did not find conclusive evidence of a difference between the two drugs (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.48 to 1.06; 1 trial, 1346 women; moderate-certainty evidence). The proportion of women experiencing maternal adverse effects of therapy was lower with dexamethasone; however, there was not conclusive evidence of a difference between interventions (RR 0.63, 95% CI 0.35 to 1.13; 2 trials, 1705 women; moderate-certainty evidence). Infant outcomes We are unsure whether the choice of drug makes a difference to the risk of any known death after randomisation, because the 95% CI was compatible with both appreciable benefit and harm with dexamethasone (RR 1.03, 95% CI 0.66 to 1.63; 5 trials, 2105 infants; moderate-certainty evidence). The choice of drug may make little or no difference to the risk of RDS (RR 1.06, 95% CI 0.91 to 1.22; 5 trials, 2105 infants; high-certainty evidence). While there may be little or no difference in the risk of intraventricular haemorrhage (IVH), there was substantial unexplained statistical heterogeneity in this result (average (a) RR 0.71, 95% CI 0.28 to 1.81; 4 trials, 1902 infants; I² = 62%; low-certainty evidence). We found no evidence of a difference between the two drugs for chronic lung disease (RR 0.92, 95% CI 0.64 to 1.34; 1 trial, 1509 infants; moderate-certainty evidence), and we are unsure of the effects on necrotising enterocolitis, because there were few events in the studies reporting this outcome (RR 5.08, 95% CI 0.25 to 105.15; 2 studies, 441 infants; low-certainty evidence). Longer-term child outcomes Only one trial consistently followed up children longer term, reporting at two years' adjusted age. There is probably little or no difference between dexamethasone and betamethasone in the risk of neurodevelopmental disability at follow-up (RR 1.02, 95% CI 0.85 to 1.22; 2 trials, 1151 infants; moderate-certainty evidence). It is unclear whether the choice of drug makes a difference to the risk of visual impairment (RR 0.33, 95% CI 0.01 to 8.15; 1 trial, 1227 children; low-certainty evidence). There may be little or no difference between the drugs for hearing impairment (RR 1.16, 95% CI 0.63 to 2.16; 1 trial, 1227 children; moderate-certainty evidence), motor developmental delay (RR 0.89, 95% CI 0.66 to 1.20; 1 trial, 1166 children; moderate-certainty evidence) or intellectual impairment (RR 0.97, 95% CI 0.79 to 1.20; 1 trial, 1161 children; moderate-certainty evidence). However, the effect estimate for cerebral palsy is compatible with both an important increase in risk with dexamethasone, and no difference between interventions (RR 2.50, 95% CI 0.97 to 6.39; 1 trial, 1223 children; low-certainty evidence). No trials followed the children beyond early childhood. Comparisons of different preparations and regimens of corticosteroids We found three studies that included a comparison of a different regimen or preparation of either dexamethasone or betamethasone (oral dexamethasone 32 mg versus intramuscular dexamethasone 24 mg; betamethasone acetate plus phosphate versus betamethasone phosphate; 12-hourly betamethasone versus 24-hourly betamethasone). The certainty of the evidence for the main outcomes from all three studies was very low, due to small sample size and risk of bias. Therefore, we were limited in our ability to draw conclusions from any of these studies. AUTHORS' CONCLUSIONS: Overall, it remains unclear whether there are important differences between dexamethasone and betamethasone, or between one regimen and another. Most trials compared dexamethasone versus betamethasone. While for most infant and early childhood outcomes there may be no difference between these drugs, for several important outcomes for the mother, infant and child the evidence was inconclusive and did not rule out significant benefits or harms. The evidence on different antenatal corticosteroid regimens was sparse, and does not support the use of one particular corticosteroid regimen over another.
