Pathophysiology

Aspirin (acetylsalicylic acid) is a nonsteroidal antiinflammatory drug (NSAID) that works primarily through its inhibition of two cyclooxygenase isoenzymes (COX-1 and COX-2), which are necessary for prostaglandin biosynthesis. The COX-1 isoform is present in the vascular endothelium and regulates the production of prostacyclin and thromboxane A ₂, prostaglandins with opposing regulatory effects on vascular homeostasis and platelet function. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation, whereas thromboxane A ₂ (TXA2) is a potent vasoconstrictor and promotes platelet aggregation. The COX-2 isoform is inducible and expressed almost exclusively following exposure to cytokines or other inflammatory mediators. The effect of aspirin on COX-dependent prostaglandin synthesis is dose dependent. At lower dosages (60–150 mg/day) aspirin irreversibly acetylates COX-1, resulting in decreased platelet synthesis of TXA2 without affecting vascular wall production of prostacyclin 5 6. At higher doses, aspirin inhibits both COX-1 and COX-2, effectively blocking all prostaglandin production.

Evidence suggesting that an imbalance in prostacyclin and TXA2 metabolism was involved in the development of preeclampsia prompted the initial studies of aspirin for preeclampsia prevention because of its preferential inhibition of TXA2 at lower doses 7 8. However, it is likely that preeclampsia is a result of poor placentation from a variety of causes, including ischemia, reperfusion, or dysfunctional maternal inflammatory response towards the trophoblast 1 9. Whether low-dose aspirin improves early placental perfusion is unknown, and likewise, the precise mechanism by which low-dose aspirin prevents preeclampsia in some women is also uncertain 10 11.

Risks of Aspirin Use in Pregnancy

Contraindications to Aspirin Use During Pregnancy

There are few absolute contraindications to aspirin therapy 27. Patients with a history of aspirin allergy (eg, urticaria) or hypersensitivity to other salicylates are at risk of anaphylaxis and should not receive low-dose aspirin. Because of significant cross-sensitivity between aspirin and other nonsteroidal drugs, low-dose aspirin is also contraindicated in patients with known hypersensitivity to NSAIDs. Exposure to low-dose aspirin in patients with nasal polyps may result in life-threatening bronchoconstriction and should be avoided. The same is true in patients with asthma who have a history of aspirin-induced acute bronchospasm 27. Relative contraindications to low-dose aspirin include a history of gastrointestinal bleeding, active peptic ulcer disease, other sources of gastrointestinal or genitourinary bleeding, and severe hepatic dysfunction. Reye syndrome has been reported rarely (less than 1%) in children younger than 18 years who are given aspirin while recovering from viral illnesses, particularly influenza and chickenpox. The decision to continue low-dose aspirin in the presence of obstetric bleeding or risk factors for obstetric bleeding should be considered on a case-by-case basis.

Timing of Use During Pregnancy

With the exception of studies of low-dose aspirin for prevention of early pregnancy loss, the majority of trials using low-dose aspirin during pregnancy have initiated treatment between 12 weeks and 28 weeks of gestation. Some investigators have reported optimal results only when treatment is started before 16 weeks 28 29 30 31. A recent meta-analysis of aggregate data from 45 randomized trials reported only a modest reduction in preeclampsia when low-dose aspirin was started after 16 weeks (RR, 0.81; CI, 0.66–0.99) but significant reductions in severe preeclampsia (RR, 0.47; CI, 0.26–0.83) and fetal growth restriction (RR, 0.56; CI, 0.44–0.70) were demonstrated when low-dose aspirin was started before 16 weeks 31. In another meta-analysis, which included data from the recent Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial, the authors reported a reduction in preterm preeclampsia only in the subgroup of patients in which aspirin was initiated before 16 weeks of gestation at a daily dose of 100 mg or more (RR, 0.33; 95% CI, 0.19–0.57) 30. In contrast, another study pooled individual data from 31 high-quality randomized trials and found that the beneficial effects of low-dose aspirin were consistent, whether treatment was started before or after 16 weeks of gestation 32.

There is no apparent benefit to stopping low-dose aspirin before delivery. Study protocols specific to pregnancy have varied, with some discontinuing low-dose aspirin at 36 weeks of gestation and others continuing low-dose aspirin until delivery 14 33 34 35. Discontinuation timing has not been related to excessive maternal or fetal bleeding. Likewise, low-dose aspirin use in the absence of other anticoagulants is not a contraindication to neuraxial blockade 36. Some patients present to care in the first trimester on low-dose aspirin. Whether first-trimester exposure is associated with adverse fetal effects or maternal benefit is not known.

