Combined impact of first-trimester risk and aspirin adherence on preterm preeclampsia prevention

Aspirin prevents preterm preeclampsia in high-risk pregnancies, but the extent to which its effectiveness depends on adherence and baseline risk remains uncertain.

To evaluate how first-trimester preeclampsia risk and aspirin adherence jointly influence aspirin's preventive effect, and to assess the potential benefits and harms of targeted versus universal prophylaxis.

We combined data from the Aspirin for Evidence-based Preeclampsia Prevention and the Screening Program for Preeclampsia cohorts, including singleton pregnancies delivering at ≥24 weeks. All pregnancies were screened for preterm preeclampsia at 11⁺⁰ to 13⁺⁶ weeks using the Fetal Medicine Foundation competing risks model, which combines maternal characteristics, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor. Aspirin adherence and baseline risk distributions were modeled using Monte Carlo simulations to estimate relative risk, absolute risk reduction, and number needed to treat under 4 adherence scenarios: full (100%), trial-based (intention-to-treat), 50%, and variable adherence positively correlated with predicted risk (ρ=0.4). Decision-curve analysis assessed net benefit across risk thresholds.

Simulations informed by 51,024 pregnancies indicated that aspirin's preventive effect varied substantially with adherence. In fixed-adherence scenarios, the strongest effect occurred with full adherence (relative risk 0.25, 95% confidence interval 0.09-0.66) and the weakest with 50% adherence (relative risk 0.70, 95% confidence interval 0.58-0.98). Under variable adherence, relative risk decreased nonlinearly with baseline risk, approaching the per-protocol effect in high-risk women but near null in low-risk women. Absolute risk reduction and number needed to treat were highly dependent on predicted risk: at 1 in 50 to 1 in 100 risks, number needed to treat ranged from 73 to 146 with high adherence and 161 to 321 with 50% adherence, whereas at lower risks, numbers needed to treat exceeded several thousand even with high adherence. Decision-curve analysis indicated that targeted prophylaxis using the Fetal Medicine Foundation model provided greater net benefit than universal treatment, primarily by avoiding unnecessary interventions.

Aspirin is highly effective for preventing preterm preeclampsia in women at increased risk, but its effect depends on predicted risk and adherence. The absolute benefit of treatment is negligible in low-risk populations. A targeted screen-and-treat strategy using the Fetal Medicine Foundation model maximizes clinical benefit while minimizing unnecessary treatment.