Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.
Dr. Charles J. Lockwood
Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.
There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally,
Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.
Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.
Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin
The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).
Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).
It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.
The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).
Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.
The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.
The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.
Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.
Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.
Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.
When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).
In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.
What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).
My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.