Effectiveness and Safety of Low-Dose Aspirin to Prevent Preterm Preeclampsia

By Ahizechukwu C. Eke, MD, PhD, MPH

Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore

SYNOPSIS: An aspirin dosage of 150 mg to 162 mg per day, when started in the first trimester of pregnancy, was linked to a decreased risk of preterm preeclampsia compared to an aspirin dosage of 75 mg to 81 mg per day.

SOURCE: Ghesquiere L, Guerby P, Marchant I, et al. Comparing aspirin 75 to 81 mg vs 150 to 162 mg for prevention of preterm preeclampsia: Systematic review and meta-analysis. Am J Obstet Gynecol MFM 2023;5:101000.

Preeclampsia, defined as a multisystemic disorder characterized by new onset of high blood pressure (after 20 weeks of gestation) plus significant end-organ dysfunction, with or without proteinuria, affects about 3% to 5% of pregnancies in the United States.^1-3 Preeclampsia remains a significant cause of maternal, fetal, and perinatal morbidity and mortality, making prevention of preeclampsia increasingly paramount. The use of low-dose aspirin for the prevention of preeclampsia and other adverse pregnancy outcomes has become increasingly common since its recommendation by the United States Preventive Services Task Force (USPSTF), and endorsement by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM).^4-6

Early research on aspirin, most of which was done in the 1980s, showed a significant decrease in the risk of preeclampsia for high-risk women. However, subsequent larger studies, such as the Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP) and the National Institute of Child Health and Human Development (NICHD) Network of Maternal-Fetal Medicine Units trials conducted in the 1990s, did not replicate these preventive findings for aspirin but demonstrated a very small and non-significant reduction in the risk of preeclampsia.^7,8 Several systematic reviews and meta-analytic studies published in the last 10-15 years have demonstrated a modest reduction in preeclampsia risk with aspirin use, with the most recent meta-analysis showing a 28% reduction in the risk of preeclampsia (relative risk [RR], 0.72; 95% confidence interval [CI], 0.62, 0.83).⁹ Most clinical trials have used aspirin doses between 60 mg and 100 mg. However, the ASPRE randomized trial is one of the few that used 150 mg to prevent preeclampsia.¹⁰ The ideal dose of aspirin for preventing preeclampsia is not yet certain from the existing evidence. Therefore, Ghesquiere and colleagues evaluated the efficacy and safety of the two most common aspirin dose categories for preventing preeclampsia.¹¹

This study was a systematic review and meta-analysis of randomized controlled trials (RCTs) that evaluated the association between low-dose aspirin use (75 mg to
81 mg vs. 150 mg to 162 mg) and preeclampsia risk between 1985 to 2023.¹¹ All RCTs that evaluated low-dose aspirin in pregnant women at risk of preeclampsia, beginning from the first trimester and followed until delivery, were included. Studies were excluded if aspirin was combined with other therapies for reducing preeclampsia risk, if therapy was started prior to pregnancy, and if aspirin was commenced at > 16 weeks of gestation. The primary outcome was development of preeclampsia at < 37 weeks of gestation. Secondary outcomes included development of preeclampsia at > 37 weeks of gestation, all preeclampsia regardless of gestational age, preeclampsia with severe features, early onset preeclampsia (development of preeclampsia at < 34 weeks of gestation), fetal growth restriction, preterm birth, stillbirth, admission to the neonatal intensive care unit, gestational age at delivery, birthweight, miscarriage, and neonatal and perinatal death. Preeclampsia was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg that occurs at > 20 weeks of gestation, in combination with significant proteinuria (urinary protein ≥ 300 mg/24 hours or ≥ 1+ protein on urine dipstick), while severe preeclampsia was defined as preeclampsia with at least one severe feature (SBP ≥ 160 mmHg or DBP ≥ 110 mmHg on two occasions at least six hours apart, impaired liver function, oliguria, thrombocytopenia, fetal growth restriction, pulmonary edema, cerebral or visual symptoms, or epigastric or right upper quadrant pain). Effect estimates were reported as pooled analyses of RR that measured the relationship between low-dose aspirin (exposure) and outcomes (preeclampsia). Heterogeneity was assessed using Higgins I² and was considered high if values exceeded 50%. Statistical analyses were conducted at 95% CI, with a P value of < 0.05 being statistically significant.

