Optimising Aspirin Use for Pre-Eclampsia Prevention: BJOG

In resource-limited contexts, where the likelihood of
healthy survival to adulthood is significantly lower for preterm infants, 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. 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 Right Dose, at the Right Time

The Cochrane review 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 ≥75mg
aspirin than those allocated <75mg aspirin. 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 (ASPRE [3],
BLASP 1998 [4], ERASME 2003 [5]) examining aspirin ≥75mg, 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 (Roberge et al. 2016), and
pre-term pre-eclampsia (Roberge et al. 2018) respectively. The first
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 compared initiation of aspirin
≤16 and >16 weeks, and dosages <100mg and ≥100mg. The risk of preterm
pre-eclampsia was only reduced in the group receiving ≥100mg from ≤16 weeks,
where the effect was strong(RR 0.33, 95% CI 0.19–0.57). However, combining
studies using 50–60mg with studies using 75–81mg likely diluted the effect of
the latter.

Both UK (NICE 2023 [12]) and US guidelines (ACOG 2021 [13])
now endorse commencement before 16 weeks. The EAGeR trial went further, and
randomised women planning conception after pregnancy loss to either 81mg
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.

For the Right Women

Strategies for aspirin administration have historically
either advised universal administration, or risk-factor based screening.
Increasingly, however, clinical prediction models such as the Fetal Medicine
Foundation model 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
<37weeks. 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. 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 nor ASPIRIN
excluded women with CKD. The UK-based Saving Babies Lives initiative recommends
150mg for most women, reduced to 75mg with renal disease to mitigate potential
renal effects of higher doses.

Adherence Matters

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, 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. The low adherence is likely to dilute any true
effect of aspirin in analyses, regardless of the large numbers of individual
patients included.

In the ASPRE trial, 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. However, subgroup analyses suggest that
early (by 16weeks) commencement may prevent pre-eclampsiarelated abruption by
improving placentation, whereas a late start may be detrimental.

Conditions With Special Considerations

HELLP Syndrome

Severe preeclampsia and HELLP syndrome have similar
placental histopathologic findings; both are associated with higher rates of
placental maternal vascular malperfusion (abnormalities inthe placental
vasculature, impairing function) and intrauterine growth restriction. 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. 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.

Chronic Hypertension

A meta-analysis has shown that in women with pre-pregnancy
chronic hypertension, aspirin did not prevent pre-eclampsia, 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.

Diabetes

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, particularly if under-diagnosed
and under-treated. A recent study identified that pregnancies with normal
PAPP-A and abnormal uterine artery Dopplers uncommonly develop preeclampsia,
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
preeclampsia 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 and ASPIRIN
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.

Source: Bethany Atkins, Dimitrios Siassakos;

BJOG: An International Journal of Obstetrics &
Gynaecology, 2025; 0:1–5 https://doi.org/10.1111/1471-0528.18095