Optimising Aspirin Use for Pre‐Eclampsia Prevention: The Critical Role of Dose, Timing and Adherence

There is abundant evidence that aspirin, commenced at 12 weeks gestation, can be very effective in preventing pre-eclampsia, including preterm pre-eclampsia, preterm delivery and severe pre-eclampsia variants such as HELLP syndrome. However, some clinicians may consider it only modestly effective and neglect its use. Thus, attempts to reduce the morbidity and mortality associated with pre-eclampsia may focus instead on managing its complications, and developing new diagnostics and drugs. Aspirin is hypothesised to improve placental development, either preventing entirely or delaying onset of pre-eclampsia. The Cochrane review by Duley et al. [1] describes a 'small-to-moderate' benefit of aspirin in preventing pre-eclampsia, preterm birth, small-for-gestational age and perinatal death. However, of 34 514 women with individual patient data available, only 9272 were randomised before 16 weeks gestation, and only 5070 received > 75 mg per day. Does the amalgamation of low- and high-doses, with early and late commencement of aspirin give the appearance of lower efficacy, and dissuade clinicians from prioritising aspirin? In resource-limited contexts, where the likelihood of healthy survival to adulthood is significantly lower for preterm infants [2], the importance of a safe, low-cost intervention such as aspirin is even more important. Underestimation of low-cost, effective interventions such as aspirin may cause considerable harm [2]. This editorial seeks to review the impact of dosage, timing and adherence to aspirin on its efficacy in pre-eclampsia prevention, and explore special considerations for utilisation. The Cochrane review [1] examined aspirin dosage. Examining studies with individual patient data available, there appeared to be a greater reduction in risk of pre-eclampsia in the minority of women allocated ≥ 75 mg aspirin than those allocated < 75 mg aspirin (9107 women, 16 trials; RR 0.78, 95% CI 0.66–0.92 vs. 22 618 women, 11 trials; RR 0.92, 95% CI 0.85–1.00). The review found no evidence of a difference by aspirin dose in foetal or neonatal death, preterm delivery or small-for-gestational age birth weight, but of the large studies [3] (ASPRE [3], BLASP 1998 [4], ERASME 2003 [5]) examining aspirin ≥ 75 mg, 61% of participants had poor adherence, and 40% commenced aspirin after 20 weeks. Two systematic reviews investigated aspirin for prevention of pre-eclampsia and foetal growth restriction [6] (Roberge et al. 2016), and pre-term pre-eclampsia [7] (Roberge et al. 2018) respectively. The first [6] clearly demonstrated that aspirin commenced before 16 weeks reduced risk of pre-eclampsia (RR 0.57, 95% CI 0.43–0.75), severe pre-eclampsia (RR 0.47, 95% CI 0.26–0.83) and foetal growth restriction (RR 0.56, 95% CI 0.44–0.70). This was strongly dose-dependent. When commenced > 16 weeks there was only slight evidence of a reduction in pre-eclampsia (RR 0.81, 95% CI 0.66–0.99), and no evidence of a reduction in severe pre-eclampsia (RR 0.85, 95% CI 0.64–1.14) or foetal growth restriction (RR 0.95, 95% CI 0.86–1.05). The second systematic review [7] compared initiation of aspirin ≤ 16 and > 16 weeks, and dosages < 100 mg and ≥ 100 mg. The risk of preterm pre-eclampsia was only reduced in the group receiving ≥ 100 mg from ≤ 16 weeks, where the effect was strong (RR 0.33, 95% CI 0.19–0.57). However, combining studies using 50–60 mg with studies using 75–81 mg likely diluted the effect of the latter. The ASPRE trial [3] (2017) randomised 1776 women, commencing 150 mg aspirin between 11 and 14 weeks, preventing over 50% of cases of pre-eclampsia (OR 0.38, 95% CI 0.20–0.74, p = 0.004). The ASPIRIN trial [8] (2020) included 11 976 women, and commenced 81 mg between 6 and 13 + 6 weeks gestation. Whilst it did not examine reductions in pre-eclampsia itself, the ASPIRIN trial found reductions in foetal loss (OR 0.86, 95% CI 0.74–1.00), maternal perinatal mortality (OR 0.86, 95% CI 0.73–1.00), delivery < 34 weeks (OR 0.75, 95% CI 0.61–0.93) and delivery < 34 weeks with a hypertensive disorder (OR 0.38, 95% CI 