Does low-dose aspirin initiated before 11 weeks' gestation reduce the rate of preeclampsia?

Preconception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization, and organogenesis. Most studies have evaluated the potential benefit of preconception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization, or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery, and fetal growth restriction. We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at <11 weeks' gestation in preventing preeclampsia and/or hypertensive disorders in pregnancy or improving pregnancy outcomes in women with recurrent miscarriage as compared with placebo or no treatment and outcome data available or provided by authors for >85% of the study population. Relative risks with 95% confidence intervals were calculated for each study and pooled for global analysis as the effect measure. We assessed statistical heterogeneity in each meta-analysis using the χ2 statistics, I2, and Tau2. Heterogeneity was considered substantial if an I2 was greater than 50% and either the Tau2 was greater than zero or there was a low P value (<0.10) in the χ2 test for heterogeneity. Random-effects meta-analysis, weighted by the size of the studies, was performed to produce an overall summary on aspirin effect for each outcome. Sensitivity analysis by sequential omission of each individual study and by fixed-effects model was performed. Publication bias was not assessed because of the small number of included studies. Statistical analysis was performed using Stata release 14.0 (StataCorp). The entry criteria were fulfilled by 8 randomized controlled trials on a combined total of 1426 participants. Low-dose aspirin initiated at <11 weeks' gestation was associated with a nonsignificant reduction in the risk of preeclampsia (relative risk, 0.52; 95% confidence interval, 0.23-1.17, P = .115), gestational hypertension (relative risk, 0.49; 95% confidence interval, 0.20-1.21; P = .121), and any hypertensive disorder of pregnancy (relative risk, 0.59; 95% confidence interval, 0.33-1.04, P = .067). Early administration of low-dose aspirin reduced the risk of preterm delivery (relative risk, 0.52; 95% confidence interval, 0.27-0.97, P = .040) but had no impact on the risk of fetal growth restriction (relative risk, 1.10; 95% confidence interval, 0.58-2.07, P = .775). Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations, therefore confirming the robustness of the analysis. The administration of low-dose aspirin at <11 weeks' gestation in women at high risk does not decrease the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy, and fetal growth restriction. However, it might reduce the risk of preterm delivery. Larger randomized controlled trials will be required to substantiate the findings.

Chaemsaithong P ，Cuenca-Gomez D ，Plana MN ，Gil MM ，Poon LC ... -  《-》

Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis.

Evidence on the impact of low-molecular-weight heparin, alone or in combination with low-dose aspirin, for the prevention for preeclampsia in high-risk patients is conflicting. We conducted a meta-analysis of studies published to assess the effectiveness of low-molecular-weight heparin for the prevention of preeclampsia and other placenta-related complications in high-risk women. A systematic search was performed to identify relevant studies, using the databases PubMed and Cochrane Central Register of Controlled Trials, without publication time restrictions. Randomized controlled trials comparing treatment with low-molecular-weight heparin or unfractionated heparin (with or without low-dose aspirin), in high-risk women, defined as either history of preeclampsia, intrauterine growth restriction, fetal demise, or miscarriage or being at high risk after first-trimester screening of preeclampsia. The systematic review was conducted according to the Cochrane Handbook guidelines. The primary outcome was the development of preeclampsia. We performed prespecified subgroup analyses according to combination with low-dose aspirin, low-molecular-weight heparin type, gestational age when treatment was started, and study population (patients with thrombophilia, at high risk of preeclampsia or miscarriage). Secondary outcomes included small for gestational age, perinatal death, miscarriage, and placental abruption. Pooled odds ratios with 95% confidence intervals were calculated using a random-effects model. Quality of evidence was assessed using the grading of recommendations assessment, development, and evaluation methodology. A total of 15 studies (2795 participants) were included. In high-risk women, treatment with low-molecular-weight heparin was associated with a reduction in the development of preeclampsia (odds ratio, 0.62; 95% confidence interval, 0.43-0.90; P=.010); small for gestational age (odds ratio, 0.61; 95% confidence interval, 0.44-0.85; P=.003), and perinatal death (odds ratio, 0.49; 95% confidence interval, 0.25-0.94; P=.030). This reduction was stronger if low-molecular-weight heparin was started before 16 weeks' gestation (13 studies, 2474 participants) for preeclampsia (odds ratio, 0.55; 95% confidence interval, 0.39-0.76; P=.0004). When only studies including low-dose aspirin as an intervention were analyzed (6 randomized controlled trials, 920 participants), a significant reduction was observed in those with combined treatment (low-molecular-weight heparin plus low-dose aspirin) compared with low-dose aspirin alone (odds ratio, 0.62; 95% confidence interval, 0.41-0.95; P=.030). Overall, adverse events were neither serious nor significantly different. Quality of evidence ranged from very low to moderate, mostly because of the lack of blinding, imprecision, and inconsistency. Low-molecular-weight heparin use was associated with a significant reduction in the risk of preeclampsia and other placenta-mediated complications in high-risk women and when treatment was started before 16 weeks' gestation. Combined treatment with low-dose aspirin was associated with a significant reduction in the risk of preeclampsia compared with low-dose aspirin alone. However, there exists important clinical and statistical heterogeneity, and therefore, these results merit confirmation in large well-designed clinical trials.