Four RCTs including 552 participants met inclusion criteria and were included in the final synthesis. Meta-analysis demonstrated that an aspirin dosage between 150 mg and 162 mg daily was associated with a significant reduction in the risk of preterm preeclampsia at < 37 weeks compared with dosages between 75 mg and 81 mg daily (RR, 0.34; 95% CI, 0.15, 0.79; P = 0.01; I² = 0%). An aspirin dosage of between 150 mg and 162 mg daily also was associated with a significant reduction in the risk of preeclampsia with severe features compared with dosages between 75 mg and 81 mg daily (RR, 0.23; 95% CI, 0.09, 0.62; P = 0.003; I² = 0%); all preeclampsia regardless of gestational age (RR, 0.42; 95% CI, 0.17, 1.05; P = 0.06); neonatal intensive care admission (RR, 0.58; 95% CI, 0.34, 0.99; P = 0.04; I² = 0%); gestational age at delivery (mean difference [MD], 1.24; 95% CI, 0.26, 2.22; P = 0.01; I² = 29%); and neonatal birthweight (MD, 176.5; 95% CI, 66.9, 286.1; P = 0.002; I² = 0%). No significant differences were observed for the risk of term preeclampsia at > 37 weeks (RR, 0.57; 95% CI, 0.12, 2.64; P = 0.48), early onset preeclampsia at < 34 weeks (RR, 0.42; 95% CI, 0.10, 1.67; P = 0.22; I² = 0%); fetal growth restriction (RR, 0.71; 95% CI, 0.41, 1.23; P = 0.22; I² = 0%); spontaneous preterm birth (RR, 0.57; 95% CI, 0.27, 1.20; P = 0.14); stillbirths, neonatal death, miscarriages, and perinatal death.

COMMENTARY

Low-dose aspirin typically is started between 12 and 16 weeks of gestation and continued until term for the prevention of preeclampsia in women with risk factors for preeclampsia, as recommended by USPSTF, ACOG, and SMFM.^4,5,12 Some of these risk factors include prior history of preeclampsia, multiple gestation, nulliparity, age > 35 years, chronic hypertension, pregestational diabetes, autoimmune diseases (anti-phospholipid syndrome, systemic lupus erythematosus), and chronic renal disease.^13,14 These major and minor risk factors are compositely stratified into high-, moderate-, and low-risk categories, and dosing of aspirin is based on this maternal risk stratification.^4,5 Current data only support the use of low-dose aspirin in women at risk of preeclampsia with high or moderate risk for preeclampsia.^5,12

Screening for preeclampsia during prenatal visits traditionally has depended on maternal demographic characteristics and medical and obstetric history, but recent studies have screened for preeclampsia by a combination of maternal clinical risk factors, biophysical markers (mean arterial blood pressure, Doppler assessment of the uterine arteries), and biochemical markers (placental growth factor, soluble vascular endothelial growth factor receptor-1, pregnancy-associated plasma protein A).^15,16 Several preeclampsia screening models have been developed from a logistic regression analysis of a combination of maternal biophysical and biochemical markers and have been validated in several settings. However, the most widely used method for preeclampsia screening is based on guidelines that recommend selecting a high-risk group who may benefit from low-dose aspirin based on medical and obstetric history during early pregnancy. Although the use of biomarkers for first trimester preeclampsia screening is promising, the combined use of biomarkers and ultrasonography in the prediction of preeclampsia should remain investigational and cannot be recommended routinely until such screening has been shown to improve pregnancy outcomes.¹²