0.17–0.85). These findings support those suggested by subgroup analyses within systematic reviews; aspirin is highly effective, if commenced before 16 weeks with good compliance. A dose of 75–81 mg is effective; 150 mg even more so. Meher et al. [9] (reproduced in the Duley et al. systematic review [1]) conducted individual patient data meta-analysis including 30 670 women, to compare the efficacy of aspirin commenced before or after 16 weeks gestation in preventing pre-eclampsia. The results showed minimal difference between the two groups; however, the majority of included trials utilised 50–60 mg aspirin, dosage likely to be only modestly effective. Additional evidence on the importance of early commencement comes from Mendoza et al. [10]. Their non-inferiority trial randomised 1604 women at higher risk of developing pre-eclampsia, to either discontinuation or continuation of aspirin at 24–28 weeks, and suggests that the likelihood of preterm pre-eclampsia may be not affected by earlier cessation of aspirin. Some have questioned whether this trial was adequately powered to detect non-inferiority [11]. Both UK (NICE 2023 [12]) and US guidelines (ACOG 2021 [13]) [12, 13] now endorse commencement before 16 weeks. The EAGeR trial [14] went further, and randomised women planning conception after pregnancy loss to either 81 mg aspirin or placebo, which continued throughout pregnancy. Those taking aspirin had higher conception rates (RR 1.10, 95% CI 1.01–1.19) and possibly higher livebirth rates (RR 1.10, 95% CI 0.98–1.22, 5.1% absolute difference). Despite a higher risk of vaginal bleeding, this was not associated with pregnancy loss. A systematic review examining early commencement of aspirin < 11 weeks did not find evidence of a reduction in pre-eclampsia; however, found only 8 trials, with a combined total of 1426 participants, who were not selected to be at high risk of pre-eclampsia [15]. The EAGeR trial therefore still raises the question; if aspirin is safe, or potentially even beneficial in the first trimester, should aspirin commence even earlier in pregnancy, or even pre-conception? Strategies for aspirin administration have historically either advised universal administration, or risk-factor based screening [16]. Increasingly, however, clinical prediction models such as the Fetal Medicine Foundation model [16] including risk factors, biomarkers (such as PAPP-A) and ultrasound findings (such as uterine artery Dopplers), more reliably identify women at higher risk of pre-eclampsia, identifying 75%–100% of women with pre-eclampsia < 37 weeks [16]. Whilst studies examining the prospective implementation of this model are lacking, this provides a strategy for targeted aspirin administration, which may in turn improve adherence, and reduce costs of aspirin. Chronic kidney disease (CKD) is one of few cautions to the use of aspirin in pregnancy, as well as a strong indication for its use [17, 18]. Some studies have excluded all women with CKD, some only women with renal failure. This has limited the available evidence to guide their management. Women with CKD should not suffer from misplaced fatalism. Neither ASPRE [3] nor ASPIRIN [8] excluded women with CKD. The UK-based Saving Babies Lives initiative [19] recommends 150 mg for most women, reduced to 75 mg with renal disease to mitigate potential renal effects of higher doses. Women, as well as clinicians, may be receiving contradictory messages about the necessity and safety of aspirin in pregnancy. Pre-eclampsia, particularly preterm, is a relatively uncommon outcome, affecting 1.5%–7.7% of births [20], and adherence to medication to prevent a possible (but uncertain) negative outcome is often challenging. Women may receive conflicting messages from non-obstetric clinicians or pharmacists regarding aspirin safety. Many women may be prescribed aspirin and not take it, as in many of the studies included in the Cochrane Review. Table 1 illustrates that in the large trials dominating the Cochrane review, only 1:4 participants took 75 mg or more daily aspirin, and of those only 1:10 with good adherence. Only 3:5 participants started aspirin before 16 weeks. The low adherence is likely to dilute any true effect of aspirin in analyses, regardless of the large numbers of individual patients included. 