Roberge Stéphanie, Nicolaides Kypros, Demers Suzanne, Hyett Jon, Chaillet Nils, Bujold Emmanuel
Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, United Kingdom.
Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, United Kingdom.
Am J Obstet Gynecol. 2017 Feb;216(2):110-120.e6. doi: 10.1016/j.ajog.2016.09.076. Epub 2016 Sep 15.
Preeclampsia and fetal growth restriction are major causes of perinatal death and handicap in survivors. Randomized clinical trials have reported that the risk of preeclampsia, severe preeclampsia, and fetal growth restriction can be reduced by the prophylactic use of aspirin in high-risk women, but the appropriate dose of the drug to achieve this objective is not certain.
We sought to estimate the impact of aspirin dosage on the prevention of preeclampsia, severe preeclampsia, and fetal growth restriction.
We performed a systematic review and meta-analysis of randomized controlled trials comparing the effect of daily aspirin or placebo (or no treatment) during pregnancy. We searched MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials up to December 2015, and study bibliographies were reviewed. Authors were contacted to obtain additional data when needed. Relative risks for preeclampsia, severe preeclampsia, and fetal growth restriction were calculated with 95% confidence intervals using random-effect models. Dose-response effect was evaluated using meta-regression and reported as adjusted R. Analyses were stratified according to gestational age at initiation of aspirin (≤16 and >16 weeks) and repeated after exclusion of studies at high risk of biases.
In all, 45 randomized controlled trials included a total of 20,909 pregnant women randomized to between 50-150 mg of aspirin daily. When aspirin was initiated at ≤16 weeks, there was a significant reduction and a dose-response effect for the prevention of preeclampsia (relative risk, 0.57; 95% confidence interval, 0.43-0.75; P < .001; R, 44%; P = .036), severe preeclampsia (relative risk, 0.47; 95% confidence interval, 0.26-0.83; P = .009; R, 100%; P = .008), and fetal growth restriction (relative risk, 0.56; 95% confidence interval, 0.44-0.70; P < .001; R, 100%; P = .044) with higher dosages of aspirin being associated with greater reduction of the 3 outcomes. Similar results were observed after the exclusion of studies at high risk of biases. When aspirin was initiated at >16 weeks, there was a smaller reduction of preeclampsia (relative risk, 0.81; 95% confidence interval, 0.66-0.99; P = .04) without relationship with aspirin dosage (R, 0%; P = .941). Aspirin initiated at >16 weeks was not associated with a risk reduction or a dose-response effect for severe preeclampsia (relative risk, 0.85; 95% confidence interval, 0.64-1.14; P = .28; R, 0%; P = .838) and fetal growth restriction (relative risk, 0.95; 95% confidence interval, 0.86-1.05; P = .34; R, not available; P = .563).
Prevention of preeclampsia and fetal growth restriction using aspirin in early pregnancy is associated with a dose-response effect. Low-dose aspirin initiated at >16 weeks' gestation has a modest or no impact on the risk of preeclampsia, severe preeclampsia, and fetal growth restriction. Women at high risk for those outcomes should be identified in early pregnancy.
子痫前期和胎儿生长受限是围产期死亡及存活者残疾的主要原因。随机临床试验报告称，高危女性预防性使用阿司匹林可降低子痫前期、重度子痫前期和胎儿生长受限的风险，但实现这一目标的药物合适剂量尚不确定。
我们试图评估阿司匹林剂量对预防子痫前期、重度子痫前期和胎儿生长受限的影响。
我们对比较孕期每日服用阿司匹林或安慰剂（或不治疗）效果的随机对照试验进行了系统评价和荟萃分析。检索了截至2015年12月的MEDLINE、Embase、科学引文索引和Cochrane对照试验中心注册库，并查阅了研究参考文献。必要时联系作者以获取更多数据。采用随机效应模型计算子痫前期、重度子痫前期和胎儿生长受限的相对风险及95%置信区间。使用Meta回归评估剂量反应效应，并报告调整后的R值。根据开始服用阿司匹林时的孕周（≤16周和>16周）进行分层分析，并在排除高偏倚风险的研究后重复分析。
总共45项随机对照试验纳入了20909名孕妇，她们被随机分配至每日服用50 - 150毫克阿司匹林。在妊娠≤16周开始服用阿司匹林时，预防子痫前期（相对风险为0.57；95%置信区间为0.43 - 0.75；P <.001；R为44%；P =.036）、重度子痫前期（相对风险为0.47；95%置信区间为0.26 - 0.83；P =.009；R为100%；P =.008）和胎儿生长受限（相对风险为0.56；95%置信区间为0.44 - 0.70；P <.001；R为100%；P =.044）有显著降低且存在剂量反应效应，阿司匹林剂量越高，这三种结局的降低幅度越大。排除高偏倚风险的研究后观察到类似结果。在妊娠>16周开始服用阿司匹林时，子痫前期的降低幅度较小（相对风险为0.81；95%置信区间为0.66 - 0.99；P =.04），且与阿司匹林剂量无关（R为0%；P =.941）。在妊娠>16周开始服用阿司匹林与重度子痫前期（相对风险为0.85；95%置信区间为0.64 - 1.14；P =.28；R为0%；P =.838）和胎儿生长受限（相对风险为0.95；95%置信区间为0.86 - 1.05；P =.34；R无数据；P =.563）的风险降低或剂量反应效应无关。
妊娠早期使用阿司匹林预防子痫前期和胎儿生长受限存在剂量反应效应。妊娠>16周开始使用低剂量阿司匹林对子痫前期、重度子痫前期和胎儿生长受限的风险影响不大或无影响。应在妊娠早期识别出这些结局的高危女性。