背景:尽管产前使用皮质类固醇来预防早产儿呼吸窘迫综合征(RDS)已得到广泛应用,但目前对于使用哪种皮质类固醇、剂量、频率、使用时机或给药途径尚无共识。
目的:评估不同类型的皮质类固醇(地塞米松或倍他米松)或不同皮质类固醇剂量方案(包括时机、频率和给药方式)对胎儿和新生儿发病率和死亡率、母婴发病率和死亡率以及儿童和成人后期生活的影响。
检索方法:为本次更新,我们检索了 Cochrane 妊娠和分娩组试验注册库、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台(ICTRP)(2022 年 5 月 9 日)和检索研究的参考文献列表。
入选标准:我们纳入了所有已识别的发表和未发表的随机对照试验或准随机对照试验,比较了任何两种皮质类固醇(地塞米松或倍他米松或任何其他可穿过胎盘的皮质类固醇),比较了在有早产风险的妇女中不同的剂量方案(包括给药时间、频率和方式)。我们计划排除交叉试验和整群随机试验。我们计划纳入仅作为摘要发表的研究以及作为全文手稿发表的研究。
数据收集和分析:至少两名综述作者独立评估了研究的纳入标准、提取数据并评估了纳入研究的偏倚风险。数据经核对以确保准确性。我们使用 GRADE 评估证据的确定性。
主要结果:我们此次更新纳入了 11 项试验(2494 名妇女和 2762 名婴儿),所有这些试验都招募了有早产风险或有医学指征需要早产的妇女。所有试验均在高收入国家进行。地塞米松与倍他米松 9 项试验(2096 名妇女和 2319 名婴儿)比较了地塞米松与倍他米松。所有试验均肌内给予两种药物,疗程中的总剂量一致(22.8 毫克或 24 毫克),但方案不同。我们评估了一项新的研究,认为该研究在大多数结局方面没有严重的偏倚风险,但其他研究由于选择、检测和失访偏倚而存在中度(6 项试验)或高度(2 项试验)偏倚。我们的 GRADE 评估结果在高到低之间,降级是由于偏倚和不精确性。
母婴结局:唯一报告的母婴主要结局是绒毛膜羊膜炎(死产和产褥期脓毒症未报告)。尽管地塞米松组绒毛膜羊膜炎的发生率较低,但我们并未发现两种药物之间存在差异的确凿证据(风险比(RR)0.71,95%置信区间(CI)0.48 至 1.06;1 项试验,1346 名妇女;中确定性证据)。地塞米松组接受治疗的妇女出现不良药物作用的比例较低;然而,干预措施之间没有确凿的证据表明存在差异(RR 0.63,95%CI 0.35 至 1.13;2 项试验,1705 名妇女;中确定性证据)。
婴儿结局:我们不确定药物的选择是否会对随机分配后任何已知死亡的风险产生影响,因为 95%CI 与地塞米松的明显获益和危害都兼容(RR 1.03,95%CI 0.66 至 1.63;5 项试验,2105 名婴儿;中确定性证据)。药物的选择可能对 RDS 的风险影响不大(RR 1.06,95%CI 0.91 至 1.22;5 项试验,2105 名婴儿;高确定性证据)。虽然在颅内出血(IVH)的风险方面可能没有差异,但结果存在很大的未解释统计异质性(平均(a)RR 0.71,95%CI 0.28 至 1.81;4 项试验,1902 名婴儿;I²=62%;低确定性证据)。我们没有发现两种药物在慢性肺部疾病(RR 0.92,95%CI 0.64 至 1.34;1 项试验,1509 名婴儿;中确定性证据)方面存在差异,我们不确定两种药物在坏死性小肠结肠炎方面的影响,因为报告该结局的研究事件较少(RR 5.08,95%CI 0.25 至 105.15;2 项研究,441 名婴儿;低确定性证据)。
长期儿童结局:只有一项试验始终长期随访儿童,报告了两岁时调整后的年龄。地塞米松和倍他米松在长期随访中发生神经发育障碍的风险可能差异不大(RR 1.02,95%CI 0.85 至 1.22;2 项试验,1151 名婴儿;中确定性证据)。药物的选择是否会影响视力障碍的风险尚不清楚(RR 0.33,95%CI 0.01 至 8.15;1 项试验,1227 名儿童;低确定性证据)。药物的选择可能对听力障碍(RR 1.16,95%CI 0.63 至 2.16;1 项试验,1227 名儿童;中确定性证据)、运动发育迟缓(RR 0.89,95%CI 0.66 至 1.20;1 项试验,1166 名儿童;中确定性证据)或智力障碍(RR 0.97,95%CI 0.79 至 1.20;1 项试验,1161 名儿童;中确定性证据)的风险无差异。然而,脑瘫的效应估计值与地塞米松增加风险和干预措施之间无差异均兼容(RR 2.50,95%CI 0.97 至 6.39;1 项试验,1223 名儿童;低确定性证据)。没有试验对儿童进行早期以外的随访。不同皮质类固醇制剂和方案的比较:我们发现了三项研究,包括比较不同的方案或皮质类固醇制剂(口服地塞米松 32 毫克与肌内地塞米松 24 毫克;倍他米松醋酸酯加磷酸盐与倍他米松磷酸盐;12 小时倍他米松与 24 小时倍他米松)。所有三项研究的主要结局的证据确定性均非常低,这是由于样本量小和偏倚风险。因此,我们在从这些研究中得出结论方面受到限制。
作者结论:总体而言,地塞米松和倍他米松之间,或一种方案与另一种方案之间,是否存在重要差异仍不清楚。大多数试验比较了地塞米松与倍他米松。尽管对于大多数婴儿和儿童早期的结局,这些药物之间可能没有差异,但对于母亲、婴儿和儿童的几个重要结局,证据尚不确定,并且不能排除重要的获益或危害。皮质类固醇不同方案的证据很少,不能支持使用一种皮质类固醇方案而不是另一种方案。
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