Prevention of Preeclampsia

The hypothesis that preeclampsia might be associated with vascular disturbances and coagulation defects resulting from an imbalance in prostacyclin and TXA2 led to the initial studies of aspirin for preeclampsia prevention. The results of several small trials suggested that low-dose aspirin may be beneficial for women at high risk of preeclampsia 37 8. However, until recently, this finding was not confirmed in larger RCTs 16 33 38, including a multicenter trial sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which included more than 5,000 women 33. The 2017 Aspirin for Evidence-Based Preeclampsia Prevention trial randomized 1,776 women at high risk of preeclampsia based on a first-trimester screening algorithm to 150-mg aspirin or placebo 39. The authors found a significant decrease in the rate of preterm preeclampsia (4.3% versus 1.6%; odds ratio, 0.38; 95% CI, 0.20–0.74). Although the 150-mg dose was used in this study, there are no available studies comparing 60–80 mg versus 150 mg. Further, the screening algorithm used includes first-trimester serum markers, including placental growth factor and pregnancy-associated plasma protein-A, as well as uterine artery dopplers, which limits the generalizability to a U.S. population. Therefore, a higher dose or doubling of the available 81-mg dose cannot be recommended at this time.

A meta-analysis pooling individual patient data from 31 RCTs showed a modest effect of low-dose aspirin prophylaxis on prevention of preeclampsia in groups of women with various risk profiles (RR, 0.90; 95% CI, 0.84–0.97) 13. A subsequent Cochrane review, which pooled aggregate data from 59 trials, reported a 17% relative reduction in preeclampsia with low-dose aspirin use 12. However, this large risk reduction may reflect publication bias (a small, early positive trial is more likely to be published) or chance findings because the largest trials in the analysis showed no significant protective effect.

The 2014 USPSTF guideline on low-dose aspirin for prevention of morbidity and mortality from preeclampsia is based on the findings of their systematic review, which pooled data from 15 high-quality RCTs, 13 of which reported preeclampsia incidence among women considered at highest risk of disease Table 1 2. A 24% reduction in preeclampsia (RR, 0.76; CI, 0.62–0.95) with low-dose aspirin prophylaxis (60–150 mg/day) was demonstrated 14. However, the authors suggested this dramatic reduction in relative risk might be closer to 10% because of “small study effects” of most of the included trials. Depending on baseline preeclampsia risk, the relative risk reduction with low-dose aspirin was associated with a small decrease in an absolute risk reduction of 2–5%.

Based on the findings from the USPSTF and others, low-dose aspirin prophylaxis (81 mg/day) after 12 weeks of gestation modestly reduces the risk of preeclampsia in women at increased risk, without resulting in adverse fetal effects, increased maternal bleeding, or placental abruption. The recommendation to give low-dose aspirin prophylaxis to high-risk women is based on the number needed to treat in individual risk groups, which in turn is based on disease prevalence and treatment effect. In low-risk groups (disease prevalence of 2%), the number needed to treat is approximately 500, compared with a number needed to treat of 50 women in a high-risk group with a disease prevalence of 20%. The USPSTF guideline recommends giving low-dose aspirin after 12 weeks of gestation to women with an absolute risk of preeclampsia of at least 8%, the lowest incidence of preeclampsia in control groups of studies included in their review 2. Based on historic and demographic risk factors, the USPSTF guideline recommends that women with any of the high-risk factors for preeclampsia should receive low-dose aspirin prophylaxis. Low-dose aspirin prophylaxis should be considered in women with more than one of several moderate risk factors for preeclampsia Table 1.

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support the USPSTF guideline criteria for prevention of preeclampsia. Low-dose aspirin (81 mg/day) prophylaxis is recommended in women at high risk of preeclampsia and should be initiated between 12 weeks and 28 weeks of gestation (optimally before 16 weeks) and continued daily until delivery. Women who were receiving medically-indicated low-dose aspirin for other established medical indications before 12–28 weeks may continue with low-dose aspirin treatment.

Stillbirth

Low-dose aspirin prophylaxis is not recommended for women with a history of stillbirth in the absence of risk factors for preeclampsia. Stillbirth and preeclampsia share many of the same risk factors, and when stillbirth is related to placental dysfunction, the underlying mechanisms are also likely similar. Few studies have focused solely on the effect of low-dose aspirin prophylaxis on stillbirth. In one early nonrandomized trial, investigators reported a nearly twofold increase in live births when low-dose aspirin was given to women with at least one prior pregnancy loss at more than 13 weeks of gestation and a negative result on antiphospholipid antibody testing 40. Findings were similar in a retrospective cohort study of 230 women with prior fetal loss at more than 10 weeks of gestation 41. However, the results of prospectively collected stillbirth data from RCTs and meta-analyses designed to study the use of low-dose aspirin for preeclampsia prevention are inconclusive 12 13 14. Until additional supportive evidence becomes available, low-dose aspirin prophylaxis is not recommended solely for the indication of prior unexplained stillbirth in the absence of risk factors for preeclampsia.