Cruz-Lemini M ，Vázquez JC ，Ullmo J ，Llurba E ... -  《-》

The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.

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 R2. 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; R2, 44%; P = .036), severe preeclampsia (relative risk, 0.47; 95% confidence interval, 0.26-0.83; P = .009; R2, 100%; P = .008), and fetal growth restriction (relative risk, 0.56; 95% confidence interval, 0.44-0.70; P < .001; R2, 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 (R2, 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; R2, 0%; P = .838) and fetal growth restriction (relative risk, 0.95; 95% confidence interval, 0.86-1.05; P = .34; R2, 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.

Roberge S ，Nicolaides K ，Demers S ，Hyett J ，Chaillet N ，Bujold E ... -  《-》

Antiplatelet therapy before or after 16 weeks' gestation for preventing preeclampsia: an individual participant data meta-analysis.

The optimum time for commencing antiplatelet therapy for the prevention of preeclampsia and its complications is unclear. Aggregate data meta-analyses suggest that aspirin is more effective if given prior to 16 weeks' gestation, but data are limited because of an inability to place women in the correct gestational age subgroup from relevant trials. The objective of the study was to use the large existing individual participant data set from the Perinatal Antiplatelet Review of International Studies Collaboration to assess whether the treatment effects of antiplatelet agents on preeclampsia and its complications vary based on whether treatment is started before or after 16 weeks' gestation. A meta-analysis of individual participant data including 32,217 women and 32,819 babies recruited to 31 randomized trials comparing low-dose aspirin or other antiplatelet agents with placebo or no treatment for the prevention of preeclampsia has been published previously. Using this existing data set, we performed a prespecified subgroup analysis based on gestation at randomization to antiplatelet agents before 16 weeks, compared with at or after 16 weeks, for 4 of the main outcomes prespecified in the Perinatal Antiplatelet Review of International Studies protocol: preeclampsia, death of baby, preterm birth before 34 weeks, and small-for-gestational-age baby. Individual participant data for the subgroups were combined in a meta-analysis using RevMan software. Heterogeneity was assessed with the I2 statistic. The χ2 test for interaction was used to assess statistically significant (P < .05) differences in treatment effect between subgroups. There was no significant difference in the effects of antiplatelet therapy for women randomized before 16 weeks' gestation compared with those randomized at or after 16 weeks for any of the 4 prespecified outcomes: preeclampsia, relative risk, 0.90, (95% confidence interval, 0.79-1.03; 17 trials, 9241 women) for <16 weeks and relative risk, 0.90 (95% confidence interval, 0.83-0.98; 22 trials, 21,429 women) for ≥16 weeks (interaction test, P = .98); death of baby, relative risk, 0.89 (95% confidence interval, 0.73-1.09; 15 trials, 8626 women) for <16 weeks and relative risk, 0.92 (95% confidence interval, 0.79-1.07; 21 trials, 22,336 women) for ≥16 weeks (interaction test, P = .80); preterm birth prior to 34 weeks, relative risk, 0.90 (95% confidence interval, 0.77-1.04; 19 trials, 9155 women) for <16 weeks and relative risk, 0.91 (95% confidence interval, 0.82-1.00; 25 trials, 22,117 women) for ≥16 weeks (interaction test, P = .91); and small-for-gestational-age baby, relative risk, 0.76 (95% confidence interval, 0.61-0.94; 13 trials, 6393 women) for <16 weeks and relative risk, 0.95 (95% confidence interval, 0.84-1.08; 18 trials, 14,996 women) for ≥16 weeks (interaction test, P = .08). The effect of low-dose aspirin and other antiplatelet agents on preeclampsia and its complications is consistent, regardless of whether treatment is started before or after 16 weeks' gestation. Women at an increased risk of preeclampsia should be offered antiplatelet therapy, regardless of whether they are first seen before or after 16 weeks' gestation.

