Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
SYNOPSIS: A reanalysis of an earlier randomized clinical trial to assess the ability of low-dose aspirin to prevent preeclampsia has shown that the drug diminishes the risk of spontaneously delivering prior to 34 weeks by about half.
SOURCE: Andrikopoulou M, Purisch SE, Handal-Orefice R, Gyamfi-Bannerman C. Low-dose aspirin is associated with reduced spontaneous preterm birth in nulliparous women. Am J Obstet Gynecol 2018;219:399.e1-399.e6.
Many previous Alerts have included reviews of methods to diminish the rates of spontaneous preterm birth (PTB) and preeclampsia. Now, a study emerges that resurrects data from an earlier randomized, clinical trial (RCT) by Sibai et al that addressed the ability of low-dose aspirin (ASA) to prevent preeclampsia.1 However, this time, Andrikopoulou et al crossed over to study the drug’s ability to diminish the rate of PTB. A well-documented feature of preeclampsia — a failure of deep (myometrial) trophoblastic invasion of the spiral arteries — has been implicated as a possible cause of PTB.2 This link has not been given the attention it deserved because of the more obvious tendency to blame preeclampsia-related PTB on the frequent need to intervene early. Also, in recent years the focus in spontaneous PTB has been on infection and cytokine-generated inflammation.
In 1993, Sibai et al explored the ability of low-dose ASA to prevent preeclampsia in nulliparous pregnant women.1 The preventive results were underwhelming, and the data languished until a group from New York decided to study what was not addressed in the earlier study: low-dose ASA and its relationship to spontaneous PTB. Through the National Institutes of Health Maternal-Fetal Medicine Network, 2,543 women from seven centers were enrolled between 1989 and 1991. Half were given 60 mg ASA per day and the other half received placebo, with administration between 13 and 25 weeks of gestation. The primary outcome was spontaneous PTB < 34 weeks, and the secondary outcomes were spontaneous PTB < 37 weeks, overall PTB at < 34 weeks and < 37 weeks, and the incidence of abruption and/or any type of hemorrhage.
There was a statistically significant difference between ASA and placebo in the primary outcome variable: the rate of PTB < 34 weeks (1.03% vs. 2.34%; odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26-0.84). Differences in the rates of PTB < 37 weeks (7.03% vs. 6.58%; OR, 1.04; 95% CI, 0.78-1.39), as well as those for PTB for any reason at < 37 weeks and at < 34 weeks, were not significant between the ASA and placebo groups. Also, there was no evidence of increased rates of hemorrhage with ASA.
Importantly, reductions in PTB < 34 weeks remained significant after adjusting for many confounding variables. Since there are some data to suggest that ASA works best when administered prior to 16 weeks,3 the authors addressed this issue. They found that ASA after 16 weeks yielded a similar doubling in the reduction of PTB < 34 weeks (OR, 2.17; 95% CI, 1.05-4.45).
Of all the variables tested, there was only one other significant difference between the study groups: a higher rate of placental abruption (0.72% vs. 0.08%; OR, 10.0; 95% CI, 1.16-100) in the ASA cohort. This finding also received some initial attention when the original study was published.1 However, since the placebo group had an unfairly low incidence of abruption (zero), and the rate of abruption in the ASA group was the same as historical controls, this relationship has been downplayed substantially.
Every few years, another reason to use ASA surfaces. Most studies do show a benefit of ASA to prevent preeclampsia, especially in high-risk patients. In addition, cardiologists have hyped its ability to prevent strokes and cardiovascular events in at-risk patients and have recommended its use in others, seemingly for no reason other than being old. ASA discourages platelet aggregation and appears to have a beneficial effect on spiral artery remodeling in the placental bed. It certainly has anti-inflammatory properties. It is inexpensive and has few side effects in those with normal clotting function.
Now, we find that it may decrease PTB at a time when prematurity exerts its greatest morbidity (< 34 weeks), even in those with no risk factors. Does this mean that every pregnant patient should take it? When confronted with a suggestion like this that is so “out there,” we always counter with “it needs more investigation.” In this case, based on the nature of the study and that this was the only real finding that was significant, that response sounds about right.
- Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213-1218.
- Kim YM, Bujold E, Chaiworapongsa T, et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2003;189:1063-1069.
- Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with the aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010;116:402-414.