Fetal Growth Restriction

Low-dose aspirin prophylaxis for prevention of recurrent fetal growth restriction is similarly not currently recommended in women without other risk factors for preeclampsia because of insufficient evidence in women with an isolated history of fetal growth restriction. However, in women at risk of preeclampsia, prophylaxis with low-dose aspirin (particularly when initiated less than 16 weeks of gestation) may reduce the risk of fetal growth restriction. Abnormal placentation resulting in poor placental perfusion (ie, placental insufficiency) is the most common pathology associated with fetal growth restriction 42. Some investigators have suggested that low-dose aspirin, initiated early in the first trimester, may prevent fetal growth restriction through its inhibitory action on platelet aggregation and improvement in placental development 43 44. One study first reported that low-dose aspirin, in combination with dipyridamole, significantly reduced the incidence of recurrent fetal growth restriction 45. Although this outcome was confirmed in a subsequent meta-analysis, the study did not identify which women were most likely to benefit from low-dose aspirin 46. There are currently no well-powered RCTs evaluating the role of low-dose aspirin in the prevention of recurrent fetal growth restriction in otherwise low-risk women. Systematic reviews of low-dose aspirin when used in the setting of preeclampsia prevention have consistently reported a 10–20% reduction in fetal growth restriction or infants who were small for gestational age 12 13 14 29 30 31 32. Evidence as to whether starting low-dose aspirin before 16 weeks of gestation influences the degree to which low-dose aspirin is beneficial in reducing fetal growth restriction is inconclusive, though some meta-analyses have suggested improved benefit with earlier initiation 29 30 31 32. Currently, because the majority of evidence supporting a reduction of fetal growth restriction from low-dose aspirin prophylaxis comes from studies of women who were also at risk of preeclampsia—not with histories of fetal growth restriction alone—there is insufficient evidence to support the use of low-dose aspirin for fetal growth restriction prophylaxis in the absence of other risk factors for preeclampsia.

Preterm Birth

The effect of low-dose aspirin on preterm birth as a primary outcome remains understudied. However, until evidence from high-quality studies directed towards prevention of spontaneous preterm birth become available, low-dose aspirin prophylaxis for prevention of spontaneous preterm birth, in the absence of risk factors for preeclampsia, is not recommended.

Aspirin has been shown to decrease uterine contractility by inhibiting COX-dependent prostaglandin synthesis 47. High doses of aspirin have been studied to treat preterm labor, but the irreversible binding to COX-2 and adverse maternal and fetal effects of high-dose aspirin prohibit its use in the clinical setting. Low-dose aspirin has been reported to reduce preterm birth (at less than 37 weeks of gestation) in 8–14% of women at risk of preeclampsia 12 13 14 32. However, whether this reflects a reduction in medically indicated or spontaneous preterm births is not clear in most studies. A recent systematic review and meta-analysis 48 analyzed individual patient data from 17 trials of preeclampsia prevention (28,797 participants) that supplied sufficient detail regarding whether delivery was spontaneous or medically indicated. In that study, treatment with low-dose aspirin resulted in a 7% reduction in the risk of spontaneous preterm birth at fewer than 37 weeks (RR, 0.93; 95% CI, 0.86–0.996) and a 14% reduction in spontaneous preterm birth at fewer than 34 weeks (RR, 0.86; 95% CI, 0.76–0.99) compared with controls. Spontaneous preterm birth at fewer than 28 weeks was reduced by 19%, but the difference was not statistically significant (RR, 0.81; 95% CI, 0.59–1.1) 48. Another study using data from a randomized controlled trial of low-dose aspirin versus placebo given to women with a history of pregnancy loss reported that low-dose aspirin, started before pregnancy and continued through pregnancy, was not associated with a reduction in overall preterm births (RR, 0.72; 95% CI, 0.42–1.23), spontaneous preterm birth (RR, 0.51; 95% CI, 0.19–1.34), or medically indicated preterm birth (RR, 0.89; 95% CI, 0.44–1.80) 49.

Early Pregnancy Loss

The combination of low-dose aspirin and unfractionated or low-molecular-weight heparin has been shown to reduce the risk of early pregnancy loss in women with antiphospholipid syndrome 50. However, low-dose aspirin has not been shown to prevent unexplained early pregnancy loss in women who do not have antiphospholipid syndrome. Pooling data from two trials (256 participants), one study reported no increase in live births among women treated with low-dose aspirin compared with placebo (RR: 0.94, CI, 0.80–1.11) 51. A 2014 study also reported no difference in live births when 1,078 women with one or two prior pregnancy losses were given low-dose aspirin or placebo before pregnancy (58% versus 53%, P=.0984). Pregnancy loss occurred in 13% of 535 women given low-dose aspirin compared with 12% of 543 women in the placebo group ( P=.7812) 35. Based on the available evidence, the use of low-dose aspirin prophylaxis is not recommended for the prevention of early pregnancy loss.