Daily low-dose aspirin did not significantly alter serum levels of pregnancy-associated plasma protein A or placental growth factor in women at high risk for preterm preeclampsia, according to a recent study.
The report, published in the American Journal of Obstetrics & Gynecology, analyzed 5,507 pregnancy-associated plasma protein A (PAPP-A) and 5,523 placental growth factor (PlGF) measurements from 1,620 participants. It was a secondary analysis of the ASPRE trial, a multicenter randomized controlled study conducted across 13 maternity hospitals in six countries which evaluated the efficacy of 150 mg of daily aspirin in preventing preterm preeclampsia in high-risk women. This analysis investigated aspirin's effects on PAPP-A and PlGF trajectories throughout pregnancy.
Methods
Researchers conducted a longitudinal analysis of repeated PAPP-A and PlGF measurements from ASPRE trial participants. Blood samples were collected at baseline (11-13+6 weeks) and follow-up visits at 19 to 24, 32 to 34, and 36 weeks gestation. The study included 798 women in the aspirin group and 822 in the placebo group.
Generalized additive mixed models (GAMM) with natural cubic spline functions were used to analyze biomarker trajectories. The models accounted for treatment effects, gestational age, and individual random intercepts and slopes.
Results
There were no significant differences in PAPP-A trajectories (interaction P=.259) or PlGF trajectories (interaction P=.335) between the aspirin and placebo groups. Mean PAPP-A and PlGF multiples of the median (MoM) values were consistently below 1.0 in both groups. Raw PAPP-A values increased throughout gestation, while raw PlGF values increased until 32 weeks, then declined.
Estimated geometric means at 36 weeks gestation were:
- PAPP-A: 32.414 IU/L (95% confidence interval [CI] = 30.867-34.034) for aspirin vs 33.931 IU/L (95% CI = 32.300-35.645) for placebo
- PlGF: 144.109 pg/mL (95% CI = 133.906-155.089) for aspirin vs 135.332 pg/mL (95% CI = 125.760-145.632) for placebo
PAPP-A MoM geometric means at different time points were:
- 12 weeks: Aspirin group = 0.812 (95% CI = 0.776-0.850), placebo group = 0.835 (95% CI = 0.798-0.873)
- 22 weeks: Aspirin group = 0.492 (95% CI = 0.472-0.513), placebo group 0.537 (95% CI = 0.515-0.559)
- 32 weeks: Aspirin group 0.437 (95% CI = 0.416-0.460), placebo group = 0.453 (95% CI = 0.431-0.476)
- 36 weeks: Aspirin group = 0.525 (95% CI = 0.497-0.555), placebo group = 0.545 (95% CI = 0.515-0.576).
PlGF MoM geometric means at different time points were:
- 12 weeks: Aspirin group = 0.707 (95% CI = 0.681-0.734), placebo group = 0.691 (95% CI = 0.666-0.717)
- 22 weeks: Aspirin group = 0.819 (95% CI = 0.783-0.856), placebo group = 0.831 (95% CI = 0.795-0.869)
- 32 weeks: Aspirin group = 0.571 (95% CI = 0.535-0.608), placebo group = 0.552 (95% CI = 0.519-0.588)
- 36 weeks: Aspirin group = 0.696 (95% CI = 0.648-0.717), placebo group = 0.658 (95% CI = 0.612-0.706).
Fixed effects estimates from GAMM for the PAPP-A MoM model were:
- Intercept: 0.05822 (standard error [SE] = 0.01146, P<.001)
- Aspirin effect: 0.00766 (SE = 0.01561, P=.620)
- Preeclampsia risk effect: -0.06567 (SE = 0.06599, P=.320).
Fixed effects estimates from GAMM for the PlGF MoM model were:
- Intercept: -0.14835 (SE = 0.00970, P<.001)
- Aspirin effect: 0.01267 (SE = 0.01309, P=.333)
- Preeclampsia risk effect: -0.68044 (SE = 0.06108, P<.001).
The PAPP-A model had an adjusted R² of 0.105 and Bayesian Information Criterion (BIC) of 493, while the PlGF model had an adjusted R² of 0.061 and BIC of 746.
In total, 160 participants across the analysis had preeclampsia (9.9%); in the aspirin group, the incidence was 66 of 798 participants (8.3%), and in the placebo group, the incidence was 94 of 822 participants (11.4%). The incidence of preterm preeclampsia (<37 weeks) was 13/798 (1.6%) in the aspirin group and 35/822 (4.3%) in the placebo group.
Treatment adherence was good—defined as ≥85% of prescribed tablets taken—in 79.9% of participants.
Sensitivity analyses restricted to women with ≥90% treatment adherence (n=1,143) yielded similar results (PAPP-A interaction P=.367, PlGF interaction P=.583). Analyses excluding preeclampsia cases also showed consistent findings (PAPP-A interaction P=.133, PlGF interaction P=.410).
The study used the Fetal Medicine Foundation algorithm at 11-13+6 weeks for screening, which combines maternal characteristics, medical history, mean arterial pressure, uterine artery pulsatility index, and serum PAPP-A and PlGF. Biomarkers were measured using the DELFIA Xpress random access platform (PerkinElmer Inc), with baseline measurements on fresh samples and follow-up measurements on samples stored at -80°C.
Limitations of the study included smaller participant numbers in later follow-up visits and about 6% mistimed observations. However, mixed-effects models addressed these issues by treating gestational age as a continuous variable.
The study authors concluded, "In women at increased risk of preterm preeclampsia, aspirin [at] 150 mg daily had no significant effects on [PAPP-A] or [PIGF] trajectories when compared to placebo."
The authors reported no conflicts of interest.