Preeclampsia, a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, often the kidneys, has been a subject of extensive research. Early investigations into its prevention explored the role of vascular disturbances and coagulation defects, particularly an imbalance between prostacyclin and thromboxane A2 (TXA2). This line of inquiry led to initial studies examining the potential of aspirin in preventing preeclampsia.
Early small-scale trials indicated that low-dose aspirin might offer benefits for pregnant women at elevated preeclampsia risk. However, larger Randomized Controlled Trials (RCTs), including a significant multicenter trial supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development involving over 5,000 women, initially did not confirm these findings. Subsequently, the 2017 Aspirin for Evidence-Based Preeclampsia Prevention trial brought renewed attention to this area. This study randomized 1,776 women identified as high-risk for preeclampsia through a first-trimester screening algorithm to receive either 150-mg aspirin or a placebo. The results showed a notable reduction in preterm preeclampsia rates (1.6% in the aspirin group versus 4.3% in the placebo group, with an odds ratio of 0.38; 95% CI, 0.20–0.74). It’s important to note that while this study used a 150-mg dose, current research hasn’t directly compared the effectiveness of 150 mg against lower doses like 60–80 mg. Furthermore, the screening algorithm’s reliance on first-trimester serum markers like placental growth factor and pregnancy-associated plasma protein-A, along with uterine artery Doppler assessments, might limit its direct applicability to all populations. Thus, recommending higher aspirin doses or doubling the commonly available 81-mg dose is not currently supported.
Meta-analyses have further explored the role of low-dose aspirin. One meta-analysis combining individual patient data from 31 RCTs suggested a modest protective effect of low-dose aspirin in preventing preeclampsia across diverse risk groups (Relative Risk [RR], 0.90; 95% CI, 0.84–0.97). A subsequent Cochrane review, analyzing aggregate data from 59 trials, reported a more significant 17% relative reduction in preeclampsia with low-dose aspirin. However, it’s cautioned that this larger reduction might be influenced by publication bias, where smaller, early positive trials are more likely to be published, or simply chance findings, as the largest trials within the analysis did not demonstrate significant protective effects.
The 2014 U.S. Preventive Services Task Force (USPSTF) guideline on low-dose aspirin for preeclampsia prevention is grounded in a systematic review of 15 high-quality RCTs. Thirteen of these trials specifically focused on preeclampsia incidence in women at heightened risk [Table 1]. This review indicated a 24% reduction in preeclampsia (RR, 0.76; CI, 0.62–0.95) with low-dose aspirin prophylaxis (ranging from 60–150 mg/day). However, the USPSTF authors proposed that the actual relative risk reduction might be closer to 10%, accounting for potential “small study effects” observed in many included trials. They also highlighted that the absolute risk reduction associated with low-dose aspirin varies depending on the baseline preeclampsia risk, ranging from a small decrease of 2–5%.
Based on these findings, including the USPSTF’s, it’s established that low-dose aspirin prophylaxis (81 mg/day) initiated after 12 weeks of gestation can modestly decrease the risk of preeclampsia in women at increased risk. Importantly, this intervention has not been associated with adverse fetal effects, increased maternal bleeding, or placental abruption. The recommendation to use low-dose aspirin in high-risk women is guided by the “number needed to treat,” which is dependent on both the prevalence of preeclampsia and the treatment effect. In low-risk populations (with a preeclampsia prevalence of around 2%), the number needed to treat is approximately 500. In contrast, for a high-risk group with a 20% preeclampsia prevalence, the number needed to treat reduces to about 50. The USPSTF guideline suggests low-dose aspirin for women with an absolute preeclampsia risk of 8% or greater, which was the lowest incidence rate observed in the control groups of the studies they reviewed. The guideline further specifies that women with any high-risk factors for preeclampsia, based on historical and demographic risk assessments, should be considered for low-dose aspirin prophylaxis. Furthermore, low-dose aspirin should be considered for women presenting with more than one moderate risk factor for preeclampsia [Table 1].
Leading professional organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM), endorse the USPSTF guideline criteria for preeclampsia prevention. They recommend low-dose aspirin (81 mg/day) prophylaxis for women at high risk of preeclampsia, to be started between 12 and 28 weeks of gestation, ideally before 16 weeks, and continued daily until delivery. Women already taking medically-indicated low-dose aspirin for other conditions before 12–28 weeks of gestation can continue their treatment.
