Pharmacodynamics of Aspirin Through Gestation: Predictors of Aspirin Response and Association With Pregnancy Outcome, a Prospective Cohort Study

Abstract

Low-dose aspirin is recommended for prevention of hypertensive disorders of pregnancy (HDP) and preterm birth (PTB) in high-risk pregnancies. There is limited data on factors impacting aspirin response in pregnancy. We aimed to evaluate predictors of aspirin response and association with pregnancy outcome with a prospective study of high-risk pregnancies taking 81 mg aspirin daily. Aspirin response was evaluated with Platelet Function Assay-100 (PFA-100) epinephrine closure time at baseline (< 16 weeks' gestation), follow-up 1 (2-4 weeks after aspirin initiation), and follow-up 2 (28-32 weeks gestation). Multivariable regression was used to identify factors associated with PFA-100 at each visit, and results presented with beta coefficient (B) and confidence interval. The median difference (MD) in PFA-100 in those with and without HDP or PTB was compared. Results included 108 who completed follow-up 1 and 96 who completed both visits with > 75% adherence. PFA-100 was increased from baseline at follow-ups 1 and 2 (MD 37 (27-49); MD 26 (15.5-38.5) respectively). At follow-up 1, obesity (B = -30 (-53 to -7) seconds), diabetes (B = -39 (-75 to -2) seconds), and age (B = 2.2 (0.3-4.0) seconds per year increased) were associated with PFA-100 response. Those with HDP in the current pregnancy versus not had similar aspirin response, but those with PTB versus term birth in the current pregnancy had reduced aspirin response at 28-32 weeks (MD -27 (-54 to -3) seconds). A daily dose of 81 mg aspirin results in platelet inhibition throughout gestation. Obesity, diabetes, and younger age are associated with reduced aspirin response in pregnancy.

Keywords: aspirin; pharmacodynamics; pharmacology; preeclampsia; pregnancy; preterm birth.

FIGURE 1

Cohort flow diagram.

FIGURE 2

Aspirin response as measured by platelet inhibition (PFA‐100 epinephrine closure time) in high risk singletons (N = 96) taking 81 mg aspirin daily with > 75% adherence documented each visit. Higher closure time indicates increased platelet inhibition, expected with aspirin use. N = 96 with > 75% adherence at follow‐ups 1 and 2. Paired sample comparison with related samples Wilcoxon signed rank test. p < 0.05 considered significant. Box plot indicates interquartile range (box) and range (whiskers).

FIGURE 3

Individual factors associated with reduced response to aspirin in pregnancy, assessed 2–4 weeks' after initiation. In multivariable regression analysis with backward selection, (A) obesity (B = −30 (−53 to −7), p = 0.01), (B) pre‐gestational diabetes (B = −39 (−76 to −2), p = 0.04) were associated with reduced response to aspirin (lower PFA‐100 epinephrine closure time). Mean and 95% confidence interval demonstrated by point and whiskers.

FIGURE 4

Aspirin response and preterm birth: (A) Aspirin response measured by PFA‐100 epinephrine closure time at 28–32 weeks was reduced in those with a preterm versus term birth, data presented as median difference (MD) measured by Mann–Whitney U test with two sided p < 0.05 considered significant. Mean and 95% confidence interval demonstrated by point and whiskers. (B) Reduced aspirin response (PFA‐100 Epinephrine closure time) is predictive of preterm birth. Thresholds indicated are: *PFA‐100 < 128: Sensitivity 75%, Specificity 73%. ^PFA‐100 < 150: Sensitivity 75%, Specificity 52%.