The benefits of aspirin are dependent on the gestational age at which it is commenced. Several large aggregate meta-analyses have shown that the largest reduction of severe preeclampsia occurs when low-dose aspirin is started before 16 weeks of gestation, which is when the majority of published trials began intervention.¹⁷ ACOG and SMFM recommend that prophylactic low-dose aspirin be started between 12 and 28 weeks of gestation (ideally between 12 and 16 weeks) in pregnant women at moderate to high risk of preeclampsia.¹⁷ Despite concerns about potential harms of low-dose aspirin, there is no evidence of increased risks of hemorrhage, intraventricular hemorrhage, early closure of the ductus arteriosus, or increased incidences of placental abruption with the use of low-dose aspirin for preventing preeclampsia. Furthermore, there is no evidence that congenital anomalies, motor impairments, developmental delay, respiratory problems, bleeding disorders, or weight or height anomalies are more common in children whose mothers were exposed to modest doses of aspirin during pregnancy.¹⁸ Aspirin may be avoided in situations where there is an allergy to nonsteroidal anti-inflammatory agents, a history of acute gastritis, or gastrointestinal bleeding.

In summary, the benefits of aspirin in reducing the risk of preeclampsia outweigh the risks. USPSTF, ACOG, SMFM, and several other national obstetric societies continue to recommend the use of low-dose aspirin between 12 and 28 weeks of gestation in people at high risk of preeclampsia and those with multiple moderate risk factors, to be continued to delivery.

REFERENCES

1. Lambert G, Brichant JF, Hartstein G, et al. Preeclampsia: An update. Acta Anaesthesiol Belg 2014;65:137-149.
2. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: Age-period-cohort analysis. BMJ 2013;347:f6564.
3. Johnson JD, Louis JM. Does race or ethnicity play a role in the origin, pathophysiology, and outcomes of preeclampsia? An expert review of the literature. Am J Obstet Gynecol 2022;226:S876-S885.
4. LeFevre ML; U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161:819-826.
5. [No authors listed]. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol 2018;132:e44-e52.
6. Combs CA, Kumar NR, Morgan JL. Society for Maternal-Fetal Medicine special statement: Prophylactic low-dose aspirin for preeclampsia prevention — quality metric and opportunities for quality improvement. Am J Obstet Gynecol 2023; May 4. doi:10.1016/j.ajog.2023.04.039. [Online ahead of print].
7. [No authors listed]. CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet 1994;343:619-629.
8. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-705.
9. Wang Y, Guo X, Obore N, et al. Aspirin for the prevention of preeclampsia: A systematic review and meta-analysis of randomized controlled studies. Front Cardiovasc Med 2022;9:936560.
10. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613-622.
11. Ghesquiere L, Guerby P, Marchant I, et al. Comparing aspirin 75 to 81 mg vs 150 to 162 mg for prevention of preterm preeclampsia: Systematic review and meta-analysis. Am J Obstet Gynecol MFM 2023;5:101000.
12. Society for Maternal-Fetal Medicine (SMFM). Executive summary: Workshop on preeclampsia, January 25-26, 2021, cosponsored by the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation. Am J Obstet Gynecol 2021;225:B2-B7.
13. Narkhede AM, Karnad DR. Preeclampsia and related problems. Indian J Crit Care Med 2021;25(Suppl 3):S261-S266.
14. Chang KJ, Seow KM, Chen KH. Preeclampsia: Recent advances in predicting, preventing, and managing the maternal and fetal life-threatening condition. Int J Environ Res Public Health 2023;20:2994.
15. Tarca AL, Taran A, Romero R, et al. Prediction of preeclampsia throughout gestation with maternal characteristics and biophysical and biochemical markers: A longitudinal study. Am J Obstet Gynecol 2022;226:126.e1-126.e22.
16. Wertaschnigg D, Reddy M, Mol BWJ, et al. Prenatal screening for pre-eclampsia: Frequently asked questions. Aust N Z Obstet Gynaecol 2019;59:477-483.
17. US Preventive Services Task Force; Davidson KW, Barry MJ, Mangione CM, et al. Aspirin use to prevent preeclampsia and related morbidity and mortality: US Preventive Services Task Force Recommendation Statement. JAMA 2021;326:1186-1191.
18. [No authors listed]. Low dose aspirin in pregnancy and early childhood development: Follow up of the collaborative low dose aspirin study in pregnancy. CLASP collaborative group. Br J Obstet Gynaecol 1995;102:861-868.