Aspirin for the Prevention of Pregnancy Loss
Let’s talk about the use of aspirin as a means of preventing pregnancy loss in women who have no other indications for its prescription (for example, prevention of preeclampsia).
On our favorite resource, UpToDate, there are two articles on this subject:
Recurrent pregnancy loss: Management (Togas Tulandi, Haya M Al-Fozan) – aspirin for the prevention of recurrent pregnancy loss is classified as a treatment method that has not proven effective and is not recommended.
Pregnancy loss (miscarriage): Comparison of treatment options and discussion of related care (Sarah Prager, Elizabeth Micks et al.) – as part of their “our approach,” the authors describe taking low-dose aspirin (81 mg) before conception in women who have had 1–2 or more miscarriages in the past. Although available data are contradictory, this approach is based on limited supporting evidence combined with the low toxicity of aspirin observed in other populations of pregnant women.
Interestingly, the authors actually refer to the same study and mention the same publications. Let’s take a closer look at how this happened and which recommendations are more reliable.
The EAGeR study (Effects of Aspirin on Gestation and Reproduction) was a multicenter, block-randomized, double-blind, placebo-controlled clinical trial conducted in four clinical centers in the United States (2007–2011). Enrollment ended on July 15, 2011.
What was the idea behind the study? Women with a history of pregnancy loss are at higher risk of recurrent losses. The pathophysiological mechanisms leading to miscarriage are not fully understood and not always identified, but one possible cause is endometrial inflammation and reduced uterine blood flow. Low-dose aspirin, with its antiplatelet and anti-inflammatory effects, could theoretically influence these factors.
Study design Initially, the study included women with only one prior miscarriage before 20 weeks’ gestation within the last year, who had previously had at least one live birth. Later, the criteria were expanded to include women with miscarriages after 20 weeks, those who had miscarriages more than a year earlier, and those with up to two previous live births.
Participants received 81 mg aspirin with 400 µg folic acid daily for up to six menstrual cycles while trying to conceive, and if conception occurred, throughout pregnancy until 36 weeks, OR placebo.
Compliance was assessed based on daily self-reports and, importantly, objectively by weighing medication bottles at each visit.
Results A total of 1,227 women aged 18–40 with 1–2 miscarriages were included. Overall, 1,228 were randomized (615 to aspirin, 613 to placebo). Of these, 1,078 completed the trial (535 aspirin, 543 placebo). Early discontinuation occurred in 13% of both groups.
Most women (67%) had only one previous miscarriage.
For 53%, the interval between the last loss and randomization was 4 months.
The primary results were published in The Lancet on July 5, 2014.
Live birth rates: No statistically significant difference between groups (aspirin 58% vs placebo 53%, p = 0.0984).
Subgroup analysis: Among women with miscarriages before 20 weeks within the previous year, the live birth rate was significantly higher in the aspirin group (62% vs 53%, p = 0.0446).
Pregnancy loss rate: Similar in both groups (13% aspirin, 12% placebo).
Adverse effects: Vaginal bleeding occurred more often with aspirin (24 vs 8 women, p = 0.0038).
Pregnancy detection (by hCG/ultrasound): Higher in the aspirin group, mainly among women with a recent miscarriage (<20 weeks within the last year).
Post hoc analyses The EAGeR data were unique, as no prior study directly evaluated aspirin’s effect on miscarriage in women without thrombophilias. Consequently, numerous secondary/post hoc analyses were performed, often re-grouping women by socioeconomic status, CRP levels, etc. However, such analyses have limitations and are not considered solid evidence (e.g., FDA does not accept them).
Examples:
Sjaarda et al., 2017: Divided women by preconception CRP levels – aspirin was more effective in those with elevated CRP.
Agrawala et al., 2019: Divided by socioeconomic status – aspirin increased pregnancy rates in low and high SES groups, but not in the middle group.
Naimi et al., 2021: Found that adherence was imperfect (many women took aspirin only 4–5 times per week). Concluded that aspirin taken at least 4x/week reduced miscarriage risk and increased live births by ~30% vs placebo.
Key point: Post hoc studies are hypothesis-generating, not proof. They raise questions for future research. For example, could adherence itself (linked to education/income) be the true factor driving differences, rather than aspirin?
Practical application If these findings are applied, the target group would be women who:
Previously had live births,
Experienced 1–2 miscarriages (especially within the last year, <20 weeks),
Begin low-dose aspirin 81 mg while trying to conceive (up to 6 cycles),
Continue until 36 weeks if pregnancy occurs.
Patients must be informed about potential risks (e.g., bleeding) and discontinue treatment if complications arise.