Why start low‑dose aspirin in the first trimester for a pregnant woman who is high‑risk for placental‑mediated complications (e.g., prior pre‑eclampsia, chronic hypertension, pre‑gestational diabetes, renal disease, antiphospholipid syndrome, systemic lupus erythematosus, multiple gestation, or abnormal uterine artery Doppler)?

Why Start Aspirin in High-Risk Pregnancy

Low-dose aspirin should be started between 12-16 weeks of gestation in high-risk pregnant women because it reduces preeclampsia by 24%, preterm birth by 14%, and intrauterine growth restriction by 20%, with an excellent safety profile and no increased risk of bleeding complications. 1, 2

Mechanism of Action

Low-dose aspirin works by inhibiting cyclooxygenase-1 in the arachidonic acid pathway, which decreases thromboxane A2 production—a key mediator of vasoconstriction and platelet aggregation. 3 This rebalancing of thromboxane A2 and prostacyclin maintains adequate uteroplacental blood flow during the critical period of placentation in the first and early second trimester. 3, 4

The pathophysiology of preeclampsia begins with defective placentation: shallow trophoblast invasion leads to poor remodeling of spiral arteries, resulting in reduced uteroplacental perfusion and placental ischemia. 3 This metabolic stress triggers release of inflammatory mediators (thromboxane A2, sFLT-1, anti-angiogenic factors) that cause maternal endothelial dysfunction, vasoconstriction, and hypertension. 3 Aspirin initiated early—ideally before 16 weeks—can improve spiral artery remodeling during the window when placentation occurs, thereby preventing the cascade that leads to preeclampsia. 1, 4

High-Risk Factors Requiring Aspirin

The American College of Obstetricians and Gynecologists and U.S. Preventive Services Task Force define high-risk factors as: 5, 6

• History of preeclampsia (especially early-onset with delivery <34 weeks) 1, 5
• Chronic hypertension 3, 5, 6
• Type 1 or type 2 diabetes 1, 5, 6
• Renal disease 5, 6
• Autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome) 1, 5, 6
• Multifetal gestation 1, 5, 6

Women with any single high-risk factor should receive aspirin prophylaxis. 5, 6 Pre-existing conditions like hypertension, diabetes, and inflammatory states contribute to poor placentation and decreased uteroplacental perfusion, making these populations particularly vulnerable. 3

Dosing Recommendations

Standard dosing is 81-100 mg daily for most high-risk women, but emerging evidence strongly supports higher doses (100-150 mg daily) for certain populations. 1, 7

Standard Dose (81 mg)

• Recommended by ACOG for most high-risk women 5, 6
• Reduces preeclampsia risk by 24% when started before 16 weeks 1, 2

Higher Dose (100-150 mg) - Consider for:

• Chronic hypertension: Standard 81 mg has shown NO benefit in preventing superimposed preeclampsia in this population (34.3% without aspirin vs 35.5% with 81 mg, p=0.79), and severe features actually increased (21.7% vs 31.0%, p=0.03). 1 International guidelines suggest 150-162 mg for this group. 1
• Diabetes (type 1 or 2): The American Diabetes Association recommends 100-150 mg daily, as diabetes independently elevates preeclampsia risk. 1
• BMI >40 kg/m²: Higher body weight increases platelet turnover and reduces aspirin absorption, requiring higher doses for adequate platelet inhibition. 1, 8
• Multiple gestation: Higher doses may be more effective in twin pregnancies. 8

Meta-analyses demonstrate that aspirin doses ≥100 mg initiated before 16 weeks are significantly more effective than lower doses (RR 0.33,95% CI 0.19-0.57, p<0.0001). 1, 7 The Royal College of Obstetricians and Gynaecologists recommends 150 mg daily, and the International Federation of Gynecology and Obstetrics suggests 150 mg or two 81 mg tablets as an acceptable alternative. 1, 7

Timing: Critical Window for Effectiveness

Aspirin must be started between 12-16 weeks of gestation, optimally before 16 weeks, to achieve maximum benefit. 1, 5, 6, 7

The rationale for this narrow window is biological: defective placentation and inadequate spiral artery remodeling occur in the first trimester. 3, 1 Aspirin initiated during this critical period can improve uteroplacental blood flow while placentation is still occurring. 1, 4 Starting after 16 weeks provides diminishing returns, though guidelines allow initiation up to 28 weeks if the patient presents late. 5, 6

Continue aspirin daily until delivery—do not stop at 36 weeks. 1 The common practice of stopping aspirin at 36 weeks "to be safe" is not evidence-based and removes protection during a high-risk period when preeclampsia can still develop or worsen. 1 Preeclampsia risk persists throughout pregnancy and even into the early postpartum period, with eclamptic seizures potentially occurring after delivery. 1

Safety Profile

Low-dose aspirin (75-162 mg daily) has an excellent safety record throughout pregnancy and does not increase risks of: 1, 2, 5, 6

• Placental abruption 1, 2, 5
• Postpartum hemorrhage 1, 2, 5
• Fetal intracranial bleeding 1, 2, 5
• Perinatal mortality 1, 2, 5
• Congenital anomalies 1, 2, 5

This safety data comes from large meta-analyses of randomized controlled trials involving tens of thousands of women. 1, 2 The FDA warning about aspirin in the third trimester refers to high doses (>100 mg), not prophylactic low doses used for preeclampsia prevention. 1

Additional Benefits Beyond Preeclampsia Prevention

Beyond the 24% reduction in preeclampsia, aspirin provides: 1, 2

• 14% reduction in preterm birth 1, 2
• 20% reduction in intrauterine growth restriction 1, 2
• Increased mean birthweight by approximately 130 grams 2

The number needed to treat to prevent one case of preeclampsia is 42 in high-risk women, with absolute risk reduction of 2-5%. 2

Special Populations

Antiphospholipid Syndrome

For obstetric APS, combine low-dose aspirin (81-100 mg daily) with prophylactic-dose low-molecular-weight heparin starting in the first trimester. 1 For thrombotic APS, use therapeutic-dose LMWH with aspirin. 1 Continue anticoagulation for 6-12 weeks postpartum. 1

Systemic Lupus Erythematosus

Start low-dose aspirin in the first trimester and add hydroxychloroquine throughout pregnancy to reduce disease activity and preeclampsia risk. 1 Test early for antiphospholipid antibodies to identify those requiring combined aspirin + LMWH. 1

Planned Cesarean Delivery

Low-dose aspirin does not increase surgical or bleeding complications for women undergoing cesarean delivery and can be safely continued until delivery. 1, 8 For spinal anesthesia, some guidelines suggest discontinuing aspirin 7-10 days before scheduled cesarean and verifying platelet count >75 × 10⁹/L, though this is not universally required for low-dose aspirin. 8

Common Pitfalls to Avoid

• Do not wait until after 16 weeks to start aspirin—efficacy decreases with later initiation. 1, 7
• Do not stop aspirin at 36 weeks—this removes protection during a critical period without evidence-based rationale. 1
• Do not use 81 mg for women with chronic hypertension—this dose has proven ineffective in this population; use 100-150 mg instead. 1
• Do not confuse low-dose aspirin (75-162 mg) with high-dose aspirin—safety concerns apply only to high doses. 1
• Do not forget to adjust dose for obesity—women with BMI >40 kg/m² require higher doses (100-150 mg) for adequate platelet inhibition. 1, 8