Meher S ，Duley L ，Hunter K ，Askie L ... -  《-》

Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history.

The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial demonstrated that in women who were at high risk for preterm preeclampsia with delivery at <37 weeks' gestation identified by screening by means of an algorithm that combines maternal factors and biomarkers at 11-13 weeks' gestation, aspirin administration from 11 to 14 until 36 weeks' gestation was associated with a significant reduction in the incidence of preterm preeclampsia (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). We sought to examine whether there are differences in the effect of aspirin on the incidence of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial in subgroups defined according to maternal characteristics and medical and obstetrical history. This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. Subgroup analysis was performed to assess evidence of differences in the effect of aspirin on incidence of preterm preeclampsia in subgroups defined by maternal age (<30 and ≥30 years), body mass index (<25 and ≥25 kg/m2), racial origin (Afro-Caribbean, Caucasian and other), method of conception (natural and assisted), cigarette smoking (smoker and non-smoker), family history of preterm preeclampsia (present and absent), obstetrical history (nulliparous, multiparous with previous preterm preeclampsia and multiparous without previous preterm preeclampsia), history of chronic hypertension (present and absent). Interaction tests were performed on the full data set of patients in the intention to treat population and on the data set of patients who took ≥ 90% of the prescribed medication. Results are presented as forest plot with P values for the interaction effects, group sizes, event counts and estimated odds ratios. We examined whether the test of interaction was significant at the 5% level with a Bonferroni adjustment for multiple comparisons. There was no evidence of heterogeneity in the aspirin effect in subgroups defined according to maternal characteristics and obstetrical history. In participants with chronic hypertension preterm preeclampsia occurred in 10.2% (5/49) in the aspirin group and 8.2% (5/61) in the placebo group (adjusted odds ratio, 1.29; 95% confidence interval, 0.33-5.12). The respective values in those without chronic hypertension were 1.1% (8/749) in the aspirin group and 3.9% (30/761) in the placebo group (adjusted odds ratio, 0.27; 95% confidence interval, 0.12-0.60). In all participants with adherence of ≥90% the adjusted odds ratio in the aspirin group was 0.24 (95% confidence interval, 0.09-0.65); in the subgroup with chronic hypertension it was 2.06 (95% confidence interval, 0.40-10.71); and in those without chronic hypertension it was 0.05 (95% confidence interval, 0.01-0.41). For the complete data set the test of interaction was not significant at the 5% level (P = .055), but in those with adherence ≥90%, after adjustment for multiple comparisons, the interaction was significant at the 5% level (P = .0019). The beneficial effect of aspirin in the prevention of preterm preeclampsia may not apply in pregnancies with chronic hypertension. There was no evidence of heterogeneity in the aspirin effect in subgroups defined according to maternal characteristics and obstetrical history.

Poon LC ，Wright D ，Rolnik DL ，Syngelaki A ，Delgado JL ，Tsokaki T ，Leipold G ，Akolekar R ，Shearing S ，De Stefani L ，Jani JC ，Plasencia W ，Evangelinakis N ，Gonzalez-Vanegas O ，Persico N ，Nicolaides KH ... -  《-》