53% under 20 weeks (thus < 50% under 16 weeks) < 1844 50% under 16.8 weeks (thus < 50% under 16 weeks) < 1647 8776 (1:4) In the ASPRE trial [3], adherence had a strong influence on efficacy. Effectiveness of aspirin was 76% for adherence more than 90%, but only 41% if it dropped below 90%. Factors such as young age, smoking, race, and history of pre-eclampsia all influenced adherence. While aspirin has been found to be generally very safe in pregnancy, some studies have suggested an increased risk of placental abruption [21]. However, subgroup analyses [6] suggest that early (by 16 weeks) commencement may prevent pre-eclampsia-related abruption by improving placentation, whereas a late start may be detrimental. Severe preeclampsia and HELLP syndrome have similar placental histopathologic findings; both are associated with higher rates of placental maternal vascular malperfusion (abnormalities in the placental vasculature, impairing function) and intrauterine growth restriction [22]. HELLP is essentially a severe manifestation of the same underlying pathophysiology, likely preventable by the same mechanisms, although challenging to research due to its rarity [22]. This is critical for clinical practice and counselling. Women with catastrophic complications such as HELLP may avoid further pregnancies, driven by a misconceived futility, when aspirin may help reduce pre-eclampsia incidence, severity or onset. If complications are the result of pre-eclampsia, such as HELLP syndrome and some pre-term birth, aspirin is likely to reduce them. A meta-analysis has shown that in women with pre-pregnancy chronic hypertension, aspirin did not prevent pre-eclampsia [23], but did significantly reduce the risk of preterm delivery. Theoretically, aspirin may improve blood flow within the placenta, but not blood flow before and to the uterus where there may be pre-existing vessel damage. A partial effectiveness could result in a later, milder onset of pre-eclampsia, possibly explaining the reduction in preterm birth. It is therefore still advisable to give aspirin to women with chronic hypertension, but lifestyle modifications before and between pregnancies may be more important [24]. Recent studies have shown that forms of placental dysfunction, such as delayed villous maturation or foetal vascular malperfusion, may be prevalent in diabetes in pregnancy [25], particularly if under-diagnosed and under-treated [26]. A recent study [27] identified that pregnancies with normal PAPP-A and abnormal uterine artery Dopplers uncommonly develop pre-eclampsia, but there is a high incidence of neonatal hypoglycaemia similarly to poorly controlled diabetes. Further research is needed as to whether aspirin could also prove beneficial in improving placental function for women with diabetes and glucose dysmetabolism. Many trials examining the use of aspirin to prevent pre-eclampsia have found evidence of little or no effect, due to low adherence, low doses and late commencement. Some systematic reviews have conflated studies with different aspirin regimens, and concluded that aspirin is only modestly effective. There should be no doubt that aspirin is a highly effective strategy to prevent and lessen the severity of pre-eclampsia, and reduce its sequelae including preterm delivery and foetal death. However, both ASPRE [3] and ASPIRIN [8] show that aspirin at doses equal or exceeding 75 mg is likely very effective, if started early in pregnancy and taken with good compliance. Available evidence supports commencement from 11 weeks gestation, and future research may support even earlier. What maternity care needs is not despondence. We need universal, early implementation of aspirin for women at higher risk of pre-eclampsia. Dimitrios Siassakos wrote an initial draft of this editorial, with Bethany Atkins. Revisions by Bethany Atkins and Dimitrios Siassakos. The final version of the editorial was reviewed and agreed by both authors. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.