Prevention of Perinatal Death and Adverse Perinatal Outcome Using Low-Dose Aspirin

Abstract

The leading causes of perinatal death are preterm birth, fetal abnormalities, and impaired placentation leading to preeclampsia and fetal growth restriction. Prophylactic use of low-dose aspirin beginning at 16 weeks’ gestation or less has been associated with significant reductions in the prevalence of these placenta-related complications. Improving deep placentation could reduce the incidence of several adverse pregnancy outcomes and rate of perinatal death. This systematic review and meta-analysis of recent randomized trials were done to compare the effect of early and late administration of aspirin on the risk of perinatal death and other adverse outcomes. EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched for relevant citations from 1965 to October 2011. Only prospective, randomized controlled trials involving pregnant women treated with low-dose aspirin (≤150 mg), with or without dipyridamole (≤300 mg), were included. Control groups had to have received placebo or no treatment. All studies that involved women who initiated treatment at 16 weeks or less and at more than 16 weeks’ gestation were included. The main outcome was perinatal mortality (fetal death after 16 weeks’ gestation or neonatal death before 28 days). Secondary outcomes were preeclampsia, severe preeclampsia, fetal growth restriction, preterm birth, placental abruption, birth weight, and gestational age at delivery. Review Manager 5.0.25 and SAS 9.2 software were used for analysis. Relative risks (RRs) were calculated and pooled for global analysis with 95% confidence intervals (CIs) and stratified according to gestational age at entry (≤16 or >16 weeks). Forty-two of 66 studies meeting inclusion criteria were included (27,222 women randomized) in the final analysis. When compared with controls, treatment with low-dose aspirin started at 16 weeks’ gestation or less compared with low-dose aspirin started at more than 16 weeks’ gestation was associated with a greater reduction in perinatal death (RR = 0.41; 95% CI, 0.19–0.92 vs RR = 0.93; 95% CI, 0.73–1.19; P = 0.02), preeclampsia (RR = 0.47; 95% CI, 0.36–0.62 vs RR = 0.78; 95% CI, 0.61–0.99; P < 0.01), severe preeclampsia (RR = 0.18; 95% CI, 0.08–0.41 vs RR = 0.65; 95% CI, 0.40–1.07; P < 0.01), fetal growth restriction (RR = 0.46; 95% CI, 0.33–0.64 vs RR = 0.98; 95% CI, 0.88–1.08; P < 0.001), and preterm birth (RR = 0.35; 95% CI, 0.22–0.57 vs RR = 0.90; 95% CI, 0.83–0.97; P < 0.001). The difference in RR according to gestational age at entry remained statistically significant (P = 0.03) when comparing women recruited at 16 weeks or less with those recruited at 16 to 24 weeks (RR = 1.01; 95% CI, 0.49–2.08; P = 0.99). In 7 studies (22%) reporting the reasons for perinatal death, 17 (65%) of 26 perinatal deaths were related to preeclampsia, fetal growth restriction, or placental abruption. Similar effects of early aspirin prophylaxis were found in women who received 80 mg or less daily and those who received 100 mg or more daily and in women selected using abnormal uterine artery Doppler as an inclusion criterion as compared with those selected using anamnesis factors only. These results suggest that prophylaxis with low-dose aspirin can lead to significant reductions in perinatal death, preeclampsia, fetal growth restriction, and preterm birth provided treatment is started at 16 weeks’ gestation or less. The beneficial effect of aspirin likely results from an improvement in the transformation of uterine spiral arteries. Abnormal uterine artery blood flow is present as early as 12 weeks’ gestation in women who will later develop preeclampsia. Because low-dose aspirin improves uterine artery blood flow between the first and the second trimesters, such a regimen should probably be initiated at 8 to 12 weeks’ gestation in high-risk women.